Exam A Module 1 Cell Injury & Adaptation

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Autosomal - Chromosomes 1 through 22

Dominant Recessive

X-Linked - X and Y chromosomes

Dominant Recessive

Carcinogenesis

Process resulting in cancer

Dominant and Recessive

The allele whose effects are observable/expressed is called dominant. The allele whose effects are hidden/masked is said to be recessive.

Carcinogenic agent

agent causing cancer

non-reversible conditions

anaplasia and neoplasia

Mesenchymal origin

sarcoma:cancer of a connective tissue structure

Vascular events of acute inflammation

(These events lead to the five cardinal signs of inflammation) -A brief initial vasoconstriction -Vasodilation - causes rubor (redness), tumor (mass) and calor (heat) -Exudation - endothelial cells contract and this together with increased pressure leads to leakage of fluid, plasma proteins and diapedesis of inflammatory cells to form an exudate. -Serous (watery) exudate - not many inflammatory cells or protein -Fibrinous exudate - contains abundant fibrin -Purulent exudate - a large number of inflammatory cells, especially neutrophils,

Vascular events of acute inflammation:

Basophils

"The basophil is the least prevalent granulocyte in the blood. It is very similar to mast cells in the content of its granules and, in addition, is an important source of the cytokine IL-4, which is a key regulator of the adaptive immune response. Although often associated with allergies and asthma, its primary role is yet unknown" (McCance & Huether, 2019, p. 206).

Bacterial Infections

"True" bacteria, filamentous, spirochetes, mycoplasma, rickettsia, and chlamydia Gram-negative versus gram-positive bacteria Various transmission routes Attach through pili (fimbriae) Result in direct confrontation with an individual's defense mechanisms Evasion of these defenses can result in bacteremia and sepsis.

The clotting (coagulation) system is a group of plasma proteins that form a fibrin mesh at an injured or inflamed site. This fibrin mesh:

(1) prevents the spread of infection to adjacent tissues, (2) traps microorganisms and foreign bodies at the site of inflammation for removal by infiltrating cells (e.g., neutrophils and macrophages), (3) forms a clot that stops bleeding, (4) provides a framework for future repair and healing. The main substance in this fibrin mesh is an insoluble protein called fibrin that is the end product of the coagulation cascade.

Tumor markers can be used in four ways:

(1) screening a healthy population or a high risk population for the presence of cancer; (2) making a diagnosis of cancer or of a specific type of cancer; (3) determining the prognosis in a patient; (4) monitoring the course in a patient in remission or while receiving surgery, radiation, or chemotherapy.

Mendelian disease

(identifiable gene that causes disease, and has a predictable inheritance pattern) are conditions with high penetrance, but are rare in occurrence - such as cystic fibrosis, muscular dystrophy and Huntington Disease.

How does the type of protein produced control cell's activity?

- can be structural (builds cell, eg muscle filaments, tubulin skeleton, collagen) - can be enzymes (for glucose use, drug degradation eg liver cell) - can be hormones, antibodies, antigens, clotting factors (made by certain cells for 'export') -There are about 23,000 genes in the human. One gene gives instructions for a small number of proteins

Huntington disease

- cerebral atrophy and neuronal degeneration that usually occurs in middle age, causing abnormalities of emotion, personality, movement and dementia leading to death after about 20 years. It is caused by an abnormal repeat of the nucleotide CAG on the short arm of chromosome 4. There is some normal variation in the number of repeats - a normal person can have up to 34. 34 - 39 confers instability which could be inherited as disease by the offspring. Affected individuals have more than 40 repeats. How does the abnormal gene kill brain cells? The abnormal gene causes the production of an abnormal protein huntingtin; this may mediate apoptosis in affected cells. Since it is a dominant inheritance, then the offspring have a 50% chance of inheriting and developing the disease. Genetic testing is available. Would you want to know if you had Huntington Disease or not?

Synthesized mediators

- in response to injury Prostaglandins Leukotrienes Platelet activating factors Activated oxygen species Nitric oxide Cytokines Interleukins -Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation -Many types -Examples: IL-1 is a proinflammatory cytokine IL-10 is an anti-infla

steps of protein synthesis

- unzipping of DNA (the gene is now called 'open') Steroid hormones influence this step - to open up a portion of the DNA - separating of 2 halves of the double spiral - making of complementary copy ( mRNA) transcription - mRNA exits nucleus to ribosome in cytoplasm - ribosome translates genetic code (sequence of bases on mRNA) translation - tRNA brings the first specific amino acid coded for by the mRNA (the 3 bases of a codon), - another tRNA brings the next amino acid coded for, adds it to first - another tRNA brings the next amino acid etc. etc. builds amino acid chain (protein)

What is transcription?

-.Transcription is the production of mRNA in the nucleus. It is a "reverse" or "mirror" image of the DNA code or sequence of bases. -Amino acids are produced from mRNA, which is bases linked together into chains. mRNA is a "mirror image" of the unzipped DNA bases. We will look at this closer in the next slide. Translation is the decoding the the mRNA and production of polypeptide chains on the ribosomes in the cytoplasm of the cell.

How genes control cells

-A gene contains a code (in the sequences of CGAT) for the production of a small group of proteins -If the cell make one of these proteins according to the instructions in the code the gene is said to be "expressed" -Proteins are functional (enzymes, hormones, receptor molecules) or structural (collagen, actin, myosin) -What the cell looks like, and what it can do depend on which of the total 23,000 genes are expressed

*Endoplasmic Reticulum

-A system of membranes that is found in a cell's cytoplasm and that assists in the production, processing, and transport of proteins and in the production of lipids. -an extensive system of interconnected membranes and flat vesicles that connect various parts of the cell. It functions as a transportation system for substances throughout the cell.

Cystic Fibrosis

-Autosomal Recessive -Cystic fibrosis is an example of an inheritance of a defect of an ion channel protein. -The cystic fibrosis transmembrane regulator (CFTR) is a chloride channel on many epithelial cells - especially in the respiratory and GI systems . -Affected patients have thick, viscous mucus that results in obstruction of respiratory airways. There is also secondary pulmonary infection from the obstructing mucus. -Thick mucus in the gastrointestional tract causes digestive abnormalities by obstructing the pancreatic duct. Pancreatic digestive enzymes cannot be released into the small intestine to digest food. This causes nutritional deficiencies from malabsorption of nutrients and even diabetes. -Cystic fibrosis is a single gene disorder, that is autosomal recessive disorder, requiring a recessive gene from both parents to produce disease. Therefore, both parents must be carriers of an autosomal recessive gene. The occurrence and recurrence risks for each child to develop the disease are 25%. -CFTR gene on Chromosome 7 is the gene that can produce cystic fibrosis. -If each parent is a carrier (they each have one dominant gene (normal) and one recessive gene (defective). Because the dominant gene is expressed, the parents do not have cystic fibrosis. Although they have one defective gene in their genotypes, it is not expressed in their phenotypes. The possibilities for their offspring (with EACH pregnancy), is: 25% normal (two dominant genes) - one from the mother and one from the father 50% carrier (one dominant and one recessive gene) - mother could contribute either the dominant or the recessive gene, and father could contribute either the dominant or the recessive gene. 25% affected (two recessive genes

Mutations

-Can be inborn if one or both parents passes on abnormal DNA in egg or sperm -Can be acquired through: ~Exposure of DNA to ionizing radiation ~Exposure of DNA to environmental chemicals ~Viral DNA insertion into host DNA ~Mistakes in replication of DNA -inborn mutations are inherited from parents (germ cells - eggs and sperm), and acquired mutations are related to DNA damage in somatic cells. This damage can be radiation, chemicals, viruses, or mistakes in DNA replication during cell division - mitosis.

5 types of tumors

-Carcinomas result from altered epithelial cells, which cover the surface of our skin and internal organs. Most cancers are carcinomas. Lung carcinoma -Sarcomas result from changes in muscle, bone, fat, or connective tissue. osteosarcoma -Leukemia results from malignant white blood cells. -Lymphoma is a cancer of the lymphatic system cells that derive from bone marrow. plasmacytomas -Myelomas are cancers of specialized white blood cells that make antibodies (plasma cells).

Cathelicdins

-Cathelicidins have a linear α-helical shape, and only one is known to function in humans. In contrast, about 50 different defensins have been identified, with a triple-stranded β-sheet structure. -Can insert into bacterial cholesterol-free cell membranes, and disrupt the membranes. -Are produced by monocytes, macrophages, and neutrophils - components of the inflammatory response. -Stored in neutrophils, mast cells, and a variety of epithelial cells.

Components of Inflammation: Cellular Surface Receptors

-Cell surface receptors -Pattern recognition receptors (PRRs) -Pathogen-associated molecular patterns (PAMPs) -Toll-like receptors (TLRs) -Complement receptors -Scavenger receptors -Integrins Cells of immunity must recognize and respond to damaged cells or to pathogenic microorganisms. These cell have receptors on their cell surfaces that specifically bind to substances (ligands) produced during tissue damage or infection.

Targets of cell injury:common to all injurious agents

-Cellular energy production (respiration): integrity of mitochondria is damaged -Cell membrane integrity: impairs ion transport and fluid balance. This causes cellular edema and loss of function to cells. Ex: is neuronal transmission in the brain. -In cerebral edema: neurons become swollen and lose there ability to transmit impulses. Cell membrane cannot depolarize and repolarize properly, because Na+ and K+ ions cannot properly cross the cell membrane, changing the electrical charge on the membrane and propagate an impulse. -DNA integrity (integrity of appratus): causing changes in the genome (number of chromosomes); changes in a single chromosome (duplications, deletions); or changes in a single gene (mutations, repeats, deletions, translocations). -Synthesis of proteins by the cell: can impair cell structure (and therefore cell function), hormone production.

cytokines

-Cellular products (soluble factors) important in the acute inflammatory response -Interleukins - produced by lymphocytes or macrophages -Lymphokines - produced by T cells -Chemokines - produced by a variety of cells, they cause chemotaxis (directed motion) of lymphocytes -Interferons (IFN)-host-specific defense against viral infections, human interferons are produced by various inflammatory cells. IFN alpha and beta are anti-inflammatory, while IFN gamma is proinflammatory and enhances cellular immunity.

Plasma protein systems triggered by the acute inflammatory response

-Complement - can be activated by immune system or by less specific products. ~Classic pathway - activated by antigen-antibody complex ~Alternate pathway - products such as bacterial or fungal cell wall polysaccharides. -Clotting system - fibrin is formed to limit infections and the resulting clot helps to stop hemorrhage. -Kinin system (e.g. bradykinin) - vasodilation, pain, increased vascular permeability.

Mutations are PERMANENT changes in structure of DNA

-Genome: whole set 2n- Polyploidy 4n, 8n etc. -Chromosomal: change in chromosome: ~Number= trisomy, monosomy ~Structure=deletion, translocation, breakage etc. -Gene: Point mutation=single base sequence ~Deletions ~Insertions ~Repeats

Cellular products (soluble factors) important in the acute inflammatory response are often called cytokines:

-Control inflammatory response ~Pro-inflammatory ~Anti-inflammatory These products (chemokines or cytokines) are either proinflammatory or anti-inflammatory - enhancing or inhibiting the inflammatory response. The molecules of chemokines or cytokines diffuse over short distances, bind to the appropriate target cell receptors, and affect the function of the target cells, to participate in the inflammatory response. The magnitude or degree of inflammation is controlled by the cytokines or chemical mediators.

Adult Multifactorial Diseases

-Coronary heart disease: ~Potential MI caused by atherosclerosis ~Risk increases if: There are more affected relatives Affected relatives are female rather than male Age of onset is younger than 55 years -Autosomal dominant familial hypercholesterolemia, high-fat diet, lack of exercise, smoking, and obesity Other: Hypertension Diabetes - Type II Obesity Alzheimer Disease Psychiatric Disorders Alcoholism Breast Cancer Colorectal Cancer

MODULE 3 (3) Emerging Infections

-Deaths from infection account for about one-third of deaths worldwide. -Infectious disease is a significant cause of death and morbidity because of ~The reemergence of old infections thought to be controlled -small pox ~The emergence of previously unknown infections-Zika and Corona-19 viruses ~The development of infections resistant to multiple antibiotics- TB, HIV ~More than 40 unknown or newly presenting infections have arisen within 1 generation (20 years).

Knowledge Check about Cancer

-Does cancer of the breast behave like cancer of the esophagus, lung, or bone marrow? Yes -All malignant cancers have the same characteristics: 1. Evading growth suppressors 2. Enabling replicative immortality 3. Tumor promoting inflammation 4. Activating invasion and metastasis 5. Genomic instability 6. Inducing angiogenesis 7. Resisting cell death 8. Deregulating cellular energetics 9. Sustaining proliferative signaling 10. Avoiding immune -Is cancer of the breast identical in all women? No genetic causes are different for each individual.

Hereditary Causes:

-Due to inhereted abnormal genes. -FAP - gene C5, Adenocarcinoma colon -Retinoblastoma - Rb gene - (C13) -Neuroblastoma - (C17) -Trisomy 21 - Down's sy - leukemias -BRCA1 and BRCA2 - breast cancer

Diseases of inflammation

-End in 'itis' -Inflammation of bladder? Gall bladder? Stomach? Meninges? Airways? Joints? Skin? Brain? Mediastinum? Large intestine? Iris? Tongue? Gums? Nerves? Bone? Is tissue always damaged as the result of inflammation?

Cellular components of the acute inflammatory response include

-Endothelial cells - chemical mediators cause contraction to increase vascular permeability. -Phagocytic cells -Cells in the blood stream undergo margination and diapedesis (travel through the capillary wall) to the tissues where they become phagocytic. Neutrophils and macrophages (derived from blood monocytes) are phagocytic. -Mast cells, platelets, neutrophils, macrophages - release a variety of chemical mediators, for example histamine. Mast cells produce leukotrienes and prostaglandins. Both are derivatives of arachidonic acid and the pathways involved are important in understanding how some agents block the inflammatory response. Two paths are involved: ~Lymphocytes, in addition to their specific immune response, produce non-specific lymphokines that affect other inflammatory cells including other lymphocytes. Examples of lymphokines are interleukins and interferons, important mediators of inflammation. ~Eosinophils - characteristic of allergic response, parasites

*active transport

-Energy-requiring process that moves material across a cell membrane against a concentration difference -used when cells use energy to move ions against an electrical or chemical gradient.

Eosinophils

-Eosinophil are another type of granular leukocytes. They have two specific functions: ~primary defense against parasites ~regulate vascular mediators released from mast cells. - Control the intensity and spread of the inflammatory response Regulation of mast cell inflammatory mediators is a critical function of eosinophils. Acute inflammatory response is usually needed only in a limited area and for a short amount of time. Eosinophils provide the control mechanism to prevent biochemical mediators from evoking more inflammation than is needed. When mast cells degranulate and release cytokines, they also produce ECF-A, which attracts eosinophils to the site of inflammation. Eosinophil lysosomes contain enzymes that degrade vasoactive molecules (the cytokines that produce vasodilation and increase vascular permeability), which controls the vascular effects of inflammation.

Summary of Acute Inflammation

-Events: Cellular injury Cytokines Cellular components Vascular responses Plasma protein cascades -Outcomes: Prevent infection Control inflammatory process Activate adaptive immunity - humoral & cellular immunity Prepare the site of injury for healing

Expressitivity

-Expressivity is the variation in a phenotype associated with a particular genotype -This can be caused by modifier genes Examples: ~von Recklinghausen disease ~Autosomal dominant ~Long arm of chromosome #17 ~Disease varies from dark spots on the ~skin to malignant neurofibromas, ~scoliosis, gliomas, neuromas, etc.

Second Line of Defense: The Inflammatory Response

-Fever -Interferons -Complement, kinin and clotting cascades -Phagocytosis - macrophages, neutrophils -Natural Killer cells -Inflammation

MAST CELL DEGRANULATION

-Histamine: Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the dilation of the postcapillary venules Retraction of endothelial cells lining the capillaries Receptors H1 receptor (proinflammatory) H2 receptor (anti-inflammatory) -Chemotactic factors Neutrophil chemotactic factor Attracts neutrophils -Eosinophil chemotactic factor of anaphylaxis (ECF-A) Attracts eosinophils

Paraneoplastic syndromes and several mechanisms are involved:

-Hormonal a. Cushing syndrome - ACTH produced by pituitary tumor, lung cancer. Excess secretion of ACTH from lung tumors b. Syndrome of inappropriate ADH (SIADH) - usually lung ca c. Hypercalcemia - PTH d. Hypoglycemia - insulin-like hormones e. Carcinoid syndrome - serotonin, bradykinin f. Polycythemia - erythropoetin g. Excess secretion of ADH from lung tumors—> hyponatremia h. Insulin secreting pancreatic tumors —> hypoglycemia I. Excess epinephrine/norepinephrine —> hypertension -Neurologic -Renal: Membranous glomerulonephritis -Rheumatic -Immunologic: myasthenia gravis, possibly in dermatologic manifestations as in dermatomyositis, acanthosis nigricans -Other tumor products - for example Trousseau syndrome in which thromboses are associated with cancers producing mucin, especially pancreatic carcinoma and other mucinous adenocarcinomas

Causes of cell injury

-Hypoxic cell injury -Free radical injury (oxidative stress) -Physical agents of injury -Chemical injury -Infectious agent injury -Injurious immunological reactions -Genetic defects -Nutritional imbalances

Classes

-IgG is the most abundant class of immunoglobulins; providing 80% to 85% of those circulating immunoglobulins. They provide most of the protective activity against infections. Due to selective transport across the placenta, maternal IgG is also the major class of antibody found in blood of the fetus and newborn. Four subclasses of IgG include: IgG1, IgG2, IgG3, and IgG4. -IgA can be divided into two subclasses, IgA1 and IgA2. IgA1 molecules are found in the blood, whereas IgA2 is found in body secretions. The IgA molecules are inside mucosal epithelial cells, which protect these immunoglobulins against degradation by enzymes also found in the secretions. -IgM is the largest of the immunoglobulins , and is the first antibody produced during the initial response to an antigen. IgM is synthesized early in neonatal life, and is present in the fetus and neonate. -IgD is found in very low concentrations in the blood, where they do not appear to have a known function. IgD is located primarily on the surface of developing B lymphocytes, where they function as one type of B-cell antigen receptor. -IgE is the least concentrated of any of the immunoglobulin classes in the circulation. It appears to have very specialized functions as a

Geriatric mechanisms of self-defense

-Impaired or delayed inflammation is likely a result of chronic illness. ~Diabetes and cardiovascular disease, among others -Medications may interfere with wound healing. Infections are more common in older adults. -Lungs, urinary tract, and skin are often affected. -Older adults have diminished immune function. -Expression and function of several, if not all, TLRs, are decreased.

Multiple Hit Theory

-Inactivation of tumor suppressor gene -Mutation inactivates DNA repair gene -Mutation of proto-oncogene creates an oncogene -Mutation inactivates more tumor suppressor genes -Cancer develops.

The Chronic Inflammatory Response.

-Inflammation usually becomes chronic because of the persistence of an infection, an antibody, or a foreign body in the wound. -Chronic inflammation lasts 2 weeks or longer regardless of cause, and have different histology and mechanisms than acute inflammation. - Chronic inflammation is usually preceded by an unsuccessful acute inflammatory response. However, chronic inflammation can occur also as a distinct process without previous acute inflammation. -Chronic inflammation is characterized by the persistence of many of the processes of acute inflammation. In addition, the presence of large amounts of neutrophil degranulation and death, the activation of lymphocytes, and the concurrent activation of fibroblasts result in the release of mediators that induce the infiltration of more lymphocytes and monocytes/macrophages and the beginning of wound healing and tissue repair

Multiple mutations are required to produce cancer.

-Inherited mutations that affect repair of DNA abnormalities - DNA replication mistakes are NOT corrected. -Oncogenes that promote accelerated cell division are activated - run away cell division - cell become LESS differentiated, more primitive - like fetal cells that have not taken on specific functions or types of cells in tissues or organs. -Gene that suppress tumor growth are inactivated - So the genes that stop accelerated cell division don't function. -Apoptosis is shut off. So cells that are not structured, or do not function correctly are allowed to replicate, in stead of being killed off.

Radiation Carcinogenesis:

-Ionizing radiation 🡪 disjunction 🡪 random fusion 🡪 mutation. -X Ray workers - Leukemia -Radio-isotopes - Thyroid carcinoma -Atomic explosion - Skin cancer, Leukemia

*Lysosomes

-cell organelle filled with enzymes needed to break down certain materials in the cell -serves as the digestive capacity of the cell. Their small sacs contain powerful hydrolytic enzymes that can break down cell excess, worn cellular components, and foreign substances.

MAST CELL SYNTHESIS OF MEDIATORS

-Leukotrienes Product of arachidonic acid from mast cell membranes Similar effects to histamine in later stages -Prostaglandins Similar effects to leukotrienes; they also induce pain -Platelet-activating factor Similar effect to leukotrienes and platelet activation

Oncogenes - the accelerator

-Oncogenes are abnormal forms of normal genes (proto-oncogenes) that regulate cell growth. Mutation of these genes may result in direct and continuous stimulation of the molecular biologic pathways (eg, intracellular signal transduction pathways, transcription factors, secreted growth factors) that control cellular growth and division. -There are > 100 known oncogenes that may contribute to human neoplastic transformation. -The ras gene encodes the Ras protein, which regulates cell division. Mutations may result in the inappropriate activation of the Ras protein, leading to uncontrolled cell growth and division. The Ras protein is abnormal in about 25% of human cancers. - Other oncogenes in specific cancers: various protein kinases (bladder cancer, breast cancer), bcr-abl (chronic myelocytic leukemia, B-cell acute lymphocytic leukemia), C-myc (small cell lung cancer), N-myc (small cell lung cancer, neuroblastoma), and C-erb B-2 (breast cancer). -Specific oncogenes may have important implications for diagnosis, therapy - response to chemo therapy, and prognosis

The immune system is continually challenged by foreign antigens (substances that are not part of the body, they are non-self):

-Pathogens - viruses, bacteria, fungi, or parasites -Noninfectious environmental agents such as pollens, foods, and bee venom -Clinically derived drugs, vaccines, transfusions, and transplanted tissues. The adaptive immune response is primarily designed to provide long-term protection (i.e., immunity) against specific invading pathogens and antigens; that is, it has a "memory" function. -The active components of the adaptive immunity include: serum proteins—immunoglobulins, or antibodies White blood cells—lymphocytes (McCance & Huether, 2019).

multifactorial inheritance

-Polygenic: Variation in traits caused by the effects of multiple genes -Multifactorial trait: Variation in traits caused by genetic and environmental or lifestyle factors -Quantitative traits: Traits that are measured on a continuous numeric scale

These bacteria contribute to our first line of defense, or innate immunity against pathogenic microorganisms. They enhance immunity by several mechanisms:

-compete with pathogens for nutrients and block attachment to the epithelium. -produce chemicals (ammonia, phenols, indoles, and other toxic materials) and toxic proteins (bacteriocins) that inhibit colonization by pathogenic microorganisms. -Help direct the adaptive immune system against pathogens.

Causes of cell injury

-Reduced oxygen: Ischemia, infarction -Chemical : ROS -Chemical: toxins, drugs -Nutritional deficiencies -Physical injury -Biological agents - viruses, bacteria etc. -Immune reactions -Genetic abnormality -Thermal injury

Single gene disorders

-Single gene disorders are the cause of many genetic diseases. They may be acquired by spontaneous mutations in somatic cells. Or mutations by DNA damage from virus, radiation, chemical exposures or drugs. -The mutations can also be inherited, and must be in the egg or the sperm (germ line mutation). Autosomal dominant - Abnormal allele is dominant, normal allele is recessive, and the genes exist on a pair of autosomes

Passengers and Drivers

-Some mutations can contribute to cancer progression (e.g., mutations in p53 or RAS). They are "driver mutations"; they promote the progression of cancer. Ex. When proto-oncogenes mutate, they become oncogenes, abnormally accelerating cell division and causing the proliferation of cells. The accelerator gets "stuck". The driver mutations are controlling cell division. Other driver mutations include: Suppression of genes that promote apoptosis of defective cells. If defective cells are not identified and destroyed by apoptosis. Then the defective cells will continue to proliferate. If genes that repair defects in DNA replication are turned off or suppressed, then these errors in DNA replication will continue to be replicated, as the cancer cells proliferate. -Conversely, not all mutations in cancer contribute to the malignancy. Some are just random events, and are referred to as "passenger mutations"; they are just along for the ride. As the genetics of cancer is analyzed, the goal is to determine which mutations are drivers and which are passengers. Ex. tumor-suppressor genes encode proteins that in their normal state negatively regulate (halt, or "put the brakes on") proliferation. When a tumor-suppressor gene mutates, the "brakes are lost". So there is nothing to stop the oncogenes from accelerating cell division.

DNA Repair

-Telomeres are repetitive, non-coding sequences (TTAGGG in humans) at the end of chromosomes. Telomere shortening during cell division limits a cell's life span -Telomeres can be lengthened by telomerase, an enzyme that adds TTAGGG repeats

Penetrance

-The percentage of individuals with a specific genotype who also express the expected phenotype: ~Incomplete penetrance= Individual who has the gene for a disease but does not express the disease ~Retinoblastoma (eye tumor in children) demonstrates incomplete penetrance (90%) ~Age-related penetrance

pattern recognition receptors (PRRs).

-The receptors of the cells of inflammation These receptors recognize: -molecular "patterns" on infectious agents or their products (pathogen-associated molecular patterns, or PAMPs), -products of cellular damage (necrosis or apoptosis; damage-associated molecular patterns, or DAMPs). -PRRs are generally found on cells that interface with the environment (i.e., skin, respiratory tract, gastrointestinal tract, genitourinary tract). Here they monitor for products of cellular damage and potentially infectious microorganisms. Most PRRs are on the cell surface, but some are secreted or intracellular.

Third Line of Defense

-The third line of defense is adaptive or acquired immunity. Once external barriers have been compromised (1st line) and inflammation (2nd line) has been activated, the adaptive immune response is called into action. The molecules and cells of the immune response are closely integrated with those of the innate response (1st and 2nd lines of defense). Both systems are essential for complete protection against infectious disease: ~ inflammation is relatively rapid, nonspecific, and short-lived ~adaptive immunity is slower acting, specific, and very long-lived. -So, inflammation is the "first responder" that contains the initial injury and slows spread of infection. And, adaptive immunity slowly augments the initial defenses against infection and provides long-term security against reinfection.

Effects of mutated DNA

-They can have no effect - we all have slight variations in the structure of our DNA -Abnormal DNA codes for ineffective proteins - 'missense; e.g. cystic fibrosis protein is ineffective -Abnormal DNA can stop protein production - 'silencing' e.g. failure of cell cycling regulation (rate of cell division) in cancer -Abnormal DNA can produce damaging proteins - e.g.'huntingtin' -The more severe the changes are in the genotype, the more abnormal the effects on the phenotype

Turner Syndrome

-Turner syndrome is caused by a missing or incomplete X chromosome. -People who have Turner syndrome have one X chromosome, and develop phenotypically as females. -The genes affected are involved in growth and sexual development, which is why girls with the disorder are shorter than normal and have abnormal sexual characteristics. Genotype is: 45XO (no second X or Y chromosome, to make 46 chromosomes). This is a monosomy of the sex chromosomes. -Turner syndrome is caused by nondisjunction, where a pair of sex chromosomes fails to separate during meiosis - the formation of an egg or sperm. Therefore, when an abnormal gamete unites with a normal gamete to form a fertilized egg, that embryo is missing one of the sex chromosomes (X rather than XX). As the embryo grows and the cells divide, every cell in the fetus will be missing one of the X chromosomes. -The abnormality is not inherited from an affected parent (not passed down from parent to child) because women with Turner syndrome are usually sterile and cannot have children. -clinical manifestations of Turner Syndrome: The missing SHOX gene (long-bone growth) causes unusually short stature. Other missing genes regulate ovarian development, which influences sexual characteristics and infertility.

innate immunity

-What we are born with -We have physical defenses (skin, mucosa, secretions) and the inflammatory response that make up our "inherited" or "inborn" immunity. This is called innate immunity. -It is our immediate, generalized response to invasion by a antigen or pathogen. -This comprises our first and second lines of defense.

adaptive immunity

-What we develop in response to meeting antigens -Inflammation sets into motion long-term, specific immune response, especially to infecting microorganisms (pathogens). This "targeted" immune response is called adaptive immunity. -It is acquired and is specific to the antigens or pathogens we are exposed to. - This specific immune response is slow to develop, but it also develops "memory" for the invading microorganisms, so it will last a lifetime. - This is the third line of defense.

Atrophy

-decrease in size of a cell or organ. Caused by: decreased workload, use, pressure, blood supply, nutrition, hormonal stimulation and nervous stimuli -usually a result of disuse, nutritional or oxygen deprivation, aging, diminished endocrine stimulation, or denervation (lack of nerve stimulation in peripheral muscles caused by injury to motor nerves). -Less endoplasmic reticulum and mitochondria -Decreased protein synthesis, increased catabolism, or both

Paraneoplastic syndromes

-effects that occur at sites distant from a tumor or its metastases: abnormal cell products -Secondary to substances secreted by the tumor or may be a result of antibodies directed against tumors that cross-react with other tissue. May occur in any organ or physiologic system. -Up to 20% of cancer patients experience paraneoplastic syndromes, often unrecognized. -The most common cancers associated with paraneoplastic syndromes: lung, renal, hepatocellular, leukemias, lymphomas, breast and ovarian, neural, gastric and pancreatic tumors.

General paraneoplastic symptoms

-fever, night sweats, anorexia, and cachexia -may arise from release of lymphokines involved in the immune response or from mediators involved in tumor cell death, such as tumor necrosis factor-α. -itching (eg, leukemia, lymphomas) may result from hypereosinophilia -Flushing may be related to tumor-generated circulating vasoactive substances (eg, prostaglandins).

Hyperplasia

-increase in numbers of cells. Physiologic hyperplasia is compensatory or hormonal. Compensatory hyperplasia- is an adaptive mechanism that enables certain organs to regenerate Hormonal hyperplasia occurs in estrogen-dependent organs, such as the uterus and breast.

Cytoplasm

-jellylike substance that makes up all living material in cell besides nucleus -a solution containing water, electrolytes, proteins, fats, and glycogen molecules. Contains organelles: (1) the ribosomes, (2) the ER, (3) the Golgi complex, (4) the mitochondria, and (5) the lysosomes.

Progeria

-lack of genome maintenance and repair -Abnormal aging of children -Inability to repair DNA defects in chromosomes

α-defensins

-often require activation by proteolytic enzymes -In the granules of neutrophils - kill bacteria

Once the phagocytic cells enter the inflammatory site, the process of phagocytosis involves four steps:

-opsonization (recognition of the target and adherence of the phagocyte to it); -engulfment (ingestion or endocytosis) and formation of phagosome; -fusion of the phagosome with lysosomal granules within the phagocyte to form a phagolysosome; and -destruction of the target

*Golgi apparatus

-packages proteins for transport -stack of membranes in the cell that modifies, sorts, and packages proteins from the endoplasmic reticulum -composed of stacks of thin, flattened vesicles or sacs. Their role is to take the substances produced in the ER, modify them, and package them into secretory granules or vesicles.

Examples of mutations that cause oncogene activation:

-point mutations - changes to a single gene, usually a few bases pairs in the DNA sequence -Translocation - large changes in DNA, where a portion of one chromosome is re-located to another chromosome (genes switch location on a chromosome during cell replication). Translocations activates oncogenes in two ways: ~excess production of a proliferation factor- ~production of proteins with growth-promoting properties - translocation of parts of chromsomes 9 and 21 can cause leukemia. -gene amplification (multiple copies of the gene),

Inflammation

-protective response that serves to bring defense & healing mechanisms to the site of injury. -Inflammation will result is the development of microscopic changes in the inflamed site, and characteristic clinical manifestations (erythema, edema, heat, pain, clotting, pus).

Dysplasia

-replacement of normal cells for abnormal cells. -abnormal cellular growth, resulting in cells that vary in size, shape, and organization. It most often refers to proliferation of precancerous cells. -Disorganized in morphology (size, shape and organization of mature cells). -Is not a true adaptive process, but is related to hyperplasia - atypical hyperplasia -Regress to an immature cell type -Are not cancer, but could be a precursor to cancer -If stimulus is removed, dysplagic changes can be reversed

Collectins

-secreted in the lung to protect against respiratory infections -Includes surfactant proteins A through D and mannose-binding lectin. -Glycoproteins

Bactericidal/permeability-inducing protein

-stored in neutrophils and intestinal epithelium -reacts with lipopolysaccharide on the surface of gram-negative bacteria, resulting in bacterial lysis.

CIS lesions can have one of the following three fates:

-they can remain stable for a long time, -they can progress to invasive and metastatic cancers, or -they can regress and disappear.

TP53 Gene - the main brake Tumor Suppressor Genes

-tp53 senses DNA damage, and induces G1 arrest (in cell division process) and induces DNA repair process. -Cells with un-repairable DNA are directed to apoptosis by the tp53 gene -"tp53 is a guardian of the genome" -Its homozygous loss (loss of gene function in both copies of the gene - in homologous chromosomes) - leads to accumulation of damaged DNA resulting in malignancy -Homozygous loss of tp53 is seen in virtually every type of cancer - two mutations, one in each copy of the gene -Over half of human malignant cells show loss of tp53

Tumor markers : abnormal genes code for abnormal cell products

-α-Fetoprotein : hepatocellular and testicular carcinomas -CEA carcinoembryonic antigen: colon cancer - β-HCG, human chorionic gonadotropin: choriocarcinoma and testicular carcinoma, -IgG serum immunoglobulins in multiple myeloma -CA 125: ovarian cancer -CA 27-29: breast cancer -PSA, prostate-specific antigen and prostatic acid phosphatase: prostate cancer.

how mast cells become sensitized in Type I hypersensitivity.

1) In the first exposure to an antigen, a dendritic cell within the nasal epithelium exposes a Th2 cell (T helper) to the antigen (pollen) that has been inhaled into the nasal passages. 2) This antigen is then presented to an immunocompetent B cell is converted to a plasma cell, which produces IgE antibodies to the antigen. 3) The IgE antibodies attach themselves to mast cell IgE Fc receptors in the mucus membranes. The mast cells are now SENSITIZED. 4) In the second exposure to the antigen, it reacts with the IgE antibodies, causing degranulation of the mast cells. This degranulation causes release of histamine and other mediators, producing the type I hypersensitivity symptoms. - 5)The release of primary and secondary mediators from the degranulated mast cells causes increased capillary dilation and permeability (edema), mucus production, and smooth muscle constriction (bronchoconstriction) (McCance & Huether, 2019, p. 256.

Activation of B Cells

1. B-cell receptor (BCR) complex is located on the surface of B lymphocytes, and its purpose is to recognize antigen, and communicate that recognition to the cell's nucleus. 2. B-cell activation starts when a B cell receptor meets its own specific antigen (brown rectangles attach to tan "Y" BCR) The antigen is ingested into the immunocompetent B cell and the antigen fragment is expressed on the MHC class II molecule of the B cell. (tan dot held in the MHC class II molecule at the bottom of the B-cell) 3. Helper Th2 cell that is sensitized to the antigen, helps the immunocompetent B cell to become a plasma cell or a Memory B cell. (connection between the MHC class II - antigen - TCR - CD4 - CD40L, along with interleukin signal). 4. There is an explosion of cloning of plasma cells and memory cells. This is controlled by lymphokines secreted by the T helper cells 5. Activated B cell is a plasma cell (antibody factory) 6. Antibodies that are released into the bloodstream, search out their specific antigen, and attach to the antigens, forming antigen-antibody complexes. 7.These antigen-antibody complexes are eliminated by either the complement cascade (remember inflammation last module) or by the liver or the spleen. 8. Also produces memory B's - which are available for a reinfection by the antigen (McCance & Huether, 2019).

"When secreted in large amounts, TNF-α has systemic effects as well:

1. Induces fever by acting as an endogenous pyrogen 2. Causes increased synthesis of proinflammatory proteins by the liver 3. Causes muscle wasting (cachexia) and intravascular thrombosis as a consequence of prolonged production in cases of severe infection or cancer 4. Probably responsible for fatalities from shock caused by gram-negative bacterial infections" (McCance et al., 2019, p. 201).

There are several steps that must be present for metastasis to occur:

1. Invasion, or local spread, which might occur by direct tumor extension. Eventually, cells migrate away from the primary tumor and invade the surrounding tissues. 2. Mechanisms important in local invasion include: -recruitment of macrophages to the primary tumor, to promote digestion of connective tissue capsules and other structural barriers by secreted proteases -changes in cell-to-cell adhesion, often by changes in the expression of cell adhesion molecules such as cadherins and integrins, making the cancer cells more slippery and mobile -increased motility of individual tumor cell, by breaking down the capsule around the tumor in order to initiate local spread. The mechanism of capsular dissolution may result from production of enzymes by the tumor or the influx of leukocytes. 3. To transition from local to distant metastasis, the cancer cells must invade local blood and lymphatic vessels. -facilitated by stimulation of neoangiogenesis and lymphangiogenesis by factors such as VEGF. 4. Metastatic cells must be able to survive in the circulation, attach in an appropriate new environment, and multiply to produce an entire new tumor. A cancer's ability to establish a metastatic lesion requires that the cancer attach to specific receptors and survive in the new environment. Metastasis contributes to cancer pain and is the major cause of death from cancer.

Line of defense

1. Natural barriers - physical, mechanical, and biochemical barriers at our body surfaces that prevent invasion by pathogens. 2. Inflammatory response - when the first line of defense is breached. Rapid activation of biochemical and cellular responses to protect the body from further injury. Biochemical includes cytokines (chemical signaling) to recruit our "immune soldiers" - neutrophils, macrophages, natural killer lymphocytes. The inflammatory response is non-specific, so it is very similar any type of invasion or injury. 3. Specific immunity - humoral immunity (antibodies) and cellular immunity (T lymphocytes). We will look at the third line of defense next week.

B-Cell Development in the Bone Marrow.

1. Pro-B cells (very immature B cells) bind to a stromal cells and initiates expression of the surface molecule CD45R and begins genetic rearrangements of the genes that control antibody production. 2. Pre-B-cells complete rearrangement of DNA for antibody production and begin expression of cytoplasmic mu (μ) heavy chain. 3. The μ- chain is incorporated into a pre-B-cell receptor (pBCR). The cell also up-regulates the IL-7 receptor (IL-7R), which interacts with IL-7 produced by the stromal cells to promote the differentiation of B cells.. 4. Some pBCRs have specificities toward self-antigen. And these cells go through apoptosis - negative selection. 5. The surviving immature B cells rearrange DNA further and express a BCR (B cell receptor) consisting of light chain and the μ-heavy chain, progressing toward B cell maturity. In the mature B cell, there is expression of sIgM and sIgD, which are receptors for antibody production 6. The immunocompetent B cell is released from the bone marrow, ready to find it's designated antigen. (McCance & Huether, 2019).

Write the letters in the correct order for the sequence of events that occur during the synthesis of a protein

1. RNA polymerase binds to DNA promoter region 2.Transcription 3. mRNA is spliced to remove noncoding sections 4. mRNA leaves the nucleu 5.Translation

Activation of the complement cascade can be done in three different pathways. The pathways converge at the third component (C3). These methods of activation include:

1.Classical pathway: activated by proteins of the adaptive immune system (antibodies) bound to their specific antigens - pictured on slide 2.Lectin pathway: activated by mannose-containing bacterial carbohydrates - so the cell walls of the bacteria can activate complement 3.Alternative pathway: activated by gram-negative bacterial and fungal cell wall polysaccharides

Tuberculous Granuloma.

A central area of amorphous caseous necrosis (C) is surrounded by a zone of lymphocytes (L) and enlarged epithelioid cells (E). Activated macrophages frequently fuse to form multinucleated cells (Langhans giant cells). In tuberculoid granulomas the nuclei of the giant cells move to the cellular margins in a horseshoe-like formation.

Aneuploidy

A somatic cell that does not contain a multiple of 23 chromosomes A cell containing three copies of one chromosome is trisomic (trisomy) Monosomy is the presence of only one copy of any chromosome Monosomy is often fatal, but infants can survive with trisomy of certain chromosomes "It is better to have extra than less"

Gram-Positive and Gram-Negative Bacteria.

A. The structure of the bacterial cell wall determines its staining characteristics with Gram stain. Gram-positive bacteria have a thick layer of peptidoglycan (left). Gram-negative bacteria have a thin peptidoglycan layer and an outer membrane of lipopolysaccharide (LPS) (right). B. Example of a gram-positive (darkly stained microorganisms, arrow) group A Streptococcus. This microorganism consists of cocci that frequently form chains. C. Example of a gram-negative (pink microorganisms, arrow) Neisseria meningitidis in cerebrospinal fluid. Neisseria form complexes of two cocci (diplococci).

Oncogenes and Tumor-Suppressor Genes:

Accelerators and Brakes (Use the car as a metaphor)

Activation of Tc cells involves interactions between:

Activated Th1 cell, APC, and immunocompetent T cell

Molecular Basis of Cancer:

Activation of growth promoting proto-oncogenes leading to oncogenes (accelerator stuck) Loss of cancer suppressor genes (brakes lost) Mutation of genes promoting apoptosis (ejector seat broken) Mutations in genes regulating DNA repair (servo mechanism broken)

Acute inflammatory response

Acute inflammatory response The first event is cell injury - from mechanical trauma, oxygen or nutrient deprivation (hypoxia/ischemia), chemical agents, infections due to micro-organisms (bacteria, fungi, viruses, parasites), heat or cold injury, ionizing radiation, presence of dead cells (the body's own or foreign), ultraviolet radiation, and the presence of foreign bodies such as sutures. The response to injury begins very quickly (acute inflammatory response), and consists of cellular response + cytokines + plasma protein systems

Active vs. Passive Immunity

Adaptive immunity can be active or passive, depending on how the person is exposed to the antigens that produce either antibodies or T cells. Active immunity is produced by: After natural exposure to an antigen After artificial exposure to an antigen via immunization Passive immunity does not involve the host's immune response at all. Rather, passive immunity occurs when preformed antibodies or T lymphocytes are transferred from a donor to the recipient. Natural acquisition occurs with the passage of maternal antibodies across the placenta to the fetus or in breast milk Artificially, is through the administration of immunoglobulins from donors who have been exposed to the antigen (pathogen) and produced antibodies. Active immunity is long-lived (usually a lifetime), passive immunity is only temporary because the donor's antibodies or T cells are eventually destroyed. Types of immunity Natural resistance - present at birth and species specific, not immunity. (For example, human does not contract canine distemper.) Acquired immunity This can be divided into: a. Active immunity - immune response of the host due to i. Natural exposure - immunity from contracting the disease - Antibodies developed from having Hepatitis B after exposure to the virus ii Immunization - immunity from a vaccine (antigen) - Immunization with Hepatitis B antigen to develop antibodies to Hepatitis B virus b. Passive immunity - administration of preformed antibodies or cells. Examples: i Maternal antibodies transferred transplacentally to the fetus, breast milk ii Immune serum (temporary) from pooled human sources - such as immunoglobulins given for Hepatitis B exposure

Natural Killer T lymphocytes

Agranular WBCs

Monocytes and macrophages

Agranular WBCs -Monocytes are produced in the bone marrow, enter the circulation, and migrate to the inflammatory site, where they develop into macrophages -Monocytes are the largest blood cells that have an indented or horseshoe shaped nucleus. They are non-specific phagocytes, meaning they attack pathogens without developing a specific attraction to an antigen (protein on the pathogen's cell membrane). - Monocytes are produced in the bone marrow, and are found in lymph nodes, liver, pancreas, respiratory tract. When monocytes become activated (by chemical mediators), they migrate to the site of injury where then change into macrophages -Macrophages are active phagocytes and are important initiators of the inflammatory response, which is necessary for initiation of the second line of defense and tissue repair. -Macrophages typically arrive at the inflammatory site 3 to 7 days after neutrophils -Macrophage activation results in increased size, plasma membrane area, glucose metabolism, number of lysosomes, and secretory products

Recognize Self from Non-self; self antigens

An antigen is a part of a molecule that can mobilize the immune system. An antigen can be a whole non-self cell, a bacterium, a virus, an MHC marker protein or even a portion of a protein from a foreign organism. MHC proteins are SELF labels - genetically coded

Aneuploidy of Sex Chromosomes

Aneuploidy of sex chromosomes are more compatible with life. So, we see more of them. -Klinefelter's syndrome - 47XXY, affects 1/1000 males S/S:Gynemastia and atrophic male genitalia. -Turner's syndrome - XO (45X), affects 1/1000 females(most result from a meiotic error in father resulting in no Y, get X from mother). Triple X (super) female 1/1000 XYY males - decreased IQ but generally minimally affected So rather than extra or fewer autosomal chromosomes, there are extra or no X or Y chromosomes.

Angiogenesis

Angiogenesis does not occur just in tumors. Wound and bone healing have natural angiogenesis. Angiogenic promoters and inhibitors control the development of new blood vessels. However, in cancerous tumors there are mechanisms that increase angiogenic promoters and decrease angiogenic inhibitors

tumor necrosis factor-alpha (TNF-α)

Another important inflammatory mediator (cytokine) Macrophages secrete TNF-α in recognition of PAMPs (pathogen-associated molecular patterns) by the TLRs (toll-gate receptors) on macrophage cell membranes. Mast cells are an additional sources of this proinflammatory cytokine. TNF-α is initially synthesized as a cell membrane-spanning protein. A protease, TNF-converting enzyme (TACE), then cleaves TNF-α into a soluble form, that is capable of transport to the site in injury. Soluble TNF-α induces proinflammatory effects, such as: -enhancement of molecule expression for endothelial cell adhesion - WBCs can adhere to endothelial cells at the site of injury -Induction of chemokine production by both endothelial cells and macrophages - production of cytokines that "call" WBCs to the site of injury

Autosomal Recessive

Autosomal Recessive inheritance pattern: Two carrier parents - normal 25%, carrier 50%, affected 25%. = With EACH pregnancy. Important characteristics for determining autosomal recessive inheritance include the following: 1.Males and females are affected in equal proportions. 2.Consanguinity is sometimes present. (Consanguinity refers to the mating of two related individuals, and the offspring of such matings are said to be inbred.) 3.The disease is seen in siblings but usually not in their parents. 4.On the average, one fourth of the offspring of carrier parents will be affected.

Natural killer cells - will attack anything 2nd Line of Defense

Generally, lymphocytes participate in adaptive immunity (third line of defense). Natural Killer Cells is one type of lymphocyte that participates in the second line of defense.

Transfusion Reactions - ABO incompatibility - Alloimmunity

Antibodies against blood group antigens ABO system Two major carbohydrate antigens A and B (co-dominant) Individuals have naturally occurring antibodies to the A and B antigens they lack Anti-A and anti-B antibody production is induced by similar antigens on naturally occurring bacteria in the intestinal tract Antibodies are usually of the IgM class O blood type (universal donor) AB blood type (universal recipient) The recognition that individuals have different blood types was first described by Karl Landsteiner (1868-1943) in the early 1900s, based on his observation that serum from one person could cause a clumping of RBCs from another.

-usually a result of disuse, nutritional or oxygen deprivation, aging, diminished endocrine stimulation, or denervation (lack of nerve stimulation in peripheral muscles caused by injury to motor nerves). Ex.Left calf is smaller than right calf when the case is removed from it

Atrophy

Thyrotoxicosis- Graves disease.

Auto antibody is over stimulating TSH (thyroid stimulating hormone) receptors on the thyroid gland - causing over production of T3 and T4 and hypertrophy of the gland - goiter.

Rheumatic fever:

Autoimmune disorder. Group A, streptococcal pharyngitis. Antibody cross react with connective tissue in - susceptible individuals 2-3 weeks - Autoimmune reaction. Inflammation - T lymphocytes, macrophages. Heart, skin, brain & joints. RF is common in children between the age of 5 and 15 years, and there is no gender or racial predisposition to the infection or the development of Rheumatic Fever.

Primary immune deficiencies are classified into five groups, based on which principal component of the immune or inflammatory systems is defective.

B-lymphocyte deficiencies result from defects in B-cells or antibody formation. T-cell immunity does not depend on competent B-cell responses; thus T-cell immune responses are not affected in pure B-lymphocyte deficiencies. T-lymphocyte deficiencies are defects in the development and function of T lymphocytes. Because T-helper cells are necessary in the development of plasma cells from B-cell, antibody production is diminished as well. Combined T- and B-lymphocyte deficiencies result from inherent defects that directly affect the development of both T and B lymphocytes. Some combined deficiencies result in major defects in both T- and B-cell immune responses, whereas others are "partial" and more adversely affect T cells than B cells. Complement deficiencies and phagocytic deficiencies frequently present like antibody deficiencies because of the close interactions among antibody complement, and phagocytes (McCance et al., 2019).

Beneficial effects of fever

BENEFITS increased cardiac output vasodilatation increases blood flow (nutrient supply and waste removal) increased oxygen delivery (hemoglobin dissociation curve shifted to right) increased antibody production decreased bacterial division.

So how can cancer be termed a genetic disease?

Because all cancers arise from gene mutations

Down Syndrome

Best-known example of aneuploidy Trisomy 21 (47, XX or 47, XY karyotype) - number of somatic chromosomes and the sex chromosomes. So Trisomy 21 has an extra chromosome 21 - thus 47 instead of 46 chromosomes. 1:800 live births Mentally retarded, low nasal bridge, epicanthal folds, protruding tongue, poor muscle tone Risk increases with maternal age Increased risk of congenital heart disease, gastrointestinal disease, and leukemia So, there are 3 of Chromosome 21, instead 2. S&S - Down Syndrome Mental retardation Neck folds Epicanthic folds Flat facial profile Simian crease Hypotonia Umbilical hernia Leukemia

Adverse effects of fever (> 41oC)

COSTS rigors nausea and vomiting circulatory collapse due to increased fluid and electrolyte loss inflammation of sweat glands leading to reduction of sweating and heat loss renal and hepatic failure cerebral edema and small intracranial hemorrhages

Fungal Infections (cont'd)

Candida albicans: Is the most common fungal infection. Resides in skin, gastrointestinal tract, mouth, and vagina. Local defense mechanisms and microbiome produce antifungal agents. Remains localized if the immune system is intact; if the immune system is compromised, then the infection can become systemic.

*structure of cells

Cell Membranes -surrounds cells and controls what enters and leaves cell. - thin, flexible barrier that surrounds a cell and controls what passes in and out Nucleus -Controls the cell, brain of cell - Organelle containing the cell's genetic material in the form of DNA and controls many of the cell's activities -the command center of the cell and contains hereditary material in the form of DNA and RNA.

Synthesis of proteins (target of cell injury)

Cell function and structure

*cellular communication

Cells in a large organism communicate by means of chemical signals that are passed from one cell to another. (chemicals such as hormones and neurotransmitters)

Chromosome in CML: Translocation

Chromosomal translocation between chromsomes 9 and 22 causes the Philadelphia chromosome. Tyrossine kinase inhibitors to tx cml. It is the on off switch of this carogenic process.

Types of Necrosis

Coagulation necrosis - most solid organs develop this kind of necrosis (as in a myocardial or renal infarct). Liquefactive necrosis - brain, wet gangrene, abscess Caseous necrosis - tuberculosis Fat necrosis - release of pancreatic enzymes (e. g. lipase) in pancreatitis. Serum tests such as lipase or amylase helpful in diagnosis. Gangrene (gangrenous necrosis) - an infarct of an extremity often with a superimposed bacterial infection. Dry gangrene is less infected, wet gangrene results from liquefaction due to inflammatory cell enzymes.

Components of Inflammation: Cascades of Plasma Proteins

Complements - ends with bacterial destruction Kinins - vasodilation , inflammation, pain, leukocyte chemotaxis Blood clotting - thrombus, sequestered bacteria

Immunodeficiencies

Congenital (Primary) - there is genetic cause for these. An example is severe combined immunodeficiency (SCID). This is also an example of the first successful gene therapy. The genetic defect that causes SCID was identified. The "normal" gene was inserted into viral RNA, and the altered virus was infused into the patient. The normal gene taken into the patient's cells by the virus and inserted into the patient's DNA. So, the normal gene replaced the defective gene in the patient's genome, and the patient's bone marrow began producing T and B lymphocytes. Acquired (Secondary) Nutritional deficiencies Iatrogenic, such as chemotherapeutic drugs Many other causes - trauma, stress, lack of sleep, aging, pregnancy, infancy, infection, malignant tumors.

Integrity of the genetic apparatus

Control

Viral-malignant connections

Cytomegalovirus: Kaposi's sarcoma Epstein-Barr virus: Burkitt's lymphoma, immunoblastic lymphoma, nasopharyngeal carcinoma Hepatitis B virus: Hepatocellular carcinoma Herpesvirus 8: Kaposi's sarcoma HIV: Kaposi's sarcoma, lymphoma Human papillomaviruses: Cervical carcinoma Human T-cell lymphotrophic virus: T-cell lymphomas, hairy cell leukemia

If a person develops a cancer

Cytotoxic T lymphocytes can identify cancer cells at "foreign" and mount an immune response to attack the cancer cells.

DNA

DNA as the Genetic Code DNA, which the is basis for genetic inheritance codes for all body proteins - cell structure, cell repair, cellular components that organize cells into tissues and tissues into organs, and organs into organ systems. DNA also codes for proteins that are cellular products or functions, such as, hormones, enzymes, and neurotransmitters.

Summary on module 2 PP 3

DNA damage - loss of control over cell division. Radiation, Chemicals & Viral infections are some known causes of cancers. Cancer evolves in multiple steps by sequentially acquiring different DNA damages. Initiation, Latent stage, Promotion and Malignant transformation are recognizable stages in carcinogenesis. Each character of malignancy depends on unique DNA alteration. Abnormal genes produce abnormal products causing systemic signs and symptoms

cell death

Damage to metabolism reaches "point of no return" necrosis and apoptosis

How long does it take for cancer to develop?

Depends to the speed of cell replication, the effectiveness of tp53 gene and the ineffectiveness of apoptosis.

*types of passive transport

Diffusion -Movement of molecules from an area of higher concentration to an area of lower concentration., Osmosis -Diffusion of water through a selectively permeable membrane Filtration -the process that separates a solid from the liquid in a heterogeneous mixture

Pathways of Spread

Direct Spread Body cavities Lymphatic Hematogenous

Polygenetic inheritance

Diseases such as coronary artery disease are known to be inherited, but they are not the result of abnormality of a single gene. Rather they are the effect of multiple genes working together to give a complex biochemical background favorable to the development and progression of disease such as atheroma.

Autosomal aneuploidies

Down's syndrome (trisomy 21) 1/800 live births. Mental retardation, a variety of physical and organ abnormalities. 97% are due to non-disjunction (90-96% in mother), 3% due to translocation. See the 3 chromosome 21 that are circled. ii. Trisomy 13, Trisomy 18. In trisomy 13 facial and brain malformations, in trisomy 18 often cardiac malformations. A variety of other malformations. Leading cause of mental retardation and miscarriage Incidence of chromosomal abnormalities 1/12 conceptions Approximately 95% of conceptions with chromosome disorders result in miscarriage 50% of first-trimester miscarriages associated with a major chromosomal abnormality 1/150 live births with a major diagnosable chromosomal abnormality

Examples of Chronic Inflammation

Edema Ulcerations Ulcerative colitis Purulent inflammation - PUS, TB Fibrinous inflammation Serous inflammation - pleural effusion Atherosclerosis Rheumatoid arthritis Chronic pancreatitis

Biochemical Barriers of 1st line

Epithelial surfaces also provide biochemical barriers by synthesizing and secreting substances meant to trap or destroy microorganisms: Mucus, perspiration (or sweat), saliva, tears, and earwax Sebaceous glands in the skin secrete antibacterial and antifungal fatty acids and lactic acid. Perspiration, tears, and saliva contain an enzyme (lysozyme) that attacks the cell walls of gram-positive bacteria. These glandular secretions result in an acidic skin surface (pH 3 to 5), which is an inhospitable environment for most bacteria.

First line of defense (Epithelial-Derived Chemicals)

Epithelial surfaces of the body (skin and in organs) secrete proteins that destroy potential pathogens, such as bacteria, fungi and viruses. These antimicrobial substances are positively charged polypeptides of two classes:—cathelicidins and defensins. -The difference in the classes is the 3-dimensional structures of the polypeptides.

Malignant

Fast growing, non capsulated, Invasive & Infiltrate Metastasize. poorly differentiated, Suffix "Carcinoma" or "Sarcoma"

Systemic effects of acute inflammation

Fever Leukocytosis - predominantly a neutrophilic response Increase in plasma proteins (acute phase reactants) The increased proteins lead to an elevated erythrocyte sedimentation rate (ESR) by promoting rouleaux formation (stacking of RBCs). The ESR is a non-specific measure of the activity of various disease processes including acute inflammation.

Systemic effects of acute inflammation

Infectious Disease

Foreign antigens from infectious microorganisms can initiate autoimmune disease through molecular mimicry. Some antigens of infectious agents so closely resemble (mimic) a particular self-antigen that the antibodies or T cells produced to protect against the infection also recognize the self-antigen as foreign (cross-reactive antibody or T cell). For many autoimmune diseases, this relationship between predisposing infections the autoimmune disease, is hypothesized. There is one confirmed example - acute rheumatic fever that may occur after a group A streptococcal sore throat

Resistin-like molecule β

Found in the intestinal goblet cells, where it protects against helminthes infections

c. What is the difference between genotype and phenotype?

Genotype is the person's genetic makeup, whereas phenotype is the physical appearance of the person. For example, the individual has the gene for Retinoblastoma, however, the individual did not develop a retinal tumor.

Neutrophils

Granular WBCs Also referred to as polymorphonuclear neutrophils (PMNs) Predominate in early inflammatory responses Ingest bacteria, dead cells, and cellular debris Cells are short lived and become a component of the purulent exudate -Neutrophil margination in inflammation

Characteristics of malignant neoplasms:

Hanahan and Weinberg described 10 hallmarks of why a cell becomes malignant, accumulating these characteristics through genetic mutations: 1. Evading growth suppressors - Suppressor genes control the rate of cell division for each type of cells. When suppressor genes loose function through mutations, cell division is not controlled and accelerates - producing cancer. Proto-oncogenes that control the rate of cell division mutate into oncogenes that increase the rate of cell division. 2. Enabling replicative immortality - The number of times a cell can replicate is determined by the size of chromosomal telomeres - caps on the ends of each arm of a chromosome. With each cell division, the telomeres become smaller, until they disappear. Without telomeres, division of that cell stops. So cells have a life span. With cancer cells, their chromosomal telomeres don't deplete, so the cells can divide indefinitely. 3.Tumor promoting inflammation - chronic inflammation promotes DNA damage, cancer-causing mutations, and the release of pro-inflammatory mediators. 4. Activating invasion and metastasis - Cells maintain "boundaries", and different cell types do not invade or compete for space and resources. The cells also "stick together" or maintain a group. These factors are necessary for the development tissues - functional units that make up organs. With cancer cells, this respect for "boundaries" and maintaining the group is lost, and the cells invade surrounding tissue as they replicate. Cancer cells also become "slippery" and break off from the tumor - moving to distant locations through the circulatory and lymphatic systems. 5. Genomic instability -Or the increased tendency for cells to mutate. Caretaker genes, such as TP53, detect DNA damage and activate repair mechanisms, which maintains genomic stability. Inherited and acquired mutations in caretaker genes eliminate this "caretaker" function, causing an increased accumulation of mutations, and increasing the malignant protentional of the cells. So, individual cells have varying degrees of mutational potential. This mutational heterogeneity may vary considerably within and among tumors. 6. Inducing angiogenesis - Cancer cells produce growth factors that stimulate the blood supply to provide oxygen and nutrients for accelerated cell growth in tumors. 7. Resisting cell death - Cancer cells have genetic mutations that inhibit apoptosis, so that defective cells do not go through self-destruction. 8. Deregulating cellular energetics - In the presence of oxygen, cells perform oxidative phosphorylation, converting one molecule of glucose into 36 molecules of ATP. In the absence of oxygen, cells make 3 ATP from one glucose molecule - glycolysis. Cancer cells, even with adequate oxygen, only use glycolysis for energy generation. The goal is to provide for the metabolic needs for rapid cell division regardless of oxygen supply to cells. 9. Sustaining proliferative signaling - RTKs (receptor tyrosine kinases) are chemical signals that bind to cell membrane receptors and promote cell division. This is the normal way to signal cell division. In cancer cells, the signaling becomes excessive and produces cell proliferation. 10. Avoiding immune detection - Cancer cells have developed ways to evade detection by the immune system, as defective cells or non-self cells. Therefore, the immune system does destroy these defective cells (McCance et al., 2019).

Fungal Infections

Large microorganisms with thick cell walls Eukaryotes Single-celled yeasts, multicelled molds, or both Disease caused by fungi: Mycosis Disease transmitted by inhalation or contamination of wounds Dermatophytes if infections invades skin, hair, or nails Infection with a fungus is called mycosis

What is the difference between heterozygous and homozygous?

Heretozygous means that the two genes at the same locus on both chromosomes are not identical. For examples, the gene on the short arm of chromosomes 6 (one from mother and one from father) are different. One codes for blue eyes and the other codes for brown eyes. Homozygous means that the two genes are identical on both chromosomes, so, two genes that code for blue eyes.

-an increase in the size of an organ or tissue caused by an increase in the number of cells making up that organ or tissue. Ex.Lining of the uterus thickens after ovulation because of increased amounts of estrogen.

Hyperplasia

-increase in the size of an organ or tissue due to the increase in size of the cells that comprise it Ex.Man who lifts weights regularly develops larger biceps.

Hypertrophy

IFN-α and IFN-β induce production of antiviral proteins, which protect uninfected cells:

IFN-α or IFN-β is released from virally infected cells attaches to a receptor on a neighboring cell if the neighboring cell is uninfected, stimulates the production of antiviral proteins These proteins interfere with transcription of viral RNA and prevent viral replication. interferons have no effect on cells that have already been virally infected.

IFN-γ

IFN-γ enhances the inflammatory response by increasing the activity of macrophages - innate immunity. It also facilitates development of the adaptive immunity against viral antigens on infected cells. This causes T lymphocyte and antibody formation against viruses.

Two major proinflammatory cytokines are IL-1 and IL-6: IL-1

IL-1 is produced by macrophages that have been stimulated by infection. IL-1 has several effects for innate immunity: -An endogenous pyrogen (i.e., fever-causing cytokine) that reacts with receptors on cells of the hypothalamus and affects the body's thermostat. -Activates phagocytes and lymphocytes, thereby enhancing both innate and adaptive immunity. -Effects on neutrophils, including induction of proliferation (resulting in an increase in the number of circulating neutrophils), chemotaxis, increased cellular respiration, and increased lysosomal enzyme activity.

Primary and Secondary Immune Responses. IgM AND IgG

Immune responses to antigen occur by two classes of immunoglobulins - IgM and IgG. IgM dominates the initial exposure to the antigen or the primary response. Whereas, IgG dominates the secondary response (second exposure to the same antigen).

Autoimmunity

Immune systems attacks self-antigens May involve humoral (B cells) or cellular immunity (T cells), or both An obvious mistake by the immune system Four mechanisms for autoimmunity Break down of tolerance - identifies self-antigens as "foreign" Sequestered antigen - in brain and anterior chamber of eye Infectious diseases - molecular mimicry Neoantigens - genetic mutations related to protein synthesis

Relative risk

Incidence rate of a disease among individuals exposed to a risk factor divided by the incidence rate of a disease among individuals not exposed to a risk factor

Invasion and Evasion

Invasion - direct confrontation with the immune system's primary defenses against bacteria Complement system physical lysis of pathogen cell walls "tagging" (opsonin) of pathogens for phagocytosis by macrophages. Antibodies - produced by activated B cells - plasma cells Phagocytosis - by neutrophils and mactrophages Bacterial growth depends of the effectiveness of the immune defenses and the ability of the bacteria to gain resources and multiply Evasion - bacteria have mechanisms to evade the immune responses

Integrity Cell membrane (cell injury target)

Ion transport, fluid balance

Factors affecting Healing: LOCAL

Local Necrosis Infection/pus Apposition Blood supply Mobility Foreign body

Which cell-surface molecule determines self from not self for adaptive immunity?

MHC proteins

Self from not self - major histocompatability complex

MHC proteins are SELF labels - genetically coded Who has the MHC proteins most similar to yours - ?

Phagocytosis

Macrophages are one of the two types of phagocytic cells. The other is neutrophils. These cells circulate in the blood and must leave the circulation and migrate to the site of inflammation before initiating phagocytosis. In the circulation rapidly moving with red blood cells are in the center of the vessels and the leukocytes tending to flow more slowly along the vessel walls. The biochemical products produced early at inflammatory sites (e.g., histamine, TNF-α, bradykinin, leukotrienes, prostaglandins) diffuse to the vessels and affect both leukocytes and endothelial cells, promoting the migration of leukocytes to the site of injury.

Major Histocompatibility Complex

Major Histocompatibility Complex (MHC) molecules "tag" cells as "self", or belonging to the cells of the body. When cells are recognized as "self" by the immune system, they do not produce an immune response, because the cells are not recognized as antigens. Most adaptive immune responses are dependent on antigen presentation by antigen presenting cells (APCs) - macrophages. Without an antigen to present to T and B cells, an immune response does not occur. Antigen presentation is the primary role of molecules of the MHC. MHC molecules are glycoproteins found on the surface of all human cells except red blood cells. They are divided into two general classes, class I and class II, based on their molecular structure, distribution among the types of cells, and function in antigen presentation. MHC class I molecules are heterodimers composed of a large α-chain along with a smaller chain called β2-microglobulin. MHC class II molecules are also heterodimers with both α- and β-chains. All MHC molecules are coded from genes on the short arm of chromosome 6.

Can there be a predisposition to cancers of every kind in a family, or is it that the genetic predisposition is to one type only?

Many types. About as many there are mutations.

Type IV - cell mediated hypersentitivity

Mechanism of Type IV, Cell-Mediated, Reactions. Antigens from target cells stimulate T cells to differentiate into cytotoxic T cells (Tc cells), which have direct cytotoxic activity, and helper T cells (Th1 cells) involved in delayed hypersensitivity. The Th1 cells produce lymphokines (especially interferon-gamma [IFN-γ]) that activate the macrophage through specific receptors (e.g., IFN-γ receptor [IFNγR]). The macrophages can attach to targets and release enzymes and reactive oxygen species that are responsible for most of the tissue destruction. -Types I, II, and III hypersensitivity reactions are mediated by antibody, but type IV reactions are mediated by T lymphocytes. Therefore, the type of immunity involved is cellular immunity. -Type IV mechanisms occur through: cytotoxic T lymphocytes (Tc cells) - attack and destroy tageted cells directly. lymphokine-producing Th1 and Th17 cells - produce cytokines that recruit and activate phagocytic cells, usually macrophages. -Destruction of the tissue is caused by: ~direct killing of cells by toxins from Tc cells ~release of soluble factors, such as lysosomal enzymes and toxic reactive oxygen species (ROS), from activated macrophages

-The replacement of one differentiated tissue by another. usually occurs in response to chronic irritation and inflammation. This transformation of cells allows for a higher likelihood of survival in a less than optimal environment. Ex.Columnar epithelium in bronchi of cigarette smoker is replaced by stratified squamous epithelium

Metaplagia

Cellular Adaptation, Injury & Death

Normal cell is in a steady state "Homeostasis" External stimuli bring change cell physiology and or anatomy If cell functions well: adaptation If cell is damaged : injury If cell goes past "no return" : death

With Barrett's esophagus -esophageal squamous cells change to intestinal-like columnar cells. Due to the constant irritation of gastric secretions in the esophagus from gastro-esophageal reflex disease (GERD).

Metaplasia - is the replacement of one mature cell type for another mature cell type - esophageal squamous cells for intestinal columnar cells.

Metastasis

Metastasis is an active process. (spread to a distant site) -Lymphatic - for example breast ca to axillary lymph nodes Blood vessels -Venous - for example colon ca to liver via portal vessels -Arterial - for example sarcomas to any other organ of the body Body cavities - for example ovarian ca to peritoneal surfaces -Cerebrospinal fluid - for example brain tumor to spinal meninges

cell respiration cell injury target

Mitochondria

When a cell is injured, consequences include

Mitochondrial damage - resulting in a reduction in ATP (energy) production, and an accumulation of reactive oxygen species (ROS). Lack of ATP inhibits cellular repair and increased ROS causes more damage to cellular components Entry of calcium into the cell - more cellular damage from activation of intracellular enzymes Cell membrane damage Plasma membrane - lysis of cells Lysosomal membrane - enzymatic digestion of cellular components Protein misfolding and DNA damage - activation of pro-apoptotic proteins - more programed cell death

What is the difference between mitosis and meiosis?

Mitosis is when a diploid (2n), somatic cell copies itself. This is usual cell division. Meiosis is when haploid cells (n) are created from a diploid cell. This happens in the production of gametes, egg and sperm.

What is the difference between monosomy and trisomy?

Monosomy means that one of the chromsomes in somatic cells has only one copy, instead of the normal two copies. For example, is Turners Syndrome, were the genetic makeup is XO - only one X chromosome, instead of XX - normal female complement of X chromsomes. Triosomy means that one of the chromosomes in somatic cells has three copies, instead of the normal two copies. For example, Down Syndrome - triosomy 21 - the person has 3 of chromosome 21, rather then only the normal 2 chromosomes.

Secondary Immune Deficiency

Normal physiologic conditions - pregnancy, infancy, and aging Psychologic stress- emotional trauma, eating disorders Dietary deficiencies/malnutrition Malignancies Metabolic disorders - diabetes, CF, alcoholism, sickle cell anemia, SLE, Down syndrome Environmental - chemicals, radiation Physical trauma/burns Medical treatments Infections

Primary Immune Deficiencies

Most primary immune deficiencies are the result of a single gene defect, that is a sporadic mutation and not inherited. The sporadic mutations occur before birth, but the onset of symptoms vary, often within the first 2 years of life. The most common symptoms include: Sinusitis (68%), pneumonia (51%), ear infections (51%), diarrhea (30%), and bronchitis (55%). The incidence of symptoms varies with each type of immune deficiency.

Naturally acquired passive immunity

Mother's antibodies No. Baby is exposed to mother's antibodies throughout fetal development. Passive immunity - antibodies are provided by the mother. Infant has not developed his own antibodies yet. The infant's T and B cells are not immunocompetent yet. They need to mature in the thymus and bone marrow. Then then will need to be activated by interaction with an APC or their specific antigens.

Natural Killer Cells

Natural killer (NK) cells recognize and eliminate cells that are infected with viruses. They can also eliminate abnormal cells, such as cancer cells. NK cells seem to be more efficient in this role when they encounter an infected cell within the circulatory system as opposed to within tissues. NK cells have inhibitory and activating receptors that allow differentiation between infected or tumor cells and normal cells. This allows the NK cell to target abnormal cells, and not attack normal cells.

necrosis

Necrotic cell death Unregulated death caused by injuries to cells Cells swell and rupture Inflammation results Healing after necrosis involves scaring - fibrous tissue or calcification (seen in atherosclerotic arteries)

Neoantigen

Neoantigen or new antigen are formed and induces an allergic reaction that can lead to autoimmunity.

Pediatric mechanisms of self-defense

Neonates: Have transiently depressed inflammatory and immune function. Have neutrophils that are not capable of efficient chemotaxis. Have a deficient complement system. Are deficient in collectins and collectin-like proteins. Are susceptible to bacterial infections.

Is cancer of the breast identical in all women?

No genetic causes are different for each individual.

Is it possible that we can find 'the cure' for cancer?

No. The causes of cancer are so individualized, it might be impossible to "cure" all of them.

is a diagnosis of cancer a death sentence?

No. There are many promising therapies, especially targeting the genetic make up of the cancer cells.

Is tissue always damaged as the result of inflammation?

No. Tissue damage initiates the inflammatory response. This response is to bring immune resources to the cite of injury. The goal is to heal the injured tissue. If inflammation is acute and properly controlled by the anti-inflammatory factors, then it does not cause tissue damage. If inflammation is excessive or becomes chronic, then it can cause further tissue damage.

Breakdown of Tolerance

Normally, self-antigens are tolerated by the immune system, where the antigens on the body's cell surfaces are recognized as belonging to the self and do not produce immune responses. Central tolerance develops when autoreactive lymphocytes (don't recognize self antigens) are eliminated (apoptosis) in the bone marrow or thymus gland during the maturation of B or T lymphocytes. Peripheral tolerance is maintained in lymph nodes through the action of T-regulatory lymphocytes or antigen-presenting cells. The breakdown of tolerance is when the immune system recognizes self-antigens as foreign.

Incidence rate

Number of new cases of a disease reported during a specific period (typically 1 year) divided by the number of individuals in the population

Most common genetic disorders are multifactorial

Often without an identifiable genetic defect - T2DM, HTN, obesity, Hyperlipidemia= These multifactorial disorders often have environmental factors that potentiate disease development. -Genome-wide associated studies are used to identify these disorder

Memory

Once a person has had experience of an antigen, the memory stays regarding how to combat it with another exposure

Staging - Progression or Spread

Once the diagnosis of cancer is established (grading), it is important to determine if the cancer has spread. This is the stage of the cancer. Staging initially involves determining the size of the tumor, the degree to which it has locally invaded, and the extent to which it has spread (metastasized).

Bacteria-Derived Chemicals

Our body surfaces are colonized with microorganisms, called the normal microbiome. The skin and the mucous membranes of have a combination of bacteria and fungi that is unique to the eyes, upper and low GI tracts, urethra and vagina. Usually, the microbiome organisms do not cause disease. There are two relationships these micro-organisms have with humans - - -commensal (to the benefit of one organism without affecting the other) or -mutualistic (to the benefit of both organisms).

Parasitic and Protozoan Infections

Parasites benefit at the expense of the host. Parasites range from unicellular protozoa to large worms. Parasitic worms (helminths) Intestinal and tissue nematodes (e.g., hookworm, roundworm) Flukes (e.g., liver fluke, lung fluke) Tapeworms Are a common cause of infection worldwide. Are rarely transmitted from human to human; are transmitted mainly through vectors. Malaria by mosquito bites Trypanosomes by the tsetse fly Leishmania spp. by sand fleas Others found in contaminated water or food (e.g., Giardia lamblia).

Exotoxins and Endotoxins

Pathogens produce a variety of toxic molecules that may kill cells, damage tissues, and protect the bacteria against inflammation. Exotoxins are proteins released during bacterial growth. Exotoxins can damage cell membranes, activate second messengers, and inhibit protein synthesis. Exotoxins are immunogenic and elicit the production of antibodies known as antitoxins. Vaccines are available for many of the exotoxin pathogens (tetanus, diphtheria, and pertussis). Bacteria that produce endotoxins are called pyrogenic bacteria because they stimulate the release of inflammatory mediators and produce fever. Endotoxins are lipopolysaccarides in the cell walls of gram negative bacteria. Endotoxin is also released from the membrane of these bacteria, during bacterial lysis by the immune response or antibiotic treatment. Therefore, antibiotics cannot prevent the toxic effects of the endotoxin (McCance & Huether, 2019).

*mitochondria

Powerhouse of the cell, organelle that is the site of ATP (energy) production

Apoptosis

Programmed cell death: apoptosis or "cell suicide" Removes cells that are being replaced or have "worn out" Removes unwanted tissue Normal process in the body No healing required with apoptosis. There is NO scaring or calcification.

Cancer

Progression of cancer from chronic inflammation > metaplasia > dysplasia > cancer in situ > to invasive carcinoma.

*types of cells

Prokaryotic and Eukaryotic

Prevalence rate

Proportion of the population affected by a disease at a specific point in time

*cell receptors

Proteins on the outside of cells that have a specific shape and can fit with other molecules, like antigens.

distinguish between proto-oncogenes, oncogenes and tumor-suppressor genes.

Proto-oncogenes direct synthesis of proteins that correctly regulate cell proliferation. An example of a proto-oncogene would be a growth factor (e.g., epidermal growth factor) or a growth factor receptor (e.g., epidermal growth factor receptor).

Mechanisms used by bacteria to survive against the immune system

Rapid Division - Since the initial immune response may take 3 to 5 days to reach protective levels, pathogens proliferate at rates that surpass the development of the immune system. Therefore, the bacteria have a head start in the battle with the immune system. Intracellular survival - Bacteria can hide from the immune response by growing in sites that are poorly protected by immune cells - such as the GI tract. Bacteria can have an advantage by surviving within cells (intracellular bacteria). Many intracellular bacteria can survive and even multiply in macrophages or in other cells. Normally a macrophage would efficiently kill bacteria, but intracellular bacteria may block killing in several ways: Robbing the phagocyte (macrophage) of oxygen. Bacteria can secrete lysins that break down the phagosome membrane, and the bacteria are released into the cytoplasm, where they multiply. Prevention of phagosome-lysosome fusion by producing toxins that prevent fusion so that the environment in the phagosome remains relatively nontoxic.

Example of Bacterial Pathogenesis

Saphylococcus aureus is a major cause of hospital-acquired (nosocomial) infections, and is commonly found on normal skin and nasal passages. It is transmitted by direct skin-to-skin contact or by contact with shared items or surfaces that have become contaminated (e.g., towels, used bandages). Skin infections occur at sites of trauma, such as cuts and abrasions, and at areas of the body covered by hair. Most infections are not serious and are localized as pustules on the skin. Systemic infection can develop from local wound infections, leading to septicemia and abscesses in internal organs (e.g., lungs, kidney, bones, skeletal muscle, meninges, brain or heart). Infection with S. Aureus starts by the micro-organisms adhering to tissue by cell surface proteins, such as connective tissue, endothelium, and collagen.

Systemic manifestations of cancer

Secondary substances secreted by the tumor, that can cause systemic (generalized) or specific (S&S) effects; Fatigue Cachexia - often difficult to explain calorically Anemia - not always due to bleeding

Why tumor markers are not ideal

Sensitivity - can the test find all the positives that are there, or does it miss positives? (false negatives) Specificity - of the positive results, are they positive for the condition under consideration only, or do they include other conditions? (false positives)

Congenital depressed immunity

Severe Combined Immune Deficiency Both T and B cell function defective Genetic origin lack of WBC enzyme, WBCs ineffective

Benign

Slow growing, capsulated, Non-invasive do not metastasize, well differentiated, suffix "oma" eg. Fibroma.

Which characteristic of adaptive immunity produces antibodies and Tc cells against a pathogen?

Specific

Characteristics of Specific Immunity

Specific Systemic Genetically coded Recognizes self from not-self Has memory

Specific and Systemic

Specific Now protected against Hepatitis, but can still be infected with any other organism, or even other types of hepatitis Systemic The specific immune system works all around the body because many of its components circulate

Strep throat

Streptococcus has several antigens One is called O B lymphocytes in the lymph nodes of the neck recognize the antigen O B lymphocytes clone - the nodes get big →pain Antibody is made against the O Anti-streptolysin O can be found in the blood for a few weeks The ASO antibody binds onto the O antigen and makes the bacterium a target for phagocytosis

First line of defense

Structural, mechanical, biologic and chemical barriers. Structural defenses - skin, conjunctivae, mucous membranes (mouth, nose, pharynx, trachea, bronchi, alveoli, esophagus, stomach, rectum, intestines, urethra, bladder, vagina). Mechanical defenses - defecation, urination, coughing, sneezing, tearing, cilia action in the airways Microbe defenses - normal bacterial and fungal flora Chemical defenses - gastric acid, saliva, tears

Factors affecting Healing: SYSTEMIC

Systemic Nutrition Vitamin deficiencies Age Immune status Other co-morbidities

Cells of specific immunity: T and B Lymphocytes

T and B lymphocytes are produced in bone marrow from pluripotent cells. T lymphocyte production requires IL-7. B lymphocyte production requires IL-7 and IL-6.

Which event is required for T cells to become immunocompetent?

T cells that produce TCRs specific for self antigens go through clonal deletion by apoptosis.

T-Helper Lymphocytes

T helper cells are required for the antigen-driven maturation of both B and T cells. They facilitate and magnify the interaction between APCs and the immunocompetent lymphocytes. This important role involves three distinct steps: 1. the Th cell directly interacts with the APC through a variety of antigen-specific and antigen-independent receptors; 2. the Th cell undergoes a differentiation process during which a variety of cytokines are activated - chemical mediators of the immune system; 3. depending on the pattern of cytokines expressed, the mature Th cell interacts with either immunocompetent B or T cells to enhance their response to an antigen, 4. this results in differentiation into B lymphocytes into plasma cells, T lymphocytes into T-cytotoxic cells.

Acquired Immune Deficiency Syndrome (AIDS)

The AIDS virus invades the helper T cells -and takes them over as viral factories. Now the person can not mount an effective T or B cell response to infection or malignancy Pathogenesis Retrovirus Genetic information is in the form of RNA Contains reverse transcriptase to convert RNA into double-stranded DNA Integrase

T helper cell activation

The antigen peptide then activates the Helper T cell receptor - sensitizing the Helper T cell to the antigen. The Helper T cell is now activated and can assist B lymphocytes to begin producing antibody to the antigen OR it can assist other T lymphocytes to become Cytotoxic T cells against the antigen.

Cellular Mediators of Inflammation

The cells of inflammation secrete and respond to biochemical mediators. This form of chemical signaling is complex and is used to recruit the cells of inflammation to the site of injury. They are also recruited and activated by products of the plasma protein systems (coagulation, complement and kinin). Cells that are destroyed, other inflammatory cells and micro-organisms also release biochemicals that contribute to the localized inflammatory response. The goal is to produce controlled inflammation at the site of injury, kill micro-organisms, and remove the debris of dead cells to promote healing (McCance & Huether, 2019).

Gastritis.

The gastric mucosa is normally protected by the thick layer of mucus, and is able to resist aurodigestion by acid and pepsin. Aspirin, and NSAIDs inhibit the production of prostaglandins, which in turn inhibits the ability of the gastric mucosa to protect itself. The superficial layer of the gastric mucosa is eroded, giving epigastric pain and bleeding which can be severe, causing hematemesis. Alcohol and histamine have a similar effect. http://www.emedicine.com/EMERG/topic820.htm

Grading of Cancer

The grade of a cancer is an estimate of malignancy -A microscopic section of the tumor is evaluated by the pathologist taking into account various features such as differentiation, mitotic activity, necrosis, and others depending on the specific tumor type being graded. -Grading cancer is done from a tissue sample or biopsy. It is examined microscopically by the pathologist for the histologic hallmarks of cancer - undifferentiated (not specific type of cell), not uniform cell structure (shape) or size. The more non-specific and the more different the cell size and shape the higher the grade of cancer.

autoimmune diseases can occur by

The immune system's identification of SELF is not always perfect or can malfunction. When immune system does not recognize all cells as SELF - autoimmune diseases can occur.

What is the difference between prevalence rate and incidence rate for a disease in a population?

The incidence rate is the number of new cases of a disease reported in one year divided by the number of individuals in the population. Whereas, the prevalence rate is the proportion of the population affected by a disease at a single point in time. So, prevalence is determined by the incidence rate and how long patients survive with the disease. If they survive more than a year, prevalence rates will be greater than incidence rates. For example: We have a town with a population of 150,000, newly diagnosed cases of CAD is 4050 in 2017, number of people who had CAD in the town in July 31, 2017 was 16,500. Incidence rate = 4050 / 150,

Chronic Bronchitis

The inflammatory response is caused by air pollutants such as noxious industrial gases and cigarette smoke. The epithelium of the tracheobronchial tree becomes thickened, edematous, friable, and produces excess mucus. This gives rise to the definition of chronic bronchitis, which is clinical: Cough and sputum on most days for at least 3 months of the year for a minimum of 2 years. The inflammation and the mucus combine to obstruct the flow of air into and out of the alveoli, and this is therefore known as an obstructive airways disease. http://www.emedicine.com/med/topic367.htm

The third plasma protein system, the kinin system, augments inflammation in several ways.

The kinin system produces bradykinin, which causes dilation of blood vessels. Bradykinin also acts with prostaglandins: -stimulates nerve endings and induce pain, -causes smooth muscle cell contraction, -increases vascular permeability (due to endothelial cell retraction in capillaries) -increases leukocyte chemotaxis.. The plasma kinin cascade is activated by the conversion of plasma prekallikrein to kallikrein. This conversion is induced by prekallikrein activator, which is identical to factor XIIa of the clotting cascade. Kallikrein then converts kininogen to bradykinin. Sources of tissue kallikreins include: saliva, sweat, tears, urine, and feces. In order to limit the extent of inflammation, kinins are rapidly degraded by kininases. These are enzymes present in plasma and tissues.

Some cytokines are anti-inflammatory and decrease the inflammatory response.

The most important are IL-10 and transforming growth factor-beta (TGF-β). IL-10 is primarily produced by lymphocytes and suppresses the growth of lymphocytes and the production of proinflammatory cytokines by macrophages. This causes the down-regulation of inflammation and the adaptive immunity

Mechanical Barriers of 1st line

The normal turnover of the cells in these sites as well as mechanisms for "washing" the surfaces may mechanically remove many infectious microorganisms and prevent their residence on the epithelial surfaces." Examples of the first line of defense: the routine sloughing off and replacement of dead skin cells also removes adherent bacteria Mechanical cleansing of the surfaces includes vomiting and urination. Goblet cells of the upper respiratory tract produce mucus that coats the epithelial surface and traps microorganisms that are removed by hair-like cilia that mechanically move the mucus upward to be expelled by coughing or sneezing. the low temperature on the skin generally inhibits microorganisms, most of which prefer temperatures near 37° C for more efficient growth

Physical barriers of 1st line

The physical barriers that protect against damage and infection are composed of tightly associated epithelial cells including those of the skin and of the membranous sheets lining the gastrointestinal, genitourinary, and respiratory tracts. The mucosal epithelial cells are highly interconnected junctions that prohibit the passage of microorganisms into the underlying tissue.

Phagocytes

The primary role of most granulocytes (neutrophils, eosinophils, basophils) and monocytes/macrophages is phagocytosis. This is the process where a cell of the immune system ingests and disposes of damaged cells and foreign material, and microorganisms (McCance & Huether, 2019). WBCs that attack pathogens and foreign antigens

Bacterial endotoxin or lipopolysaccharide (LPS) activates almost every aspect of inflammation:

The release of LPS from gram-negative bacteria triggers cytokine production, including tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8), and secondary mediators of inflammation, such as nitric oxide (NO) and platelet-activating factor (PAF). At low levels of LPS the effect is local. Moderate levels of LPS cause more systemic inflammatory responses. High levels of LPS may lead to septic shock and death. ARDS, Acute respiratory distress syndrome; DIC, disseminated intravascular coagulation (McCance & Huether, 2019).

Coagulation (Clotting) Cascade

The result of this cascade of plasma proteins is the formation of a fibrin meshwork at an injured or inflamed site Prevents the spread of infection Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity Forms a clot that stops bleeding Provides a framework for repair and healing Main substance is an insoluble protein is fibrin

If a person gets another strep throat

The same thing happens but much faster and on a larger scale because of the memory B cells from the previous time This is an example of immune system "memory".

Immunogens

To be immunogenic, an antigen has a portion of its molecular structure that is recognized by and bound to an antibody and/or to specific receptors on a T lymphocyte. The portion of the antigen that is recognized for binding is called its antigenic determinant, or epitope. The matching portion on the antibody or T lymphocyte receptor is sometimes referred to as the antigen-binding site, or paratope. Most large molecules (e.g., proteins, polysaccharides, nucleic acids) contain many epitopes, and the immune response will consist of a mixture of specific antibodies against several of these epitopes.

Carcinoma in situ

These early stage cancers (Stage 0) are localized to the epithelium and have not penetrated the local basement membrane or invaded the surrounding tissue. Based on these characteristics, they are not malignant but are often called carcinoma in situ (CIS). CIS can vary from low-grade to high-grade dysplasia.

Rheumatic Fever may progress to Chronic Rheumatic Heart Disease (RHD).

This is a stage that involves the heart. In this case, the heart muscle, the myocardium is affected and this may result in symptoms like shortness of breath, congestive heart failure, pericarditis causing a pericardial friction rub, and valvular deformities leading to mitral valve stenosis.

Hypersensitivity

This is an exaggerated or damaging immune response Type I - anaphylaxis (asthma, allergies) Type II - tissue specific attack (certain organ) Type III - Ag - Ab triggered (PSGN) Type IV - cell mediated (slow, poison ivy, TB)

SUMMARY Important characteristics of the specific immune system:

Tolerance - distinguishing self from non-self. Tolerance to self antigens is not entirely passive, suppressor T cells have a role. Also embryologic deletion, and anti-idiotypic antibody (anti-ID). Specificity (to specific antigens) - each T or B cell recognizes only specific antigens. Memory - antigen recognition is present over time Enhanced response (secondary) Controlled by genes

Tumor invasion and metastasis

Tumor invasion - a number of factors are involved: Mechanical Lytic enzymes Decreased cell-to-cell adhesion Increased motility Production of factors stimulating angiogenesis (new blood vessel formation)

Edema of skin or larynx: anaphylactic hypersensitivity

Type I Hypersensitivity: Immediate, life threatening Type I reactions are mediated by antigen-specific IgE and the products of tissue mast cells. Most common allergies (e.g., pollen allergies) are type I reactions and are allergic - against environmental antigens. However, IgE can also contribute to some autoimmune and alloimmune conditions. Additionally, many common allergies (e.g., poison ivy) are not IgE mediated, but are T cell mediated hypersensitivity reactions.

Type II hypersensitivity - Tissue specific

Type II (tissue-specific) hypersensitivity reactions are characterized by a specific cell or tissue being the target of an immune response. Cells have antigens that are called tissue-specific antigens. These antigens are expressed on the cell membranes of only specific cells or tissues. Each type of cell has its OWN SPECIFIC antigens. The symptoms of type II diseases are determined by which tissue or organ expresses the particular antigen the immune system has been sensitized to. Environmental antigens (e.g., drugs or their metabolites) can bind to the plasma membranes of specific cells (especially erythrocytes and platelets) and become targets of type II reactions (McCance & Huether, 2019, p. 260).

PSGN - Type III immune complex mediated hypersensitivity

Type III Hypersensitivity - example: post-streptococcal glomerulonephritis (PSGN) Immune complex mediated hypersensitivity GENERALIZED - Not organ specific Type III Hypersensitivity - Humoral Immunity - antigen-antibody complexes Type III hypersensitivity is caused by antigen-antibody complexes that are formed in the circulation when the immune system produces antibodies against invading pathogens. These antigen-antibody complexes are later deposited in vessel walls or extravascular tissues. The difference between type II and type III mechanisms is that in type II hypersensitivity antibody binds to the antigen on the cell surface, whereas in type III the antibody binds to antigen that was released into the blood or body fluids. The antigen-antibody complex is then deposited in the tissues. Type III reactions are not organ specific, and symptoms are not determined by the particular antigen. The harmful effects of type III hypersensitivity is that immune complex deposition is caused by complement activation and chemotactic factors for neutrophils. The neutrophils bind to antibody and C3b contained in the complexes and attempt to ingest the immune complexes.

Manmade monoclonal antibodies

in various diagnostic tests specific antibodies have become increasingly useful in classifying tumors, identifying viruses, and many other uses will potentially emerge. Therapeutic uses are quite possible.

TNM - Staging of tumors

Various systems are used depending on the specific tumor type. The stage of a cancer is the extent of disease. The TNM system is often used where T refers to the primary tumor, N refers to lymph nodal involvement, and M to distant metastases. T - tumor characteristics N - lymph node involvement M - Presence of metastasis TNM system: T indicates tumor spread, N indicates node involvement, and M indicates the presence of distant metastasis. The prognosis generally worsens with increasing tumor size, lymph node involvement, and metastasis. Staging also may alter the choice of therapy, with more aggressive therapy being delivered to more invasive disease Ex. T1N1MO = Small tumor of primary organ site, with regional lymph node involvement, but no metatasis to other sites in the body

Life cycle virus

Viruses cannot reproduce by themselves. They need the DNA mechanisms in human cells to replicate. When a virus enters a cell, its outer coat dissolves and the viral RNA is integrated into the DNA of the cell. This is done by using Reverse Transcription to convert the single strand of RNA into a double strand that "fits" into the cell's DNA.

Is it possible to avoid cancer by lifestyle choices?

You can decrease your risk, but not possible to avoid it.

Neoplasia

is unrestrained growth. - cancer

Reversible cell injury - cell swelling.

Water - cellular swelling (hydropic degeneration). A failure of the cell membrane pump leads to sodium accumulation in the cell; water comes in secondarily causing "cloudy swelling". Lipids - fatty change. An example is the liver in malnutrition or alcoholism. Fat deposition in vacuoles in the cell cause "fatty swelling".

MODULE 3 (2) Steph's Strep - An Example of Antibody Response

What are her signs of inflammation? Erythema, edema, pain, exudate Where did the pus on her tonsils come from? Inflammatory response to streptococcus bacteria by neurtrophills and macrophages Where is the antigen? On the epithelium of the oral pharynx and tonsils How does she produce antibody? B cells that have receptors for the streptococcus bacteria are presented the antigen by macrophages that have consumed the invading pathogenic bacteria. With the assistance from sensitized Helper T cells, the activated B cells are converted into plasma cells, which begin producing antibody against the Streptococcus bacteria. What does the 'rapid test' for streptococcus test for? A rapid strep test, also known as a rapid antigen detection test (RADT), can detect group A strep antigens. Results are available in 10-20 minutes. What does the Anti Streptolysin O titer mean? Antistreptolysin O (ASO) is an antibody targeted against streptolysin O, a toxic enzyme produced by group A Streptococcusbacteria. ASO and anti-DNase B are the most common of several antibodies that are produced by the body's immune systemin response to a strep infection with group A Streptococcus. This test measures the amount of ASO in the blood (McCance & Huether, 2019).

Knowledge check 2 https://www.medscape.com/content/1997/00/40/88/408860/art-wh3017.fig4.jpg

What is the name of the white abnormal area? What is the adaptive process? Dysplagia - related to the rapid cellular division and the abnormally or variation in the cells. What caused this adaptation? HPV - human papaloma virus Is it reversible? No Is it treatable? Yes Is it preventable? Yes, Gardasil Who should receive Gardasil? Girls before sexually active. AND Boys before sexually active -genital warts and testicular cancer.

Write a word in each blank to complete the sentences.

When a genetic condition is present at birth it is called __congenital____. Variation in a __multifactorial___ disease is caused by the combined effects of environment and genes. Variation in a disease is caused by the combined effects of multiple genes. This is called ___polygenic____ . An individual with whom a pedigree begins is called a ____proband______.

Retinoblastoma

White reflex with retinoblastoma autosomal dominant, incomplete penetrance

Once a person has cancer, does it make him/her more susceptible than the general population for developing other types?

Yes

Cancer

a malignant tumor

Tumor

a mass, usually implying a neoplasm. Non-neoplastic masses are sometime referred to as tumors. Remember the cardinal signs of inflammation? A patient with a mass may have an abscess, granuloma (notice the suffix oma) or benign or malignant neoplasm.

MODULE 2 (3) Neoplasm

a precise but general term = a new growth, benign or malignant

Development of T-Cell Subsets.

activation of an immunocompetent T cell (purple cell) by the APC (green cell). The most important step in clonal selection is the production of populations of helper T (Th) cells (Th1, Th2, and Th17) and regulatory T (Treg) cells that are necessary for the development of cellular and humoral immune responses.

Mutagenic agent

agent causing mutation

Oncogenic agent

agent causing neoplasm

The antibodies produced are called immunoglobulins. They react with antigens directly to form an immune complex. This may lead to:

agglutination (clumping), precipitation, neutralization of bacterial toxins, viruses, opsonization (preparation of the capsule of bacteria to render it susceptible to phagocytosis), activation of inflammatory response, initiation of the complement cascade and destruction of the cell or micro-organism.

Integrins

are cell surface receptors that promote cell adhesion and attachment. They also mediate intracellular signaling for inflammation with pathogens, damaged cells, and soluble lipoproteins associated with vascular damage (LDL cholesterol). Through integrin receptors, macrophages can identify and remove old red blood cells and cells undergoing apoptosis. (McCance & Huether, 2019).

Antigen

are molecules that react with antibodies or antigen receptors on B and T cells. Most antigens are immunogenic, they induce an immune response resulting in the production of antibodies or cytotoxic T cells. Although antigen and immunogen are often used as synonyms, there are some differences between the two. Therefore, a substance may be antigenic but not immunogenic.

MODULE 2 (2)Interferons (IFNs)

are proteins that protect against viral infections and modulate the inflammatory response. Different kinds of IFNs are produced by different types of cells. Macrophages are the primary producers of type I interferons (IFN-α and IFN-β), and T lymphocytes produce type II interferon (IFN-γ). IFNs do not kill viruses directly but instead prevent them from infecting additional healthy cells.

Plasma protein systems (cascades)

are triggered by the acute inflammatory response, and are linked through Hageman Factor (XII). All of these protein systems contain inactive enzymes (proenzymes) or inactive plasma proteins -These inactive proteins are sequentially activated during the "cascade" process - ~The first proenzyme is converted to an active enzyme by some event (injury) > ~This active plasma protein becomes the substrate to convert the next inactive enzyme to an active form > ~there is then a series of enzyme (plasma protein) activation until the final product of the cascade is formed. Consider this a "domino effect" where one enzyme activates the next proenzyme, which activates the next, and activates the next, until the product of the cascade is produced.

Causing Type I diabetes mellitus.

autoimmune disease of the islets of Langerhans in the pancreas. (1) and islet cells infiltrated with Tc lymphocytes (2) - purple dots. These Tc lymphocytes do not recognize self and will destroy the islet cells.

Epiglottitis

bacterial inflammation of the epiglottis caused by Haemophilus influenzae. It occurs mostly in children, and is of sudden onset. The epiglottis becomes edematous, and may obstruct the airway. The throat is sore, difficulty in swallowing leads to drooling, and the voice is muffled. http://www.online-ambulance.com/articles/doc/18/grp/Your/art/Epiglottitis.htm

Release of ___________ ions from intracellular stores into the cytoplasm during ischemia damages the cell.

calcium or potassium

Complement Cascade

can destroy pathogens directly, and activates or collaborates with every other component of the inflammatory process. -It can be activated by the immune system or by less specific products Classic pathway - activated by antigen-antibody complex Alternate pathway - products such as bacterial or fungal cell wall polysaccharides. Lectin pathway - activated by bacterial carbohydrates in cell walls

Genetic and epigenetic theory

cancer is a genetic disease: all above agents act through this

Antimicrobial lectins

carbohydrates that are found in intestinal epithelium, work activity against gram-positive bacteria

Epithelial cell origin

carcinoma: cancer of an epithelial (glandular) structure

*Modes of chemical signaling

contact-dependent, paracrine, hormonal, neurohormonal, and neurotransmitter

SOURCES OF CHEMICAL MEDIATORS IN INFLAMMATION

controls all aspects of the inflammatory response

Toll-like receptors (TLRs)

expressed on the surface of cells that have direct and early contact with potential pathogenic microorganisms. These sites include: mucosal epithelial cells, mast cells, neutrophils, and macrophages. TLRs recognize a large variety of PAMPs and can result in activation of the cell and the release of soluble products (e.g., cytokines) that increase local resistance to the pathogenic microorganism. TLRs are also a bridge between innate immunity and the adaptive immunity, activating cytokines that increase the response of lymphocytes to foreign antigens on the pathogens.

The host defenses against fungal infection include:

fungistatic properties of neutrophils and macrophages T lymphocytes are crucial in limiting the extent of infection and producing cytokines to further activate macrophages. Resistance to the host's immune system is complex. Pathologic fungi readily adapt to the host environment, responding to temperature variations, low oxygen levels, more alkaline pH, and other conditions in the host tissue by undergoing changes in morphology. Fungi also switch from avirulent mold forms to virulent yeast forms.

Progression

further changes in tumor cells as it grows

transudates

have little protein or cellular components. An example would be an effusion of fluid in a patient with congestive heart failure.

Hypertrophy

increase in size of a cell or organ. Hypertrophy is either physiologic or pathologic. Physiologic hypertrophy is the result caused by increased demand, stimulation by hormones (e.g., atrial natriuretic peptide hormone), and growth factors (e.g., IGF-1). Weight lifting with increase size in skeletal muscle is an example of physiologic hypertrophy. With a decrease in weight lifting, muscular hypertrophy will diminish. Pregnancy is another example of physiologic hypertrophy, with hormone-induced uterine enlargement. Pathologic hypertrophy of the heart results from chronic increased afterload, such as, hypertension or heart valve dysfunction. Myocardial hypertrophy can progress to maladaptive states, including dysrhythmias, heart failure, and sudden death.

Anaplasia

is loss of differentiation, reverting to the cell's precursor.

Compared to normal aerobic metabolism, cells that use anaerobic metabolism produce more ____________ and less _________.

lactic acid; ATP

Inflammation is usually initiated by cellular injury, which results in:

mast cell degranulation, activation of three plasma systems (Complement, clotting and kinin) release cytokines (lymphokines, interluken, interferon, chemokines).

A transfusion with an incompatible ABO blood type

may lead to a strong, potentially lethal type II hypersensitivity cytotoxic response called hemolytic transfusion reaction (HTR). Ex. if a person with type B blood receives a transfusion of type A blood, their anti-A antibodies will bind to and agglutinate the transfused RBCs. In addition, activation of the classical complement cascade will lead to a strong inflammatory response, and the complement membrane attack complex (MAC) will mediate massive hemolysis of the transfused RBCs. The debris from damaged and destroyed RBCs can occlude blood vessels in the alveoli of the lungs and the glomeruli of the kidneys.

*cytoplasmic organelles

mitochondria, ribosomes, endoplasmic reticulum, Golgi apparatus, lysosomes

Irreversible cell injury

necrosis- Widespread disruption of cell function; cell death in an organ or tissues that is still part of a living person sets off a major inflammatory immune response dislocated ribosomes, failure of Na+/K+ pump, swelling of mitochondria, failure of enzyme systems, DNA degradation and nuclear breakdown, membrane disruption, activation of inflammation.

Cell death by __________ causes inflammation, but cell death by __________ does not.

necrosis; apoptosis

MAST CELLS

origin of chemical mediators that cause inflammation -Cellular bags of granules located in the loose connective tissues close to blood vessels: ~Skin, digestive lining, and respiratory tract -Activation: ~Physical injury, chemical agents, immunologic processes, and toll-like receptors Chemical release in two ways

The Closed Barrier

part of the First Line of Defense. The digestive, respiratory, and genitourinary tracts and the skin form closed barriers between the internal organs and the environment.

Preformed mediators

produced and stored in secretory granules - cytokines are released when the granules are disrupted, triggering inflammation Histamine Serotonin Lysosomal enzymes

Two major proinflammatory cytokines are IL-1 and IL-6: IL-6:

produced by macrophages, lymphocytes, fibroblasts, and other cells. - IL-6 has several functions: ~Directly induces hepatocytes (liver cells) to produce many of the proteins needed in inflammation (acute-phase reactants, discussed later in this chapter). ~Stimulates growth and differentiation of blood cells in the bone marrow ~Growth of fibroblasts (required for wound healing).

Kinin system (e.g. bradykinin

provides an source of inflammatory mediators to support the inflammatory response Functions to activate and assist inflammatory cells Primary kinin produced is bradykinin Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis

Complement receptors

recognize products from activation of the complement system. Complement activation is achieved by immune complexes of antibody and antigen. Both CR3 and CR4 are receptors that facilitates phagocytosis by neutrophils and monocytes/macrophages.

Metaplasia

replacement of one mature cell type for another due to chronic irritation or injury. It is associated with cellular damage, repair and regeneration. This is a reversible condition if the irritant is removed - quit smoking If the irritant of smoking is not removed, a malignant transformation can occur in the metaplastic epithelium

*ribosomes

site of protein synthesis

Multistep hypothesis:

stepwise pathogenesis of cancer with accumulation of mutations

Graves Disease

the antibody attaches to the thyroid stimulating hormone receptors in the thyroid gland. (Not recognizing these receptors as SELF). This attachment over stimulates the gland, causing excessive production of thyroid hormone (T4), resulting in hyperthyroidism and goiter. Not only are antibodies (B cells) stimulating the TSH receptors, but the T cells are also mounting an immune response against the thyroid gland. In the microscopic slide the purple dots are Tc lymphocytes that have not recognized the thyroid gland as "Self" and are attacking the gland tissues.

*passive transport

the movement of substances across a cell membrane without the use of energy by the cell

*signal transduction

the transmission of molecular signals from a cell's exterior to its interior

A patient may require a blood transfusion because

they lack sufficient RBCs (anemia) or because they have experienced significant loss of blood volume through trauma or disease.

Carcinogenesis

tumor development. An agent which causes tumor formation is called a carcinogen. The steps in this process are: -Initiation (probably DNA damage). Cancers form from one cell. Known initiators that alter DNA are radiation, chemicals (including hormones and drugs), and viruses -Promotion (carcinogen acts to change cell into cancer) Multiple 'hits' are necessary over time to cause a proto-oncogene into an oncogene, or to disable a tumor suppressor gene. The damage to DNA that causes the conversion of proto-oncogenes to oncogenes, and transforms a normal cell into a cancer cell. **DNA damage occurs from viral RNA incorporated into the DNA of cells, inherited DNA defects (from parents), exposure to radiation or chemicals that damages DNA - which leads to genetic mutations.

Duchenne muscular dystrophy

x-linked disorders The Y chromosome contains only a few dozen genes, so most sex-linked traits are located on the X chromosome and are said to be X-linked Sex-linked (X-linked) disorders are usually expressed by males because females have another X chromosome to mask the abnormal gene X-linked recessive characteristics: Most X-linked disorders are recessive Affected males cannot transmit the genes to sons, but they can to all daughters Sons of female carriers have a 50% risk of being affected Duchenne muscular dystrophy (DMD; OMIM 310200) is an X-linked recessive disorder that is caused by mutations in the dystrophin gene: the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons. frameshift errors from large insertions or deletions (60%) small frame shift rearrangements (40%) These mutations cause a lack the dystrophin protein, which is a major structural component in muscle. Dystrophin links the internal cytoskeleton of muscle cells to their extracellular matrix. This is called the dystrophin-associated protein complex (DAPC) at the sarcolemma. The DAPC is destabilized when dystrophin is absent, which results in diminished levels of DAPC proteins, which causes progressive fiber damage and membrane leakage. The DAPC also has a signalling role, the loss of which contributes to pathogenesis DMD. DMD patients are usually wheelchair-bound by 12 years of age and die of respiratory failure in their late teens or early twenties. Many boys have an abnormal electrocardiogram by the age of 18, indicating damage to the cardiac muscle.

β-defensins

β-defensins are synthesized in active forms. Both classes of antimicrobial peptides can activate innate and adaptive immunity Found in epithelial cells lining the respiratory, urinary, and intestinal tracts, as well as in the skin Antibacterial properties Protect against HIV

Exam A Module 1 Cell Injury & Adaptation

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