MIC 319

TLR and CLR

-Cell surface + endosome -membrane bound -cell surface

Salmonella enteritis and Typhimurium are characterized by

-Diarrhea with 24 hours after infections accompanied by acute intestinal inflammation with fever -employs multiple virulence factors to overcome resistance and induce intestinal inflammation -unlike Citrobacter (or ETEC), Salmonella replicates intracellularly, even in macrophages, and invades beyond the intestinal lumen

Unintended and non-infectious

-Harmless foreign molecules (allergens) -Our own healthy cells -transplants from other donors

The three general functions of barrier cells that prevent intruder from entering

-Mechanical/physical -chemical -microbiological

What are some common effector mechanisms of barriers?

-Mucus -Acid -microflora -cilia

IL-1

-Secreted by macrophages -Also called osteoclast-activating factor. Causes fever, acute inflammation. -Activates endothelium to express adhesion molecules. -Induces chemokine secretion to recruit WBCs.

Characteristics of infectious pathogens

-Size: microscopic, very few are macroscopic -Distinct life cycles: virus, bacterium, fungus, parasite, worm -Location: inside of eukaryotic cells.

PRRs (pattern recognition receptors)

-TLRs (1-10 in humans) (Toll-like receptors) -CLR's (C-type Lectin receptors) -NLR's (Nucleotide binding oligomerization receptors) -RLR's -ALR's

M2 Macrophage

-anti-inflammatory -matrix producing -pro-angiogenesis -Pro wound healing

Diseases involving chronic inflammation

-cancer -cardiovascular disease -ocular disease -autoimmune disease -pulmonary disease -neurodegenerative disease -periodontitis -metabolic syndrome -age-related frailty

pepsinogen

-converted by HCl in the stomach to pepsin -The inactive form of pepsin that is first secreted by specialized (chief) cells located in gastric pits of the stomach.

Innate mechanisms to eliminate dangerous pathogens

-eat and digest the extra cellular pathogens (phagocytosis) IF they are > 0.5 uM and smaller than the phagocyte (macrophages and neutrophils) -Communicate their detection inside the body (sentinel cells to delivery or activation of more innate cells) -punch holes into bacterial membranes (complement) -laser tag pathogen (complement) to enhance their phagocytosis -kill the host cell that harbors an intercellular pathogen such as viruses (NK cell) and similarly, tumors -release poison onto them if they are parasites or worms (eosinophils and basophils) -Communicate desired functions (cytokines, or cell surface ligand) and desired location -barrier function(simply not letting them ending your body)

M1 Macrophage

-pro-inflammatory -bactericidal -phagocytic

4 different subclasses of infalmmation

1) Local infection or host cell damage will result in ACUTE inflammation 2) failure to generate a local inflammation barrier against microbes results in SEPSIS 3) Impaired deactivation/chronic activation will results in CHRONIC inflammation 4) Deactivation of acute inflammation results in RESOLUTION and WOUND HEALING

Systemic infection sequence (gram negative)

1. Macrophages activated in the lover and spleen secrete TNF-alpha into the blood stream 2. Systemic edema causing decreased blood volume, hypoproteinemia, and neutropenia, followed by neutrophilia. Decreased blood volume causes collapse of of vessels. 3. Disseminated intravascular coagulation leading to wasting and multiple organ failure. 4. Death

Local infection response sequence (gram negative bacteria)

1. Macrophages activated to secrete TNF-alpha in the tissue 2. Increased release of plasma proteins into tissue. Increased phagocyte and lymphocyte migration into tissue. Increased platelet adhesions to blood vessels (physical barrier) 3. Phagocytosis of bacteria. Local vessel occlusion. Plasma and cells drain to local lymph node 4. Removal of infection = adaptive immunity

The human intestine harbors an estimated ____ trillion bacteria

30

Basophils

A circulating leukocyte that produces histamine.

innate immunity

A form of defense common to all animals that is active immediately upon exposure to pathogens and that is the same whether or not the pathogen has been encountered previously.

Kartagener Syndrome

A form of primary ciliary dyskinesia characterized by the triad of situs inversus, chronic sinusitis, and brochiectasis. It occurs due to mutations that impair the structure or function of cilia. Cystic fibrosis also causes chronic respiratory infections, but not the situs inversus. -occurs when one or both of the dynein arms (ODA and IDA) are missing due to genetic abnormalities

Cystic fibrosis

A genetic disorder that occurs in people with two copies of a certain recessive allele; characterized by an excessive secretion of mucus and consequent vulnerability to infection; fatal if untreated.

Innate Lymphoid Cells (ILCs)

A group of lymphocytes that lack specificity in their mechanism of antigen recognition; includes natural killer (NK) cells. Amplify cytokines.

Draining of lymph nodes

A lymph node downstream of a site of infection that receives antigens and microbes from the site via the lymphatic system. Draining lymph nodes often enlarge enormously during an immune response and can be palpated; they were originally called swollen glands.

Hypothalamus

A neural structure lying below the thalamus; it directs several maintenance activities (eating, drinking, body temperature), helps govern the endocrine system via the pituitary gland, and is linked to emotion and reward.

Melanin

A pigment that gives the skin its color

Natural Killer cell

A type of white blood cell that can kill tumor cells and virus-infected cells as part of innate immunity.

Perivascular cell infiltration =

Accumulation of inflammatory cells around the blood vessels

Acidophile bacteria

Acidophiles or acidophilic organisms are those that thrive under highly acidic conditions (usually at pH 2.0 or below). -Most acidophile organisms have evolved extremely efficient mechanisms to pump protons out of the intracellular space in order to keep the cytoplasm at or near neutral pH. Therefore, intracellular proteins do not need to develop acid stability through evolution. However, other acidophiles, such as Acetobacter aceti, have an acidified cytoplasm which forces nearly all proteins in the genome to evolve acid stability. For this reason, Acetobacter aceti has become a valuable resource for understanding the mechanisms by which proteins can attain acid stability.

After the initial reaction of the innate immune system the _________ system begins its work

Adaptive immune

adhesion molecules

Allow the cells of a tissue to recognize one another and stick together.

PH affect the protonation action of

Amino acids (arginine, lysine, histidine, glutamate, and apartate. This can change a proteins folding and activity

AMP's insert into the microbes membranes using

Amphipathic pathways (incomplete)

Pemphigus

An acute or chronic disease of adults, characterized by occurence of successive crops of bullae that appear suddenly or apparently normal skin and disappear, leaving pigmented spots. It may be attended by itching and burning and constitutional disturbance. The disease if untreated is usually fatal. A characteristic finding is a positive Nikolsky sign: When pressure is applied tangential to the surface of affected skin, the outer layer of epidermis will detach from the lower layer. (Probably autoimmune)

Pepsin

An enzyme present in gastric juice that begins the hydrolysis of proteins

Desmosomes

Anchoring junctions that prevents cells subjected to mechanical stress from being pulled apart; button like thickenings of adjacent plasma membranes connected by fine protein filaments

Cathelicidin and lecticidin belong to

Anti Microbial Peptide group (AMP's)

Autoantibodies

Antibodies produced by B cells that mistakenly attack and destroy "self" cells belonging to the patient; autoantibodies are the pathophysiologic agent of most autoimmune disorders

Dendritic cell

Antigen-presenting cell. Shows T and B cells what to attack

bone marrow derived cells

B cells

Memory cells

B lymphocytes that do not become plasma cells but remain dormant until reactivated by the same antigen.

Lactobacilli

Bacteria that produce lactic acid from carbohydrates

Prevent pathogens from attaching and crossing epithelial in contact with the environment

Barrier tissues

Hydrolysis

Breaking down complex molecules by the chemical addition of water

Dendritic cells

Bridge to the adaptive immune response. specialized white blood cells that patrol the body searching for antigens that produce infections.

C. Rodentium

C. rodentium is a gram negative, murine specific bacterial pathogen that is closely related to the clinically important human pathogens enteropathogenic E. coli and enterohemorrhagic E. coli. Upon infection with C. rodentium, immunocompetent mice suffer from modest and transient weight loss and diarrhea.

Acute imflammation

Calling in the white blood cells to destroy invading pathogens

Histamine

Chemical stored in mast cells that triggers dilation and increased permeability of capillaries.

Which pairing of a cell and antimicrobial molecule is FALSE? -foveolar cell-mucus -goblet cell-mucus -paneth cells - AMPs -chief cells- bicarbonate -parietal cells- HCl

Chief Cells and Bicarbonate pairing

Cystic fibrosis transmembrane regulator (CFTR) operates a

Chloride channel. Without the chloride secretion, exocrine secretions (including digestive juices, sweat and mucus) becomes thick and less lubricant.

stomach cancer risk factors

Chronic H.pylori, malignant neoplasm's in stomach

Different innate killer cells and killer molecules are required to

Combat intruding pathogens

Complement proteins

Complement proteins are proteins that lyse the cell wall of an antigen. They are part of the nonspecific defense mechanisms of the immune system.

large intestine function

Concentrates, mixes, and stores waste material; Absorbs water, ions, and vitamins; Produces some B vitamins and vitamin K

Mucus separates the luminal contents of the lungs and gut from

Contact with the lumens epithelial cells

Lactobacillus are our friends as they

Contribute to the slight acidity of the digestive, urinary and genital systems through their metabolic production of lactic acid

DAMPs

Damage-associated molecular patterns: TLRs react with these non self antigens on damaged tissue, --> then release proinflmmatory cytokines and chemokines Derived from: plasma membrane, nucleus, ER, mitochondria, cytosol

Antibiotics

Drugs that block the growth and reproduction of bacteria

Bronchus

Either of the two subdivisions of the trachea conveying air into the lungs.

Bladder

Elastic, hollow, muscular organ that provides temporary storage for urine.

Lysozome

Enzyme that can destroy bacterial cell walls and some viral capsules (present in saliva; tears; mucous)

Urease

Enzyme that changes urea into ammonia and carbon dioxide

Which pair is made up of a barrier cell and one of its correct innate effectors

Epidermis - Microbiome

Connects throat to stomach service as a conduit for solid and liquid food

Esophagus

Microvilli

Fingerlike extensions of plasma membrane of apical epithelial cells, increase surface area, aid in absorbtion, exist on every moist epithelia, but most dense in small intestine and kidney

AMP's (antimicrobial peptides) comprise the simplest

Form of innate membrane attacks

Keratin filaments

From Epidermis ensures strength and adhesion to the junction

H. Pylori

Gastric adenocarcinoma and MALT lymphoma

Surfactant

Generates a lipoprotein mono layer at the air-liquid interface to lower the surface tension which eases blowing up the air sacs.

Mucus is made up of heavily

Glycoly (incomplete)

Mucins are produced by specialized epithelial cells called

Goblet cells and also by glands in the submucosal tissue

Some chronic diseases seem to associate with perturbations of the

Gut microbiome

Cilia

Hairlike projections that extend from the plasma membrane and are used for locomotion

Kartagener's syndrome

Immotile cilia due to a dynein arm defect. Results in male and female infertility (sperm immotile), bronchiectasis, and recurrent sinusitis (bacteria and particles not pushed out); associated w/ situs inversus.

Neutrophilia

Increased numbers of neutrophils.

Detection of MAMP's or DAMP's results in inflammation and "aid" in response to

Infection or cell injury

Lipoxins

Inhibit neutrophil chemotaxis and adhesion to endothelial cells; antagonist to other substance in its pathway

NLR, ALR, RLR

Intracellular

Phagosome

Intracellular vesicle containing material taken up by phagocytosis.

Opsonization of microbes

Is done by complement; enhance phagocytosis

How does a healthy microbiome contribute to the barrier function of tissues?

It competes with newly arriving foreign microorganisms for resources thus making an overgrowth for these potentially harmful pathogens much more difficult

Desmosomes (anchoring junctions)

Joins the intermediate filaments in one cell to those in a neighbor

Mechanical and chemical barriers of the skin

Keratin scales (mechanical) and fatty acids and glycolipids (chemical)

secrete glycolips and anti microbial proteins. Also synthesize cytoskeleton and use cholesterol to synthesize vitamin D

Keratinocytes

Produce keratins, NOT Derived from the bone marrow, secrete glycolipids, secrete antimicrobial peptides, act as sentinel cells with PRR's for infectious pathogens, can be activated to secrete inflammatory cytokines as well as chemokines, act as sentinel cells with PRR's for host cell damage, can be activated to produce melanocytes stimulating hormone (alpha-MSH) for protection from Ultraviolet B (UV B)

Keratinocytes in relation to their role in innate immunity

Receptors of the innate immune system

LPS, peptidoglycan, double stranded viral RNA

Lamellar bodies

Lamellar bodies in the alveoli of the lungs, fuse with the cell membrane and release pulmonary surfactant into the extracellular space

Macrophage

Large white blood cell that removes bacteria, foreign particles, and dead cells

The mucociliary escalator

Layer of mucus moved by cilia lining the respiratory tract that traps bacteria and other particles and moves them into the throat.

Paneth cells produce which antmicrobial proteins?

Lysozyme and AMPs

Maresins

Macrophage mediator in Resolving Inflammation

dust cells (alveolar macrophages)

Macrophages found on the surface of alveoli that sterilize bacteria

Bicarbonate function

Major body buffer involved in acid-base regulation

Membrane disruption

Method of Disinfection Membranes contain proteins, therefore can be affected by protein disrupting reactions (see Protein Disruption) Membranes are also composed of lipids and can be disrupted by compounds that destroy lipids -SURFACTANTS are soluble compounds that reduce surface tension, which dissolves lipids; they are used in dishwater and detergent solutions (also known as WETTING AGENTS) -They work by "jabbing" themselves into fatty substances with their fatty acid chains; this pulls the membrane apart -this usually doesn't kill the cell outright, however it allows other chemicals to enter the cell Examples of Surfactants -Alcohols -Detergents -Quaternary ammonium compounds (QUATS) -Phenols Textbook: Figure 12.3

The microbiome

Microorganisms in a particular environment including the surface of barrier tissues

Which bone-marrow-derived innate cells can promote inflammation?

Monocytes

Mice that cannot activate alpha-defensins are

More susceptible to S. Typhimurium. Alpha-defensins are cleaved by matrix metallaproteinase 7 (MMP7 known as MAT) before they become active.

Neutrophils

Most abundant white blood cell., The most abundant type of white blood cell. Phagocytic and tend to self-destruct as they destroy foreign invaders, limiting their life span to a few days.

There are 21 distinct ______ genes

Mucin

The structural basis for mucus are net-like glycoproteins called

Mucins

Foveolar cells

Mucus producing cells which covers the inside of the stomach protecting it from corrosive nature of gastric acid

Resolvins

Naturally occurring substances identified as signalling molecules involved in the normal dampening of the inflammation response.

AMP's recognize and bind to

Negatively-charged membranes (underrepresented in host cell ) or unique carbohydrates

As long as the tissue remains infected, granule proteins are released from

Neutrophils

MMP7 is produced by

Paneth Cells, just likes the AMP's

Mucus is slippery and can readily expel trapped microbes by

Peristaltic movement of the intestine, exhalation/cough, and a special transport system in the airways (cilia)

MAMPS's or DAMP's generate a

Physical barrier (cells and blood clots) that contains the spread of the infection or host cell destruction

Lactic acid

Produced in muscle cells from the reduction of pyruvate (under anaerobic conditions) to regenerate NAD+ so that glycolysis can continue. A rise in lactic acid usually accompanies an increase in physical activity.

What is the difference between mucus and pus?

Pus, not mucus, contains chromosomal DNA of neutrophils in response to an inflammatory event

Immediate innate response

Recognition, nonspecific phagocytes (macrophages, neutrophils, etc.), release of cytokines, release of molecules. Phagocytosis. Occurs with 4 hours

Resolution of inflammation

Restoration of normal structure. Granulation tissue -- highly vascularized, fibrotic. Abscess -- fibrosis surrounding pus. Fistula -- abnormal communication. Scarring -- collagen deposition resulting in altered structure and fxn.

AMP's are synthesized and

Secreted as inactive precursors

Continues digestion via pancreatic enzymes and bile, lives intimately with the micro biome and absorbs water, minerals, nutrients and vitamins

Small intestine

The microbiome shapes many processes to include

Stimulation of basal immune activity, especially in the gut.

Secretes acid and enzymes and mixes them with food for its digestion

Stomach

Composite and function of the microbiome

The microbiome consists of microbes that are both helpful and also potentially harmful. Most of the bacteria are mutually beneficial to us.

Barrier tissues

Tissues and organs that form protective boundaries between the external and internal environments of a body; include skin and the mucosal tissues (gastrointestinal, respiratory, reproductive, urogenital tracts) as well as distinct immune cells and systems.

TLR

Toll-like receptor. A membrane receptor on a phagocytic white blood cell that recognizes fragments of molecules common to a set of pathogens.

TNF-a

Tumor Necrosis Factor Alpha - (an inflammatory cytokines) makes the blood vessel permeable causing liquid to leak out into tissues which results in a loss of blood volume dropping blood pressure causing shock

Prostaglandins enhance

Vascular permeability

Leukotrienes mediate the local accumulation of

WBC's during acute inflammation

Tissue repair and healing is controlled by local barrier cells and innate _______

White blood cells

Thrombus

a blood clot attached to the interior wall of an artery or vein

Goblet cells

a column-shaped cell found in the respiratory and intestinal tracts, which secretes the main component of mucus. (Mucin glycoproteins

tight junction

a firm seal between two adjacent animal cells created by protein adherence

Epiglottis

a flap of cartilage at the root of the tongue, which is depressed during swallowing to cover the opening of the windpipe.

Trachea

a large membranous tube reinforced by rings of cartilage, extending from the larynx to the bronchial tubes and conveying air to and from the lungs; the windpipe.

Monocyte

a large phagocytic white blood cell with a simple oval nucleus and clear, grayish cytoplasm.

stratum spinosum

a layer of the epidermis that provides strength and flexibility to the skin

T-cell

a lymphocyte that identifies pathogens and distinguishes one pathogen from another

Chronic inflammation

a response of blood vessels to harmful substances, such as germs, damaged cells, or irritants; can lead to heart disease, cancer, allergies, and muscle degeneration

Antigens

a toxin or other foreign substance that induces an immune response in the body, especially the production of antibodies.

Disseminated intravascular coagulation

abnormal activation of the proteins involved in blood coagulation, causing small blood clots to form in vessels and cutting off the supply of oxygen to distal tissues

Thrombosis

abnormal condition of a blood clot

Gap junction

allows the passage of small water-soluble ions and molecules

Hemidesmosome

anchors intermediate filaments in a cell to the basal lamina

Receptors of adaptive immunity

antibodies (Ab) and T-cell receptors (TCR)

Heparin

anticoagulant found in blood and tissue cells

Hematopoietic cells

any blood cell or its precursor cell types

Cytokine

any of a number of substances, such as interferon, interleukin, and growth factors, that are secreted by certain cells of the immune system and have an effect on other cells.

Surfactant

any substance that interferes with the hydrogen bonding between water molecules and thereby reduces surface tension

Deep vein thrombosis

blood clot forms in a large vein, usually in a lower limb

Melanocyte

cell in the basal layer that gives color to the skin

Keratinocyte

cell that produces keratin and is the most predominant type of cell found in the epidermis

Sentinel cell

cells that help the immune system detect signs of invasion by producing cytokines when their pattern recognition receptors recognize an invading microbe

CXCL8 (IL-8)

chemotactic factor recruits neutrophils, basophils, and T cells to site of infection

D.A.M.P.

damage associated molecular patterns. Released from damaged host cells and their organelles

Neutropenia

deficiency of neutrophils

Eosinophils (granulocyte)

destroy parasites and increase during allergic reactions

gastric lipase

enzyme to digest fat, produced by chief cells

Wound healing

excessive matrix metalloproteinase activity and myofibroblast accumulation in teh wound margins can result in contracture, which produces deformities of the wound and surrounding tissues, most often of the palms, soles.

type 1 pneumocytes

extremely thin alveolar cells that are adapted to carry out gas exchange

Mast cells

found in the connective tissue of the dermis; respond to injury, infection, or allergy by producing and releasing substances, including heparin and histamine

adaptive immunity

immunity or resistance to a specific pathogen; slower to respond, has memory component

Chloride channel

in cystic fibrosis, this channel is either absent or defective (mutation)

swelling (edema)

increased flow of fluids from blood to tissue spaces

melanocyte-stimulating hormone (MSH)

increases the production of melanin in melanocytes of the skin

Chronic bronchitis

inflammation of bronchi persisting over a long time; type of chronic obstructive pulmonary disease (COPD)

Antimicrobial peptides (AMPs)

inhibit cell wall synthesis; form pores in plasma membranes, resulting in lysis; and destroy DNA and RNA

Pemphigus causes blisters because the skin cells cannot firmly attach to each other. Pemphigus is an autoimmune disease that produces antibodies against which strength-producing transmembrane protein? A integrin B laminin C keratin D plaque

integrin

adherens junctions

joins an actin bundle in one cell to a similar bundle in a neighboring cell

Macrophage

large phagocyte found in lymph nodes and other tissues of the body

B lymphocytes (B cells)

lymphocytes which mature in the bone marrow and that are involved in the production of antibodies

MAMPs

microbe-associated molecular patterns. Different cells of the innate immune system express identical pattern recognition receptors to recognize these MAMPs or PAMPs (pathogen-associated molecular patterns)

Peptic ulcer

open sore or lesion of the mucous membrane of the stomach or duodenum

Stratum corneum

outermost layer of the epidermis, which consists of flattened, keratinized cells

Diapedesis

passage of blood cells (especially white blood cells) through intact capillary walls and into the surrounding tissue

Perivascular

pertaining to around a vessel

Alveolar macrophages (dust cells)

phagocytose small particles in alveoli

Efferocytosis

process by which dying/dead cells (e.g. apoptotic or necrotic) are removed by phagocytic cells

Apoptosis

process of programmed cell death

Liver

produces bile

Lipid mediators of inflammation

prostaglandins and leukotrienes

dynein arms

protein extension from a microtubule doublet in a cillia or flagella that is involved in the energy conversion that drives the bending of it

Interferons

proteins (cytokines) secreted by T cells and other cells to aid and regulate the immune response

Interleukins

proteins (cytokines) that stimulate the growth of B and T lymphocytes

Pattern Recognition Receptors (PRRs)

proteins on or in cells that recognize specific compounds unique to microbes or tissue damage, allowing the cells to sense the presence of invading microbes or damage

Autoimmune response

response when the immune system acts against its own cells and destroys healthy tissue in the body.

situs inversus

reversed position of organs

Tight junctions

seals neighboring cells together in an epithelial sheet to prevent leakage of molecules between them

Parietal cells

secrete HCl and intrinsic factor

chief cells of the stomach

secrete pepsinogen and gastric lipase

Sebaceous glands

secrete sebum (oil) into the hair follicles where the hair shafts pass through the dermis

Chief cell

secretes pepsinogen and gastric lipase

dendtritic cells

specialized leukocytes that patrol the body searching for antigens that produce infections (sentinel cell)

cell polarity

the ability of cells to generate functionally distinct regions

hypoproteinemia

the presence of abnormally low concentrations of protein in the blood

Alveoli

tiny sacs of lung tissue specialized for the movement of gases between air and blood

Sepsis

toxic inflammatory condition arising from the spread of microbes, especially bacteria or their toxins, from a focus of infection

Lamina Propria

underlying layer of areolar tissue that supports the respiratory epithelium