Biology - Immunology

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1. Characteristics of Innate defenses?

- General protection mechanism that attempt to stop pathogens from invading body OR to quickly eliminate those that do no manage to invade - Genetically programmed (innate) and "ready to go" - in contrast to adaptive repsosnes, which take time to develop after pathogen or toxin has been recognized as nonself Include: (1) physical barrier (2) cellular defenses (3) chemical defesnes a. PHYSICAL BARRIER - 1st line of innate defense encountered by potential pathogen as soon as it lands on surface of animal i. Human skin 1) Physical barrier of skin - bacteria rarely penetrate intact skin; by same token, broken skin increases risk of infection 2) Saltiness and dryness of skin - Environment may not be hospitable to growth of bacterium 3) Presence of normal flora - Bacteria + fungi that normally live and sometimes reproduce in great numbers on our body surfaces w/o causing disease - Will compete with pathogens for space and nutrients ii. If pathogen lands inside nose or another internal organ, it faces other innate defenses 1) Mucus - Slippery secretion produced by mucous membrane found in inner surfaces of nose (as well as digestive, respiratory, and urogenital systems) - Mucus traps microorganisms so they can be removed by beating of cilia - which continuously move mucus and its trapped debris away 2) Lysozyme - Enzyme made by mucous membranes that attacks cell walls of many bacteria - Cause them to lyze (burst open) 3) Defensins - Made by mucous membranes - are peptides of 18-45 AA that contain hydrophobic domains - Toxic to wide range of pathogens: bacteria, microbial eukaryotes, enveloped viruses - Insert themselves into plasma membranes of these organisms - make membranes permeable => killing invaders - Also produced in phagovytes - where they kiull pathogens ingested vy phgagocytosis 4) Harsh conditions in animal´s internal environement can also kill pathogens - Ex. Gastric juice in stomach is deadly environment for many bacteria b/c HCl and proteases that are secreted into it a. Cell signaling pathways stimulate body´s defenses - 2nd line of innate defense - Pathogens able to penetrate body´s outer and inner surfaces encounter more complex innate defenses - Defense repsosnes triggered by nonself molecules i. Pattern recognition receptors (PRRs) - Important role in distinguishing self from nonself - PRRs present in cells that play roles in innate immune system => macrophages, dendritic cells, natural killer cells - Pathogen associated molecular patterns (PAMPs): molecules recognized by PRRs - these molucels are unique to large classes of microbes, such as bacterial lipopolysachharides - found in bacterial cell membrane - Invading pathogen an be regarded as signal => in response to signal, body produces molecuels (complement proteisn, interferons, cytokines) that regulate phagocytosius and other defense processes - Toll-like receptors: key group of PRRs; activate signal transduction pathway involved in both innate and adaptive denfeses ii. Mechanism 1) Fragment of bacterium binds to toll-like receptor 2) Protein kinase cascade occurs 3) Shape of transcription factor NF-kB is altered => activation of NF-kB (nuclear factor kappa light chain enhancer of activated B cells) 4) NF-kB enters nucleus and binds to promoters 5) Genes encoding defensive proteins are transcribed b. SPECIALIED PROTEINS that participate in innate immunity i. Complement proteins - Blood contains more than 20 different proteins that make up antimicrobial complement system - System activated by carious mechanisn, including both innate and adaptive defense repsosnes - Proteins act in characteristic seq., or cascade, with each protein activating the next: 1) Protein attach first to specific compenents on surface of microbe OR to antibody that has already bound to mcirobe´s antigen (surface); in either case - binding helps phagocytes recognizes and destroy microbe 2) Then, complement proteins activate inflammatory responses AND attract phagocytes to site of infection 3) Finally, complement proteins lyse invading cells (such as bacteria9 ii. Interferons - When cell is infected by pathogen => it produces small amount of signaling proteins called interferons - Increase resistance of neighboring cells to infecvtion - Class of cytokines - Various molecuels, incl. dsRNA (viral), induce production of interferons => Important as 1st line of defense against VIRUS - Intererons bind to receptors on plasma membranes of uninfected cells - stimulating signaling pathway that inhibits viral reproduction if cells are subsequently infected - Stimulate cells to hydrolyze bacterial or viral proteins to peptides => initial step in adaptive immunity c. Cell that participate in innate immunity i. Phagocytes - Some phagocytes travel freely in circulatory and lymphatic systems; other can move out of blood vessels and adhere to certain tissues - Pathogenic cells, viruses, or fragments of these invaders are recognized by phagocytes - ingest them by phagocytosis - Defensins, NO, and reactive Oxygen intermediates inside these phagocytes then kill these pathogens ii. Natural killer cells - Distinguish virus-infected cells and some tumor cells from their normal counterpart - Initiate apoptosis of these target cells - Natural killer cells interact also with ADAPATIVE defense mechanism by lysing antibody-labeled target cells iii. Dendritic cells - Phagocytes act as messengers b/w innate and adapative systems (1) Endocytose microbes, viruses, and even virus-infected host cells (2) Once inside dendritic cell - particles digested to fragments, and if fragments have PAMPs, dendritic cell "presents" antigenic fragment on surface - along with class II MHC proteins (3) Secret also signals that activate cells of adaptive immune system Often innate immune system with nonspecific defense - adequate to prevent or fight off pathogenic infection In many cases - system works together with adaptive immunity => detects + responds to specific pathogens

Biological factors of anatomical barriers?

Biological factors (natural flora of skin and intestines) - The normal flora of the skin and in the gastrointestinal tract can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces.

a. T cell receptors?

bind to antigens on cell surfaces Like B cells, T cell possess specific membrane receptors - T cell receptor is not an Ig, but a glycoprotein with molecular weight of about ½ that of IgG i. Structure - Made up of 2 polypeptide chains - each encoded by separate gene - 2 chains have distinct regions with constant + variable AA seq. - Variable region: as in Ig, variable regions provide site for specific binding to antigens; but one major difference: whereas antibody can bind to any antigen, whether present on surface of cell or not; T cell receptor binds ONLY to antigen displayed by MHC protein on surface of antigen-presenting or target genes!!! ii. Activation of T cell - Activated by contact with specific antigen => proliferates and forms a clone - It s descendants form clones of 2 types of effector T cells (1) Cytotoxic T cells (Tc cells) - recognize virus-infected OR mutated cells and kill them by inducing lysis (2) T helper cells (Th cells) - assist both cellular + humoral immune responses

- Immunological tolerance? how is it for innate and adaptive immune system?

ensures that self antigens are not normally attacked INNATE IMMUNE SYSTEM: Cells of the innate immune system use pattern recognition receptors (PRR) to distinguish pathogens from the normal molecules of the host ADAPTIVE IMMUNE SYTEM: - The adaptive immune system has a far more DIFFICULT recognition task: it must be able to respond specifically to an almost unlimited number of foreign macromolecules, while avoiding responding to the large number of molecules made by the host organism itself - Self molecules do not induce the innate immune reactions required to activate the adaptive immune system - The immune system is genetically capable of responding to self molecules but learns not to do so

How is complement systme activated?

i. Activation of complement - The activation of complement involves the sequential proteolysis of proteins to generate enzymes with catalytic activities - The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex - Over 25 proteins and protein fragments make up the complement system.

How is steps of inflammation? (6)

(1) Damaged tissues attract mast cells which release histamine, which diffuses into capillaries (2) Histamine causes capillaries to dilate and become leaky; complement proteins leave capillaries and attract phagocytes (3) blood plasma and phagocytes move into infected tissue from capillaries (4) phagocytes engulf bacteria and dead cells (5) histamine and complement signalling cease; phagocytes are no longer attracted (6) Signaling molecules stimulate endothelial cell division, healing the woujd

Response (time after infection by pathogen)?

(1) Early (0-4 hr) => Innate, nonspecific (1st line) => - Barrier (skin and lining of organs) - Dryness, low pH - Mucus Lysozyme, defensing (2) middle (>4-96 hr) Innate, nonspecific (2nd line - - Inflammation - Fever - Phagocytosis - Natural killer cells - Complement system Interferons (3) Late (> 96 hr/4 days) Adaptive, specific - humoral immunity (antibodies from B cells) celliular immunity (T cells)

The 3 lineages of blood cells?

(1) Erythroid lineages - Erythrocytes + reticulocytes are the oxygen carrying RBC - both reticulocytes and erythrocytes are functional and are released into the blood. - In fact, a reticulocyte count estimates the rate of erythropoiesis. - Reticulocytes are immature red blood cells (RBCs). They're made in the bone marrow and are released into the bloodstream, where they circulate for about 1-2 days before developing into mature red blood cells. (2) LYMPHOID LINEAGES - Lymphocytes (B and T cell) are the cornerstone of the adaptive immune system - They are derived from common lymphoid progenitors. - The lymphoid lineage is primarily composed of T-cells and B-cells (types of white blood cells) - This is lymphopoiesis. (3) Myeloid lineages - Myelocuyes - include granulocytes (basophil, neutrophil, eosinophil), megakayrotyces (thrombocyte = platelet) and macrophages (from monocyte) are derived from commion myeloid progenitors - Inviolved in such diverse roles as innate immunity, adaptive immunity, and blood clotting - Myelopoiesis - Granulopoiesis (or granulocytopoiesis) is haematopoiesis of granulocytes. Megakaryocytopoiesis is haematopoiesis of megakaryocytes.

What are the 2 subdivision of immune system?

(1) Innate (nonspecific) - 1st line of defence a) cellular components b) humoral components (2) Adapative (specific) - 2nd line of defence a) cellular components b) humoral components The immune system is composed of two major subdivisions, the innate (or non-specific) immune system and the adaptive (or specific) immune system. The innate immune system is our first line of defense against invading organisms while the adaptive immune system acts as a second line of defense and also affords protection against re-exposure to the same pathogen. Each of the major subdivisions of the immune system has both cellular and humoral components by which they carry out their protective function. In addition, the innate immune system also has anatomical features that function as barriers to infection.

Others humoral factors that plays a role in innate immune system? (5) LILI´D

(1) Lactoferrin + transferrin => bind iron, essential nutrient for bacteria; limit bacterial growth (2) Interferons - proteins that limit virus replication in cells (3) Lysozyme - breaks down the cell wall of bacteria. (4) IL-1 - induces fever + production of acute phase proteins, some which are antimicrobrial b/c they can opsonize bacteria (5) Defensin - antimicrobial effect

What are the neutrophils?

(1)Neutrophils - are recruited to the site of infection where they phagocytose invading organisms and kill them intracellularly - In addition, these cells contribute to collateral tissue damage that occurs during inflammation.

THe macrophages?

(2) Macrophages - Tissue macrophages and newly recruited monocytes, which differentiate into macrophages, also function in phagocytosis and intracellular killing of microorganisms - In addition, macrophages are capable of extracellular killing of infected or altered self target cells - Furthermore, macrophages contribute to tissue repair and act as antigen- presenting cells, which are required for the induction of specific immune responses.

The (3)Natural killer (NK) and lymphokine activated killer (LAK) cells?

(3)Natural killer (NK) and lymphokine activated killer (LAK) cells - can nonspecifically kill virus infected and tumor cells - These cells are not part of the inflammatory response but they are important in nonspecific immunity to viral infections and tumor surveillance.

Erythroid lineages?

) Erythroid lineages - Erythrocytes + reticulocytes are the oxygen carrying RBC - both reticulocytes and erythrocytes are functional and are released into the blood. - In fact, a reticulocyte count estimates the rate of erythropoiesis. - Reticulocytes are immature red blood cells (RBCs). They're made in the bone marrow and are released into the bloodstream, where they circulate for about 1-2 days before developing into mature red blood cells.

Myasthenia gravis?

- - Myasthenia gravis the affected individuals make antibodies against the acetylcholine receptors on their own skeletal muscle cells => for muscle contraction These antibodies interfere with the normal functioning of the receptors so that the patients become weak and may die because they cannot breathe (no muscle contraction) Myasthenia gravis is an autoimmune disease which results from antibodies that block or destroy nicotinic acetylcholine receptors at the junction between the nerve and muscle. This prevents nerve impulses from triggering muscle contractions

1. WBC defensive roles?

- 1 ml of human blood typically contain about 5 billion RBC and 7 billion larger WBC (leukocytes) - all of tehse cells originate from multipotent stem cells in bone marrow i. 2 major families of WBC (1) Lymphocytes - B cells and T cells - B lymphocytes - differentiate to form antibody-rproducing cell and memory cell - T lymphocytes - kiull virus-infected cells or cancer cells; regulate activities of other WBC - smaller than other WBC and are not phagocytic (2) Phagocytes i. Include: - Basophils (I,A) - release histamine; may promote development of T cells - Eosinophils (A) - kill antibody-coated parasites - Neutrophils (I) - stimulate inflammation; engulf and digest microorg. - Mast cells (I) - release histamine when damaged - Monocytes (I, A) - develop into macropages and dendritic cells - Macrophages (I, A) - engulf and digest microorg.; activate T cells - Dendritic cells (A) - present antigens to T cells - Natural killer cells (I) - attack and lyse virus-infected or cancerous body cell

1. How does adaptive immunity develop?

- As result of clonal selection - Generated by DNA changes- chromosomal rearrangements and other mutations - occur just after B and T cells are formed in bone marrow => milliosn of different B cells develop, each of which can produce only one kind of antibody - There are also millions on diff T cells, each with one specific kinds of T cell receptor - Adaptive immune system is "predevelioped" - all of machinery available to respond to immense diversity of antigens is already there, even b/f antigens are ever encountered i. Mechanism (1) When pathogen enter body (2) Stimulate innate immune system (3) Addition to trigger innate immune system defenseive responses => innate immune system triggers adaptive defensive repsosnes via specific antigens that are presented on surfaces of antigen presenting cell (dendritic cells particularly) (4) Trigger proliferation of lymphocytes (T and B cells) that are specific for those particular antigens (5) Clonal selection: antigen binding "selects" a particular B OR T cell for proliferation; when antigen fits surface receptor on a B OR T cell and binds to it => that cell is activated (6) It divides to form a clone of ells (genetically identical gr. Derived form signel cell) all of which recognize and react to same antigen

1. Clonal deletions?

- Body is tolerant of its own moelcuels - same molecules that would generate immune response in another individual - Ine way that immune system does this is through clonal deletion - Occurs primarily in thymus - during early differentiation of T and B cells => cells encounter self antigens - Any immature B or T cell that show potential to mount immune response against self antigens undergoes APOPTOSIS within short times

1. How immune system protein work?

- Cells that defend human bodies work together,; interacting with one antoehr and with cells of invading pathoigens - Cell-cell interactions => accomplished by variety of key proteins, including receptors, other cell surface protein, signaling molecuels a. 4 major player (1) Antibodies - Proteins that bind specifically to certain substances identified by immune system as NONSELF - Recognize and bind specific configurations of atom - Molecules that bind antibodies are called antigens => this binding can directly inactivate viruses and toxisn - On nonself cells, antibody-antigen compelxces => can act as tags - making cell easier for immune system cell to recognize and attact - Antibodies produced by B cells (2) Major histocompatibility complex (MHC) - Protein used to display antigens on surfaces of self cells, so that antigens can be detected by antibodies and by cells of immune system - MHC proteins also fx as important self-identifying label i. 2 major classes of MHC proteins a) MHC I: proteins found on surface of most cells in mammalian body b) MHC II: proteins found in immune system cells (3) T cell receptors - Integral membrane proteins on surface of T cells - Recognize and bind to antigen presented by MHC proteins on surfaces of other cells (4) Cytokines - Soluble signaling proteins released by many cell types - Bind to cell surface receptors and alter behavior of their target cells - Various cytokines activate or inactivate B cells, macrophages, and T cells

a. The 5 classes of Ig

- Constant region of heavy chain detemrioen class of Ig - ex. Wheteher it will be an integral membrane receptor (e.g. on surface of B cell)= or soluble antibody that is secreted into bloodstream (1) IgG - General structure: monomer - Location: free in blood plasma; about 80% of circulating antibodies - Function: most abundant antibody in primary + secondary immjune resposnes; crosses placenta and provides passive immunization to fetus - Most abundant class is IgG => soluble antibody protein make up 80% of total Ig content of bloodstrum; made in greatest quantity during 2nd immune response - IgG defend body in several way; ex. Binds to antigens => become attached by heavy chains to macrophages => attachment permits macrophages to destroy antigen by phagocytosis (2) IgM - General structure: pentamer - Location: surface of B cell; free in blood plasma - Function: antigen receptor on B cell membrane; 1st class of antibodies released by B cell during primary response (3) IgD - General structure: monomer - Location: Surface of B cell - Function: cell surface receptor of mature B cell; important in B cell activation (4) IgA - General structure: dimer - Location: saliva, tears, milk, ando thjer body secretions - Function: protects mucosal surfaces; prevents attachment of pathogens to epithelial cells (5) IgE - General structure: monomer - Location: secreted by plasma cells in skin and tissues lining GI and respiratory tract - Function: binds to mast cells and basophils to sensitize them to subsequent bidning of antgen => trigger release of histamine => contribuees to inflammation + some allergic responses

1. Cellular immune response?

- Direcvted against antigens that have become establiushed within cell on host animal - Detects and destroys virus-infected or mutateted cells, such as cancer cells expressing unique proteins caused by mutaitons - T cells in lymph nodes, bloodstream, intercellular spaces carry out cellular immune responses - T cell have integral membrane proteins - T cell receptors - recognize and bind to antigens - T cell receptor similar to antibodies in structure and fx, each including specific molecular configuration that bind to speicifc antigens - Once T cell bound to antigen => initiates immune repsosne => result in total destruction of antigen-containing cell a. 2 types of effector T cells (1) T-helper cells (Th) (2) Cytotoxic T ells - Work along with proteins of major histocompatibility complex (MHC proteins) -. Present antigen on surfaces of cells an d contribute to immune systems tolerance for body´s own cells

a. Ig Diversity result from DNA rearrangement and other mutations - how?

- Each mature B cell makes one- and only one - specific antibofdy targeted to signle epitope - 1 antibody gene: 2,100 bP DNA - 10 million different antibofies => 21 billion bp DNA!!! => 7x size of entire human genoime! Must be another way to genereate antibody diversity!!! i. Diversity - So.. instead of single gene encoding each Ig, genome of differentiating B cell has limited number of alleles for each of several regions (domain s) of protein => combination of these alleles generate diversisty - Shuffling this genetic deck => generate enormous immunological diversity - Each gene encoding Ig chjains is in reality a "supergene" assembled by means of genetic recombination from several clusters of smaller genes scattered along part of chromosome - Every cell in body has hundreds of Ig genes located in separate clusters that are potentially capable of participating in synthesis of both variable and constant regions of Ig chains; most body cells and tissues - these genes remain intact and separated from one another. But.. during B cell development - genes are cut out, arranged, and joined together in DNA recombination event => one gene form each cluster is chosen randomly for joining, and others are deleted - => in this manner, unique Ig supergene is assembled from randomly selected "parts" - each B-cell precursor assembles 2 supergene - (1) for for specific heavy chain and (2) assembled independently, for specific light chain EXAMPLE: Mice variable region of heavy chain assembled from 100 V, 30 D, and 6 J genes; each B cell randomly select one gene from each of these clusters to make final coding seq. (VDJ) of heavy chain variable region; so number of different heavy chains can be made through this random recombination is quite large 100 V*30D * 6J* => 18,000 possible combinations If we assume similar amount of diversity in light chain variable region, number of possible combinations of light-and heavy-chaisn varable region is: 18,000 different light chains x 18,000 diffgerent heavy chains => 324 million possibilities! - Evevn more diversity generated by various kinds of mutation that occur during recombination events - Mutation can occur through imprecise recombination and high spontaneous mutation rates in Ig genes - Genetic events irreversible - once final coding swq. Assembled for variable regions of B cells light and heavy chains => B cells epitope specificity cannot change! - => generate enormous diversity of IG from same starting genome - Once pre-transcriptiopnal processing compelteted, each supergene transcribed and then translated to produce Ig light chain or heavy chains => combine to form active Ig protein Variable region for heavy chain of specific antibofdy: - Encoded by one V gene, one D gene, one J gene - Each of these genes taken form ppool of like genes - V: variable gens - D: diversity genes - J: joining genes - join to constant region Constant region: selected from another pool of genes - Number of combination to make Ig heavy chain from tehse ppools of genes is (100V)(30D)(6J)(8C) => 144,000 - C: constant genes V,D,J: => makes up light chain C:= > make heavy chain

a. Constant region is involved in Ig class switching ?

- Generally a B cell make only a class at a time - Class switching: can occur in which BNB cell changes Ig class it syntehsises Ex. B cell making IgM can switch class - Early in its life, B cell produces IgM molecuels, which are receptors resp for recognition of specific antigen - At this time, constant region of heavy chain is encoded by in this case; 1st constant region gene, the "mu (symbol for micro)" gene - IF B cell later becomes plasma cell during humoral immune response => another deletion occurs in cell´s DNA of part of of constatnt region gene cluster => get different constant region of heavy chain => modification leads to class switching - However.. Ig has same variable region - therefore same antigen specificity - as IgM produced by parent B cell - New Ig proteins fall into 1 of 4 other classes (IgA, IgD, IgE, or IgG) => depending on which constant region genes is placed adj. to variable region genes i. What trigger class switching? - Th cells direct course of immune response and determine nature of attack on antigen - These Th cells induce class switching by sending cytokine signals - Cytokines binds to receptor on target B cell => generate signal transduction cascades => recombination and altered expression of Ig genes

Transcription factors of hematopoesis?

- Growth factors initiate signal transduction pathways, thereby altering transcription factors that, in turn activate genes that determine the differentiation of blood cells. - The early committed progenitors express low levels of transcription factors that may commit them to discrete cell lineages. Which cell lineage is selected for differentiation may depend both (1) on chance and (2) on the external signals received by progenitor cells. - Several transcription factors have been isolated that regulate differentiation along the major cell lineages (1) PU.1: commits cells to the myeloid lineage (2) GATA-1 has an essential role in erythropoietic and megakaryocytic differentiation (3) The Ikaros, Aiolos and Helios transcription factors play a major role in lymphoid development.

1. The immunoglobulins? (Humoral immune response)

- Immunoglobulin: antibodies belong to this class

Malfunction of immune system?

- In addition, in some cases the immune response can be directed toward self tissues resulting in autoimmune disease (e.g. rheumatoid arthritis, T1DM)

How can INFLAMMATION CAN CAUSE MEDICAL PROBLEMS?

- Inflammation generally a good thing - Sometimes, inflammatory response is INAPPROPRIATELY strong -resulting in some allergies, autoimmunity, and sepsis => response causes more damage than was originally there (1) Sepsis - in some cases of severe bacterial infection, inflammatory response DOES NOT remain local.. extends throughout bloodstream in condition called sepsis - as in local infection or injury, blood vessels dilate -but they do so throughout body - LOWERING BP => result in medical emergency and can be lethal (2) Symptoms of swelling, pain, fever caused by excessive inflammation can be bothersome to point of incapacitation - Diseseas such as rheumatoid arthritis and chronic obstructive puilmonary disease - Accidents such as athletic injuries - result in tissue damage and inflammatory response - Use drug: act on various vytokiens and signal trnduction pathways to reduce infalmamtion and its symtpoms - Ex. Aspirin work by inhibiting enzyme in pathway for synthesis of PG - Other anti-infalmamtory drug act on PG pathway, on actions TNF, on action of histamine

3. What is immunological memory?

- Involves both clonal expansion and lymphocyte differentiation. - The adaptive immune system can remember prior experiences. This is why we develop lifelong immunity to many common infectious diseases after our initial exposure to the pathogen, and it is why vaccination works. a. PRIMARY IMMUNE RESPONSE - If an animal is immunized once with antigen A, an immune response (antibody, T- cell-mediated, or both) appears after several days, rises rapidly and exponentially, and then, more gradually, declines. This is the characteristic course of a primary immune response, occurring on an animal's first exposure to an antigen. b. SECONDARY IMMUNE RESPONSE - If, after some weeks, months, or even years have elapsed, the animal is immunized again with an antigen, it will usually produce a secondary immune response that differs from the primary response - the lag period is shorter, and the response is greater and more efficient. - IMMUNLOGICAL MEMORY: These differences indicate that the animal has "remembered" its first exposure to antigen A. The secondary response reflects antigen-specific immunological memory. c. When naïve cells encounter their antigen for the first time i. 1st exposure to antigen - EFFECTOR CELL: the antigen stimulates some of them to proliferate and differentiate into effector cells, which then carry out an immune response (effector B cells secrete antibody, while effector T cells either kill infected cells or influence the response of other cells). - MEMORY CELLS: Some of the antigen-stimulated naïve cells multiply and differentiate into memory cells (memory B cells and memory T cells), which do not themselves carry out immune responses but are more easily and more quickly induced to become effector cells by a later encounter with the same antigen 2nd exposure to antigen - Memory cell: When they encounter their antigen, memory cells (like naïve cells), give rise to either (1) effector cells OR (2) more memory cells - Memory cells respond more rapidly than did the naive cells. Although most effector T and B cells die after an immune response is over, some survive as effector cells and help provide long-term protection against the pathogen - A small proportion of the plasma cells produced in a primary B cell response, for example, can survive for many months in the bone marrow, where they continue to secrete their specific antibodies into the bloodstream

1. Humoral immune response? (adaptive)

- L. humor, fluid - Antibodies reach with antigens on pathogens in blood, lymph and tissue fluids - Produce staggering diversity of antibodies capable of binding to almost any conceibable antigen human encoutners - Antibodies secreted by B cells and travel freely in blood and lymph - Particular B cell also possesses receptors on its surface with same specificity as antibodies it produces - 1st time specific antigen invades body - may be presented and detected by binding to T cell receptor => binding activates B cell with appropriate antibody; => proliferates => daughter cells make and secret multiple copies of antibody - everyday, billions of B cells survive the test of clonal deletion - and relreased from bone marrow into circulation Some B cells develop into plasma cells - B cell make receptor protein on its cell surface - If B cell activated by antigen binding to this receptor => gives rise to cloens of plasma cells and memory cells - Plasma cells (effector B) secrete antiboidies into bloodstream - Usually naïve B cell develop into antibody-secreting plasma cell + a T-hlper ce4ll with same specificity MUST ALSO BIND TO ANTIGEN => B cell division + differentiation stimulated by chemical signals from Th-cells - As plasma cell develop => number of ribosomes + amount of ER in cytoplasms increase greatly => allow cells to synthesize + secrete large amount of antibody proteins - up to 2000 molecuels per second - All plasma cells arising fro given B cell produce antibodies that are specific for antigen that originally bound to parent B cell => antibody specificity maintained as B cell proliferate

a. SELLECTION OF T CELLS DURING DEVELOPMENT IN THYMUS GLAND?

- MHC protein play vital role in selection (1) Binding to MHC proteins => positive selection - T cell receptor should bind not to antigen alone, but to antigen-MHC compelx => b/c T cells are activated by antigen presented on surface of cells, not free antigen - For those T cells that bind MHC protein - not removerd; for those that do not recognize MHC protein (not bind to antigen-re+psenting ells) => eliminated soon after they develop - Rest of T cells go on to next selection step (2) Binding to self peptides bound to self MHC proteins => negative selection - T cells that bind to self antigens presented n MHC proteins => eliminates them; i.e. eliminate those T cells that react to self antigens - Negative selcvtion through clonal deletion is a mech that prevents adaptive immune system form reacting to self molecules

How is inhibioton of host complement factors by viruses?

- Members of the herpesvirus, orthopoxvirus and retrovirus families mimic (competitive inhibit) or interact with complement regulatory proteins to block complement activation and neutralization of virus particles.

2. What is epitopes?

- Most large molecules, including virtually all proteins and many polysaccharides, can act as antigens. - Epitopes: Those parts of an antigen that bind to the antigen-binding site on either an antibody molecule or a lymphocyte receptor - Most antigens have a variety of epitopes that can stimulate the production of antibodies, specific T cell responses, or both. - Immunodominant epitopes: Some epitopes produce a greater response than others, so that the reaction to them may dominate the overall response - Any epitope is likely to activate many lymphocyte clones, each of which produces an antigen-binding site with its own characteristic affinity for the epitope.

Myeloid lineages?

- Myelocuyes - include granulocytes (basophil, neutrophil, eosinophil), megakayrotyces (thrombocyte = platelet) and macrophages (from monocyte) are derived from commion myeloid progenitors - Inviolved in such diverse roles as innate immunity, adaptive immunity, and blood clotting - Myelopoiesis - Granulopoiesis (or granulocytopoiesis) is haematopoiesis of granulocytes. Megakaryocytopoiesis is haematopoiesis of megakaryocytes.

a. Structure of Ig

- Several types of Ig, but all contain tetramer - consisting of 4 polypeptiode chains - Each Ig molecule - 2 polypeptides are identical light chains, and 2 are identical heavy chains - Disulfide bond: hold chains together i. Polypeptide chain - Each polypeptide chain has a constant region + variable region 1) Constant region: AA seq. - similar among Ig; determine the destination and fx - the class of each Ig 2) Variable region: AA seq. are different for each specific Ig; 3D antigen-binding sites are determined by their 2nd strucutres and are responsible for antibody specisifity - 2 antigen-binding sites on each IG are identical, making antibody bivalent "("two-binding") => ability to bind 2 antigen molecules at one ; along with presence of multiple epitopes on surface of many antigens (incl. large proteins, viruses, bacteria) =>mpermit antibodies to form large complexces with antigen => complexes easy target for ingestion and breakdown by phagocytes

1. What are the 3 phases of defensive response?

- Several ways of defending against pathogens - harmful organisms and viruses that can cause disease - Defense system based on distinction between self - own molecules - and nonself or foreign molecules a. 3 phases of defensive response (1) Recognition phase - Organism must be able to discriminate b/w self and nonself (2) Activation phase - Recognition event leads to mobilization of cells and molecules to fight the invader (3) Effector phase - Mobilized cells and molecules destroy the invader

1. The clonal selection theory?

- The most remarkable feature of the adaptive immune system is that it can respond to millions of different foreign antigens in a highly specific way - Human B cells, for example, can make a huge number of different antibody molecules that react specifically with the antigen that induced their production. The question is how? a. Clonal selection theory - According to the clonal selection theory (proposed in the 1950s), an animal first randomly generates a vast diversity of lymphocytes and then selects for activation those lymphocytes that can react against the foreign antigens that the animal actually encounters - As each lymphocyte develops in a central lymphoid organ, it becomes committed to react with a particular antigen before ever being exposed to the antigen. A cell committed to respond to a particular antigen displays cell-surface receptors that specifically recognize the antigen - The human immune system is thought to consist of many millions of different lymphocyte clones, with cells within a clone expressing the same unique receptor. - Before their first encounter with antigen in a peripheral lymphoid organ, a clone would usually contain only one (1) or a small number of cells. A particular antigen may activate hundreds of different clones, which in turn, start to proliferate (clonal expansion). - The encounter with antigen also causes the cells to differentiate into effector cells. - T cells operate in a similar way. - Note that the receptors on B cells are antibody molecules and that those on the B cells labeled "B-beta " in this diagram bind the same antigen as do the antibodies secreted by the effector "B-beta" cells

1. Inflammation? (part of innate immune system

- When tissue is damaged because of infection or injury => body responds with inflammation - Inflammation can happen almost anywhere in body, internally as well as on surface a. Important phenomenon (1) Isolate damaged area to stop spread of damage (2) Recruits cells and molecules to damaged location to kill invader (3) Promote healing b. Mast cells (1) 1st responders to tissue damage are mast cells - adhere to skin and lining of organs and release numerous chemical signals, including: a) Tumor necrosis factor - cytokine protein that kills target cells and activate immune cells b) Prostaglandins - Fatty acid derivatives involved in various responses, incl. widening of blood vessels - PG interact with nerve endings and are partly responsible for pain caused by inflammation c) Histamine - AA derivatives that leads to itchy, watery eyes and rashes seen with some types of allergic rx c. Events 1) Damaged tissues attract mast cells which release histamine, which diffuses into blood vessels 2) Histamine causes vessels to dilate and become leaky; complement proteins leave vessels and attract phagocytes 3) Blood plasma and phagocytes move into infected tissue from vessels 4) Phagocytes engulf bacteria and dead cells ¬ Produced several cytokines, which among other fx signal brain to produce a fever => rise in temperature accelerates lymphocyte production and phagocytosis ¬ In some cases, pathogens are temperature-sensitive and their growth is inhibited 5) Histamine and complement signaling cease; phagocytes are no longer attracted 6) Growth factor from WBC and platelets stimulate cell division in skin cells, healing wound ♣ Redness + heat of inflammation result from dilation + leakiness of blood vessels in infected or injured area ♣ Pain of inflammation result from increased pressure due to swelling, action of leaked enzymes on nerve endings, and action of PG - increase sensitivity of nerve endings to pain ♣ Following inflammation- pus may accumulate; pus is mixture of leaked fluid and dead cells: bacteria, nejutrophils (most abundant WBC) , and damaged body cells ♣ Pus is normal result of inflammation and gradually consumed and further digeste by macrophages

(4)Eosinophils

- have proteins in granules that are effective in killing certain parasites.

The complement system (humoral barriers)

- is the major humoral non-specific defense mechanism - Once activated complement can lead to increased vascular permeability, recruitment of phagocytic cells, and lysis and opsonization of bacteria - The complement system helps or "complements" the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is not adaptable and does not change over the course of an individual's lifetime - The complement system is the part of innate immune system; however, it can be recruited and brought into action by the adaptive immune system. - The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors. When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. i. Activation of complement - The activation of complement involves the sequential proteolysis of proteins to generate enzymes with catalytic activities - The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex - Over 25 proteins and protein fragments make up the complement system.

1. Adaptive immune responses - general?

- use simple defense strategies that rely on protective barriers, toxic molecules, and phagocytic cells that ingest and break up invading microorganisms. Depend on such innate immune responses as a first line of defense, but they can also mount much more sophisticated defenses, called adaptive immune responses. - In vertebrates, the innate responses CALL the adaptive immune responses into play, and both work together to eliminate the pathogens. - Whereas the innate immune responses are general defense reactions, the adaptive responses are HIGHLY SPECIFIC to the particular pathogen that induced them. Any substance capable of eliciting an adaptive immune response is referred to as an ANTIGEN (antibody generator). - The adaptive immune system recognizes the fine molecular details of macromolecules: it can distinguish between two proteins that differ in only a single amino acid.

T1DM?

2) childhood (type 1) diabetes - immune reactions against insulin-secreting cells in the pancreas kill these cells, leading to severe insulin deficiency - For the most part, the mechanisms responsible for the breakdown of tolerance to self antigens in autoimmune diseases are unknown. It is thought, however, that activation of the innate immune system by infection or tissue injury may help trigger anti-self responses in individuals with defects in their self-tolerance mechanisms, leading to autoimmunity.

What is hematopoesis?

=> development of blood cells MULTIPOTENTIAL HEMATOPOIETIC STEM CELLS - Multipotential hematopeietic stem cells (HSCs) reside in the medulla of the bone (bone marrow) and have the unique ability to give rise to all of the different mature blood cell types - HSCs are self renewing: when they proliferate, at least some of their daughter cells remain as HSCs, so the pool of stem cells does not become depleted - The other daughters of HSCs (common myeloid and common lymphoid progenitor cells), however can each commit to any of the alternative differentiation pathways that lead to the production of one or more specific types of blood cells, but cannot self-renew. - This is one of the vital processes in the body

2. What happens when immunological tolerance goes wrong?

Autoimmune diseases - The tolerance mechanisms sometimes break down, causing T or B cells (or both) to react against the organism's own tissue antigens. We present two examples for such diseases. myasthenia graivs childhood (T1) diabetes

Innate immune system - the anatomical barrier?

ANATOMICAL BARRIERS Among the mechanical anatomical barriers are the skin, cilia, mucus, peristaltics, flushing of tear and saliva Associated with these protective surfaces are chemical and biological agents. (1) Mechanical factors (skin, cilia, mucus, peristaltics, flushing of tear and saliva) - The epithelial surfaces form a physical barrier that is very impermeable to most infectious agents. Thus, the skin acts as our first line of defense against invading organisms. - The desquamation of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces. - Movement due to cilia or peristalsis helps to keep air passages and the gastrointestinal tract free from microorganisms. - The flushing action of tears and saliva helps prevent infection of the eyes and mouth - The trapping effect of mucus that lines the respiratory and gastrointestinal tract helps protect the lungs and digestive systems from infection. (2) Chemical factors (low pH in stomach and sweat) - Fatty acids in sweat inhibit the growth of bacteria - Lysozyme and phospholipase found in tears, saliva and nasal secretions can breakdown the cell wall of bacteria and destabilize bacterial membranes. - The low pH of sweat and gastric secretions prevents growth of bacteria. - Defensins (low molecular weight proteins) found in the lung and gastrointestinal tract have antimicrobial activity. - Surfactants in the lung act as opsonins (substances that promote phagocytosis of particles by phagocytic cells). (3) Biological factors (natural flora of skin and intestines) - The normal flora of the skin and in the gastrointestinal tract can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces.

1. 4 features of adaptive immune system?

Adapative immunity has 4 key features (1) Specificity (2) Ability to distinguish self from nonself (3) Ability to respond to an enormous diversity of nonself molecules (4) Immunological memory a. SPECIFICITY - Lymphocytes (B and T cells) are crucial component of adaptive immunity - T cell receptors and antibodies produced by B cells recognize and bind to specific nonself substances (antigens) => initiates adaptive immune response - Antigenic determinants/epitopes: specific sites on antigen that immune system recognize; such as a certain seq. of AA thay may be present in a protein - antigens are usually proteins or polysaccharides, and there can be multiple antigens on a single invading bacterium - single antigenic molecule can have multiple, different antigen determinants - host responds to presence of antigen with highly specific defenses involving T cell receptors and antibodies; these receptors and soluble protein bind to antigenic determinants - Each T cell and each antibody is specific for single antigenic determinants - Remainder of text refer antigenic determinants simply as "antigens" b. DISTINGUISHING SELF FROM NONSELF - Adaptive immune system has another set of mechanism for distinguishing self from nonself vs. that of innate immune system (with pattern recognition receptor + pathogen asspcitaed molecular pattern) - Human vbody contains tens od thousands of diff proteins, each with specific 3D structure capable of generating immune responses => thus every cell in body bear tremendous number of antigens Crucial req. of individual´s adaptive immune system is that it recognize body´s own antigens and do not attack them => accomplished by: (1) clonal deletion (2) negative selection (3) action of Treg cells c. DIVERSITY - Challenges to immune system are numerous - Pathogens take many forms: viruses, bacteria, protists, fungi, multicellular parasites - Each pathogenic species usually exists as many subtly diff genetic strains, and each strain processes multiple surface features - Estimates vary, but reasonable guess is that human can respond specifically to 10 million different antigens - Upon recognizing an antigen, adaptive immune system responds by activating lymphocytes of appropriate specificity d. IMMUNOLOGICAL MEMORY - After innate immune system responds to particular type of pathogen once, adaptive immune system "remembers" that pathogen and can usually respond more rapidly and powerfully to same threat in future - Saves us from repeat of childhood diseases such as chicken pox - Vaccination against specific diseases works b/c adaptive immune system "remembers" that antigens that were introduced into the body

Interplay between innate and adaptive immune responses?

Although these two arms of the immune system have distinct functions, there is interplay between these systems (i.e., components of the innate immune system influence the adaptive immune system and vice versa). Innate immune responses are activated directly by pathogens and defend all multicellular organisms against infection. In vertebrates, pathogens, together with the innate immune responses they activate, stimulate adaptive immune responses, which then work together with innate immune responses to help fight the infection.

Cell determination theories?

Cell determination appears to be dictated by the location of differentiation. For instance, the thymus provides an ideal environment for thymocytes to differentiate into a variety of different functional T cells. For the stem cells and other undifferentiated blood cells in the bone marrow, the determination is generally explained by the: (1) determinism theory of hematopoiesis - saying that colony stimulating factors (CSF) and other factors of the hematopoietic microenvironment determine the cells to follow a certain path of cell differentiation. - This is the classical way of describing hematopoiesis. In fact, however, it is not really true. (2) Stochastic theory - The ability of the bone marrow to regulate the quantity of different cell types to be produced is more accurately explained by a (2) stochastic theory - claims that undifferentiated blood cells are determined to specific cell types by randomness. The hematopoietic microenvironment prevails upon some of the cells to survive and some, on the other hand, to perform apoptosis and die - By regulating this balance between different cell types, the bone marrow can alter the quantity of different cells to ultimately be produced.

Chemical factors of anatomical barriers?

Chemical factors (low pH in stomach and sweat) - Fatty acids in sweat inhibit the growth of bacteria - Lysozyme and phospholipase found in tears, saliva and nasal secretions can breakdown the cell wall of bacteria and destabilize bacterial membranes. - The low pH of sweat and gastric secretions prevents growth of bacteria. - Defensins (low molecular weight proteins) found in the lung and gastrointestinal tract have antimicrobial activity. - Surfactants in the lung act as opsonins (substances that promote phagocytosis of particles by phagocytic cells).

How is coagulation system? (humoral barrier - innate)

Coagulation system - Depending on the severity of the tissue injury, the coagulation system may or may not be activated. - Some products of the coagulation system can contribute to the non-specific defenses because of their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells - In addition, some of the products of the coagulation system are directly antimicrobial. - For example, beta-lysin, a protein produced by platelets during coagulation can lyse many Gram positive bacteria by acting as a cationic detergent.

Dendritic cells?

DENDRITIC CELLS i. - Present in most tissues, dendritic cells express high levels of TLRs and other pattern recognition receptors, and they function by presenting microbial antigens to T cells in peripheral lymphoid organs Mechanism - Ingest invading mcirobes or their product at site of infection - Microbial PAMPs activate dendritic cell through toll-like-receptors to express co-stimulatory proteins on their surface - Migrate in lymphatic vessels to nearby lymph node , where activated dendritic cells activate small fraction of T cells that expres receptor for microbial antigens displayed on dendritic cell surface - T cell proliferate and some migrate to site of infection; where they help elinminate microbes by either helping to activate macrophage or killing infected cells (1) In most cases, they recognize and phagocytose invading microbes or their products or fragments of infected cells at a site of infection and then MIGRATE with their prey to a nearby LYMPH NODE (2) in other cases, they pick up microbes or their products directly in a peripheral lymphoid organ such as the SPLEEN - In either case, the microbial antigens activate the dendritic cells so that they, in turn can directly activate the T cells in peripheral lymphoid organs to respond to the microbial antigens displayed on the dendritic cell surface. - Once activated, some of the T cells then migrate to the site of infection, where they help destroy the microbes. - Other activated T cells remain in the lymphoid organ, where they help keep the dendritic cells active, help activate other T cells, and help activate B cells to make antibodies against the microbial antigens. Thus, innate immune responses are activated mainly at sites of infection (or injury), whereas adaptive immune responses are activated mainly in peripheral lymphoid organs such as lymph nodes and spleen.

Innate immune system - the humoral barriers?

Humoral factors play an important role in inflammation, which is characterized by edema and the recruitment of phagocytic cells These humoral factors are found in serum or they are formed at the site of infection. - complement system - coagulation system - others

1. Immunological memory?

IMMUNOLOGICAL MEMORY - 1st time exposed to particular antigen there is time lag (usually several days) before B cell-produced antibody molecuels and T cell specific to that antigen slowly increase - But... for years afterward- immune system "remembers" that particular antigen, allowing body to mount faster response next time it encounters antigen a. How does immune system "remembers"? Activated lymphocytes divide and differentiate to produce 2 types of daughter cells: (1) Effector cells - Carry out attack on atigen - Effector B cells - the plasma cells: - secrete antiboides - Effector T cells: release cytokiens and other molecuels that initiate rx that destroy nonself or altered cells - Lives only few days (2) Memory cells - Long-lived cells that retain ability to start dividing on short notice to produce more effector and more memory cells - Memory B and T cells may survive in body for decades, rarely dividing b. Effector + memory cells can respond to antigen in 2 different ways: (1) Primary immune response - When body first encoutners particular antigen, primary immune response activated - "naïve" lymphocytes that recognize antigen proliferate to produce clones of effector + memory cells (2) Secondary immune response - After primary immune response to particular antigen, subseq. Encounter with same antigen will trigger much more rapid and powerful 2nd immune response - Memory cells that bind with antigen proliferate, launching huge army of plasma cell + effector T cells c. MECHANISM 1) B cell make antibody that bind specific antigen 2) Binding along with signals from T-helper cells, stimujlate B cell to divide, resulting clone of cells 3) Primary immune response: some cells develiop into plasma cells (effector B cells) that secrete same antibody as parent cell 4) Potential secondary immune response: few cells develiop into non-secreting memory cells that divide at low rate, prolonging the clone

2. Innate immune system vs. adaptive immune system?

INNATE IMMUNE SYSTEM - Response is antigen-INDEPENDENT - There is IMMEDIATE maximal response - NOT antigen-specific - Exposure results in NO immunologic memory ADAPATIVE IMMUNE SYSTEM - Response is antigen-DEPENDENT!!! - There is lag time b/w exposure and maximal response - Antigen-specific - Exposure results in IMMUNOLOGIC MEMORY¨ -- Although the innate and adaptive immune systems both function to protect against invading organisms, they differ in a number of ways. (1) The adaptive immune system requires some time to react to an invading organism, whereas the innate immune system includes defenses that, for the most part, are constitutively present and ready to be mobilized upon infection. (2) Second, the adaptive immune system is antigen specific and reacts only with the organism that induced the response. In contrast, the innate system is not antigen specific and reacts equally well to a variety of organisms. (3) Finally, the adaptive immune system demonstrates immunological memory. It "remembers" that it has encountered an invading organism and reacts more rapidly on subsequent exposure to the same organism. In contrast, the innate immune system does not demonstrate immunological memory.

Innate immune system vs. adaptive immune system?

INNATE IMMUNE SYSTEM - Response is antigen-INDEPENDENT - There is IMMEDIATE maximal response - NOT antigen-specific - Exposure results in NO immunologic memory ADAPATIVE IMMUNE SYSTEM - Response is antigen-DEPENDENT!!! - There is lag time b/w exposure and maximal response - Antigen-specific - Exposure results in IMMUNOLOGIC MEMORY Although the innate and adaptive immune systems both function to protect against invading organisms, they differ in a number of ways. (1) The adaptive immune system requires some time to react to an invading organism, whereas the innate immune system includes defenses that, for the most part, are constitutively present and ready to be mobilized upon infection. (2) Second, the adaptive immune system is antigen specific and reacts only with the organism that induced the response. In contrast, the innate system is not antigen specific and reacts equally well to a variety of organisms. (3) Finally, the adaptive immune system demonstrates immunological memory. It "remembers" that it has encountered an invading organism and reacts more rapidly on subsequent exposure to the same organism. In contrast, the innate immune system does not demonstrate immunological memory.

Lymphoid lineages?

LYMPHOID LINEAGES - Lymphocytes (B and T cell) are the cornerstone of the adaptive immune system - They are derived from common lymphoid progenitors. - The lymphoid lineage is primarily composed of T-cells and B-cells (types of white blood cells) - This is lymphopoiesis.

Mechanism of clonal selection theory?

MECHANISM (1) Precursor cell (2) Proliferatition and diversification in bone marrow (B-alfa, B-beta, B-gamma) - different reting cells (3) Antigen bidning to specific B cell (B-beta) in peripheral lymhpod organ (4) Proliferation (clonal expansion) and differentiation of B-betal cells (5) Antibody-secreting effectibve B-beta cells => secrete antiboides; that bind same antigen as do antibodies secreted by effectiror "B-beta" cells

Mechanical factors of anatomical barriers?

Mechanical factors (skin, cilia, mucus, peristaltics, flushing of tear and saliva) - The epithelial surfaces form a physical barrier that is very impermeable to most infectious agents. Thus, the skin acts as our first line of defense against invading organisms. - The desquamation of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces. - Movement due to cilia or peristalsis helps to keep air passages and the gastrointestinal tract free from microorganisms. - The flushing action of tears and saliva helps prevent infection of the eyes and mouth - The trapping effect of mucus that lines the respiratory and gastrointestinal tract helps protect the lungs and digestive systems from infection.

. How is the development of T and B cells?

Multipotential hemamtopoietic stem cells => common lymphoid progenitor cell => T and B cells i. ii. - - - Common lymphoid progenitor cell for T cell => migrate to thymus from hematopoietic tissues via blood => developing T cell Common lymphoid progenitor cell for B cell => stays in hematopietic tissue => develop into Bv cells T cells and B cells derive their names from the organs in which they develop. T cells develop in the thymus B cells develop in the bone marrow in adults or the liver in fetuses. - Both T and B cells are thought to develop from the same common lymphoid progenitor -cells. The common lymphoid progenitor cells themselves derive from multipotential hematopoietic stem cells, which give rise to all of the blood cells, including red blood cells, white blood cells, and platelets - These stem cells are located primarily in hematopoietic tissues - mainly the liver in fetuses and the bone marrow in adults - T cells develop in the thymus from common lymphoid progenitor cells that migrate there from the hematopoietic tissues via the blood. In most mammals, including humans, B cells develop from common lymphoid progenitor cells in the hematopoietic tissues themselves. a. CENTRAL LYMPHOD ORGANS: hematopoietic tissues + thymus; because they are sites where lymphocytes develop from precursor cells, the thymus and hematopoietic tissues are referred to as central (primary) lymphoid organs. b. Peripheral lymphoid organs (Secondary) - Most lymphocytes die in the central lymphoid organs soon after they develop, without ever functioning. - Others, however, MATURE and MIGRATE via the blood to the peripheral (secondary) lymphoid organs - mainly, the lymph nodes, spleen, and epithelium- associated lymphoid tissues in the GI tract, respiratory tract, and skin. - It is in these peripheral lymphoid organs that foreign antigens activate T and B cells - T and B cells become morphologically distinguishable from each other only after they have been activated by antigen; Resting T and B cells look very similar i. Effector cells - After activation by an antigen, both proliferate and mature into effector cells. - Effector B cells secrete antibodies. In their most mature form, called plasma cells, they are filled with an extensive rough endoplasmic reticulum that is busily making antibodies - In contrast, effector T cells contain very little endoplasmic reticulum and do not secrete antibodies; instead, they secrete a variety of signal proteins called cytokines, which act as local mediators.

a. MHC PROTEINS?

PRESENT ANTIGEN TO T CELLS - T cell receptor do not bind directly to antigen; theey bidn to antigens bound to cell surface glycoprotein- MHC protein - MHC protein is a cell surface marker of genetic individuality - Diversity of MHC protein => means many possibilities for presenting antigen to T cell receptor i. 2 classes of MHC proteins; both fx to present antigens to diff T lymphocytes - Tenk at du må oppnå 8; - MHC I * CD8 => 8 - MHC II* CD4 => 8 (1) Class I MHC - Proteins are present on surface of every nucleated cell in body - Enable Tc cells to recognize virus-infected cells and kill them (or cancer cell?) - Viral protein fragment that are antigenic are complexed with MHC I inside the cell and then the complex is carried to plasma membrane - A T c cell with appropriate T cell receptor bind to MHC-antigen copmpelx - TO ensure binding, Tc cell also has cell surface protein called CD8 => recognize MHC I (2) Class II MHC - Proteins found mostly on surfaces of B cells, macrophages, and other antigen present cells incl. dendritic cells - When one of these cells ingest pathogen such as bacterium, vbacterial antigens broken down ion pahosoem - MHC II moplecule may bind to one of fragment and carry it to cell surface => present to Th cells - Th cell have surface protein called CD4 - that recognizes and bind to MHC II i. Mechanism a) Antigen-rpeeesenting cell takes up antigen by phagocytosis b) Cell breaks down antigen into fragment in phagosome c) Class II MHC protein bind to antigen fragment d) MHC present antigen to Th cell

Innate immune system - the cellular barriers?

Part of the inflammatory response is the recruitment of polymorphonuclear eosinopiles and macrophages to sites of infection. These cells are the main line of defense in the non-specific immune system. (1) neutrophils (2) macrophages (3) natrula killer and lymphokine activated killer cells (NK + LAK) (4) eosinophils

Hematopoietic growth factors

Stem cell factor: RBC and WBC production is regulated with great precision in healthy humans, and the production of granulocytes is rapidly increased during infection. The proliferation and self-renewal of these cells depend on stem cell factor (SCF). => regulate the proliferation and maturation of the cells that enter the blood from the marrow, and cause cells in one or more committed cell lines to proliferate and mature. i. 3 more factors that stimulate production of committed stem cells (1) colony-stimulating factors (CSF) - granulocyte macrophage CSF (GM-CSF) - granulocyte CSF (G-CSF) - macrophage CSF (M-CSF) These stimulate much granulocyte formation and are active on either progenitor cells or end product cells. (2)Erythropoetin (EPO) - is required for a myeloid progenitor cell to become an erythrocyte. (3) Thrombopoietin - makes myeloid progenitor cells differentiate to megakaryocytes (thrombocyte- forming cells, i.e. platelets). CYTOKINES ALSO PLAYS A ROLE HERE! - Different IL, TNF-alfa, etc.

1. What is the role of immune system? (general)

The defence against: (1) Pathogenic organisms (viruses, bacteria, fungi, unicellular organisms, worms) (2) Tumor cells - We are constantly being exposed to infectious agents. The main function of the immune system is to enable us to resist infections. The ability to distinguish between self and non-self is necessary to protect the organism from invading pathogens and to eliminate modified or altered cells (e.g. malignant cells). - Since pathogens may replicate intracellularly (viruses and some bacteria and other parasites) or extracellularly (most bacteria, fungi and other parasites), different components of the immune system have evolved to protect against these different types of pathogens. - It is important to remember that infection with an organism does not necessarily mean diseases, since the immune system in most cases will be able to eliminate the infection before disease occurs. Disease occurs only when the bolus of infection is high, when the virulence of the invading organism is great or when immunity is compromised. Although the immune system, for the most part, has beneficial effects, there can be detrimental effects as well - During inflammation, which is the response to an invading organism, there may be local discomfort and collateral damage to healthy tissue as a result of the toxic products produced by the immune response.

1. Innate immune system - general element of it (3)?

The elements of the innate (non-specific) immune system include: a. anatomical barriers - mechanical factors => skin, cilia, mucus, peistaltics, flushing of tears and saliva - chemical factors => low pH in stomach and sweat - biological factors => natural flora of skin and intestines b. humoral barriers (secretory molecules) - complement system - coagulation system - others: lactoferrin, interferon, lysozyme, defensin c. cellular barriers (cellular components) - neutrophil and eosinophil granulocytes - macrophages - natural killer (NK) cells

2 main classses of adaptive immuen system?

a. 2 MAIN CLASSES: (1) Humoral immune response (= antibody response, B cell-mediated response) i. The antibodies - Block ability of viruses to bind receptors - Block effect of toxins by masking them - Mark pathogens for destruction (2) Cellular immune response (= T cell-mediated immune response) - Induce apoptosis? - Activate macrophages => phagocytosis - Activate B cells => antibody production Adaptive immune responses are carried out by white blood cells called lymphocytes. There are two classes of such responses, (1) Humoral immune response (antibody response, B cell- mediated response) and (2) Cellular immune response (T-cell- mediated immune response), which are carriet out by different classes of lymphocytes, called B cells and T cells, respectively. i. The antibody - In antibody responses, B cells are activated to secrete antibodies, which are proteins called immunoglobulins (Igs). - Binding of antibody inactivates viruses and microbial toxins (such as tetanus toxin or diphtheria toxin) by blocking their ability to bind to receptors on host cells. - Antibody binding also marks invading pathogens for destruction, mainly by making it easier for phagocytic cells of the innate immune system to ingest them. ii. Cellular immune response - activated T cells react directly against a foreign antigen that is presented to them on the surface of a host cell, which is therefore referred to as an antigen-presenting cell. - T cells can detect microbes hiding inside host cells and either kill the infected cells or help the infected cells or other cells to eliminate the microbes. - The T cell, for example, might kill a virus-infected host cell that has viral antigens on its surface, thereby eliminating the infected cell before the virus has had a chance to replicate. - In other cases, the T cell produces signal molecules that either activate macrophages to destroy the microbes that they have phagocytosed or help activate B cells to make antibodies against the microbes.

3. How is the cellular immune response - ACTIV A TION + EFFECTOR phase?

a. ACTIV A TION PHASE (1) Viral protein made in an infected cell is degraded into fragments and picked up by class I MHC protein (2) T cell receptor recognizes an antigenic fragment bound to class I MHC protein on infected cell (3) Tc cell proliferates and form a clone b. EFFECTOR PHASE (1) T cell receptor again recognizes an antigenic fragment bound to class I MHC protein (2) T cell releases perforin.. which lyzes the infected cell before the viruses can multiply

2. How is the humoral immune response - ACTIVATION + EFFECTOR phase?

a. ACTIVATION PHASE (1) Antigen taken up by phagocytosis and degraded in lysosome (2) IL-1 (a cytokine) activates Th cell (3) T cell receptor recognizes an antigenic fragment bound to class II MHC protein on macrophage (4) Cytokines released by Th cell stimulate it to proliferate (5) Th proliferates and form a clone b. EFFECTOR PHASE (1) Binding of antigen to specific IgM receptor on B cell trigger endocytosis, degradation, and display of processed antigen (2) A T cell receptor recognizes antigenic fragment bound to class II MHC protein on B cell (3) Cytokines released from Th cell activate B cell proliferation (4) B cells proliferate and differentiate into plasma cell and memory cell (5) Plasma cell produces antibodies

1. Role of blood and lymph tissues in defense?

a. Blood plasma i. Yellowish solution containing: - Ions - Small molecule solutes - Soluble proteins = - Suspended in plasma are RBC, WBC, platelets - RBC normally confined to closed circulatory system (heart, aa, capillaries, vv.) - WBC and platelets found in closed circulatory system + lymph b. Lymphoid tissues i. Includes: - Thymus - Bone marrow - Spleen - Lymph nodes ii. Lymph - Fluid that is derived from blood (but lacking RBC) and other tissues - Accumulates in intercellular spaces throughout body - From these spaces - lymph moves slowly into vessel of lymphatic system - Tiny lymph capilalries conduct fluid to larger ducts that eventually join together - forming one large vessel - ex. thoracic duct - which joins major v. (L. subclavian v.) near the heart - By this system of vessels - lymph eventually returned to blood and circulatory system iii. Lymph nodes - At many sites along lymph vessels are small, roundish strucutres - lymph nodes - Contain a type of WBC - lymphocyte - As lymph pass through lymph node- lymphocytes encounter foreign cells and molecules that have entered body, and if they are recofnized as nonself => immune response initiated

a. Cytotoxic T cells and MHC I?

a. Cytotoxic T cells and MHC I proteisn contribute to cellular immune response - In virus infected or mutated cell, foreign, or abnormal proteins or peptide fragment combine with MHC I molecules - Restlting complex displayed on cell surface and presented to Tc cells - When T c cell recognizes an bind to this antigen-MHC I complex,=> activated to proliferate - In effector phase => Tc cells recognize and bind to cells bearing same antigen-MHC I complex - BOudn T c cells produce substance called perforin => lyses bound target cell; in addition Tc can bind specific receptor (Fas) => inititates apoptosis in that cell - T c recognize MHC protein complexes with nonself antigen; they help rid body of its own virus-infected or cancerous cells i. Mechanism of cellular immune response a) Activation phase (1) Viral protein made in infected cell is degraded into fragments and picked up by class I MHC protein (2) T cell receptor recognizes an antigenic fragment bound to class I MHC protei on infected cel (3) Tc cell proliferates and forms a clone b) Effector phase (4) T cell receptor again recognizes an antigenic fragment bound to class I MHGC prtotein (5) T cell releases perforin that lyses infected. Cell before viruses can multiply

1. 2 general types of defense mechanism - what are they?

a. Innate defenses (or nonspecific defenses) - Provide 1st line of defense against pathogens - Typically act very rapidly and include barriers such as skin, molecules that are toxic to invaders, phagocytic cells that ingest invaders - System recognizes broad classes of organisms or molecuels and responds quickly, within minutes or hours b. Adapative defenses (specific defenses) - Aimed at specific pathogens - Activated by innate immune system - Ex. Adaptive defense system can make antibody protein that will recognize, bind to, and aid destruction of specific virus - if that virus ever enters body - Typically slower to develop than innate erpsonse and longer-lasting

5. What are the cells of immune system?

a. Myeloid cells i. Granulocytic - Neutrophils - Basophils - Eosinophils ii. Monocytic - Macrophages - Kupfer cells - Dendritic cells b. Lymphoid cells i. T cells - Helper cells (Th) - Suppressor cells (Tregs) - Cytotoxic cells (Tc) ii. B cells - Plasma cells - Memory cells iii. NK cells § All cells of immune sytem have origin in BONE MARROW => include (1) myeloid + (2) lymphoid cells; differentiate along distinct pathways. § Myeloid progenitor cell in bone marrow give rise to erythrocytes, platelets, neutrophils, monocytes/macropages, and dendritic cells § Lymphoid progenitor cell give rise to NK, T cells, B cells

PAMPs?

How does innate and adapative immune system work together? (PRR and dendritic cells)

a. Pathogen-associated molecular patterns (PAMPs) => pattern recognition receptors (1) Located on surface of phagocytes (2) Secreted receptors (marking pathogens thorugh binding them) (3) Located on surface of e.g. dendritic cells (Toll-like receptors) => acticate intracellular signal molecules that lead to secretion of extracellular signal molecules that promote inflammation and help activate adaptive immune responses - Lymphocytes usually respond to foreign antigens only if the innate immune system is first activated. - The rapid innate immune responses to an infection depend largely on pattern recognition receptors made by cells of the innate immune system. - These receptors recognize microbe-associated molecules (pathogen- associated molecular patterns; PAMPs) that are not present in the host organism. - (1) Some of the pattern recognition receptors are present on the surface of professional phagocytic cells (phagocytes) such as macrophages and neutrophils, where they mediate the uptake of pathogens, which are then delivered to lysosomes for destruction. - (2) Others are secreted and bind to the surface of pathogens, marking them for destruction by either phagocytes or a system of blood proteins collectively called the complement system. - (3) Still others, including the Toll-like receptors (TLRs), activate 3. How does innate and adapative immune system work together? (PRR and dendritic cells) intracellular signaling pathways that lead to the secretion of extracellular signal molecules that promote inflammation and help activate adaptive immune responses. The cells of the vertebrate innate immune system that respond to antigens and activate adaptive immune responses most efficiently are dendritic cells. b. DENDRITIC CELLS i. - Present in most tissues, dendritic cells express high levels of TLRs and other pattern recognition receptors, and they function by presenting microbial antigens to T cells in peripheral lymphoid organs Mechanism - Ingest invading mcirobes or their product at site of infection - Microbial PAMPs activate dendritic cell through toll-like-receptors to express co-stimulatory proteins on their surface - Migrate in lymphatic vessels to nearby lymph node , where activated dendritic cells activate small fraction of T cells that expres receptor for microbial antigens displayed on dendritic cell surface - T cell proliferate and some migrate to site of infection; where they help elinminate microbes by either helping to activate macrophage or killing infected cells (1) In most cases, they recognize and phagocytose invading microbes or their products or fragments of infected cells at a site of infection and then MIGRATE with their prey to a nearby LYMPH NODE (2) in other cases, they pick up microbes or their products directly in a peripheral lymphoid organ such as the SPLEEN - In either case, the microbial antigens activate the dendritic cells so that they, in turn can directly activate the T cells in peripheral lymphoid organs to respond to the microbial antigens displayed on the dendritic cell surface. - Once activated, some of the T cells then migrate to the site of infection, where they help destroy the microbes. - Other activated T cells remain in the lymphoid organ, where they help keep the dendritic cells active, help activate other T cells, and help activate B cells to make antibodies against the microbial antigens. Thus, innate immune responses are activated mainly at sites of infection (or injury), whereas adaptive immune responses are activated mainly in peripheral lymphoid organs such as lymph nodes and spleen. --- (1) Dendritic cells ingest invading microbes or their products at site of infeciton (2) microbial PAMPs activatedendritic cells (through toll-like receptors) to express co-stimulatory proteins on their surface and (3) to migrate in lymphatic vessels to nearby lymph nodes; where (4) activated dendritic cevlls activate smalll fraction of T cells that express receptor for microbial antigens dispalyed on dendritic cell surface (5) These T cells proliferate and some then migrate to site of infection whree they help eliminate microbes, by either helping to activate macrophages or killing infected cells

Regulatory T cell?

a. Regulatory T cell suppress humeral and cellular immune responses - 3rd class of T cells: regulatory T cells (Tregs) - ensures immune system does not attack self cells and molecuels indiscriminately - Like Th and T cells - Tregs mature in thymus gland - carry T cell receptors and become activated if they bind to antigen-MHC complexes i. How Tregs differentiate from Th and Tc cells (1) Antigens Tregs recognize are self antigens (2) Activation of Tregs cause them to secrete cytokine IL-10 => block T cell activation and leads to apoptosis of Tc and Th cells that are bound to same antigen-presenting cell - Thus Tregs constitute anothjer mech for distinguishing self from nonself ii. If Tregs are destroyed in thymus of mouse 1) Mouse gros up with an out-of control immune system; strong immune repsosne to antigens (autoimmunioty) 2) In humans, rare X-linked hereditary disease occurs when gene critical to Treg fx is mutated - Infant with this diseases - IPEX (immune dysregulation polyendocrinopathy and enteropatjhy, X-linked) => immpune repsosne that attacks pancreas, thyroid, and intestines - Most affected individuals die within first few years of life

. Self-tolerance depends on a number of distinct mechanisms (4): => what are these?

a. Self-tolerance depends on a number of distinct mechanisms (4): (1) Receptor editing (central) - Developing lymphocytes that recognize self molecules (self-reactive lymphocytes) change their antigen receptors so that they no longer recognize self antigens (2) Clonal deletion (central or peripheral) - Self-reactive lymphocyte die by apoptosis when they bind their self antigen (3) Clonal inactivation (central or peripheral) - Self-reactive lymphocytes becomes functionally INACTIVATED when encounter their self antigen (4) Clonal suppression (peripheral) 1. Immunological tolerance? - How do cells of innate and adaptive immune system use to difference self from nonself? Mechanism of self-tolerance? - Regulatory T cells (Tregs) suppress activity of self-reactive lymphocytes CENTRAL TOLERANCE - Some of these mechanisms - especially the first two (receptor editing + clonal deletion)- operate in central lymphoid organs when newly formed self-reactive lymphocytes first encounter their self antigens, and they are largely responsible for the process of central tolerance. PERIPHERAL TOLERANCE - Clonal inactivation and clonal suppression, by contrast, operate mainly when lymphocytes encounter their self antigens in peripheral lymphoid organs, and they are responsible for the process of peripheral tolerance Clonal deletion and clonal inactivation, however, are known to operate both centrally and peripherally.

T-helper cells and MHC II?

a. T-helper cells and MHC II proteins contribute to humoral immune response (1) ACTIVATION PHASE - When Th cell survives selection processes and bind to antigen-repsentign cell => release cytokines => activate Th cell to proliferate => producing clone of Th cells with same specificity => activation phase of humoral immune response => occur in lymphoid tissues (2) EFFECTOR PHASE - Th cells activate naïve B cells with same specificity to produce antibodies - B cells are also antigen-presenting cells => B cells take up antigens bound to their surface Ig receptors by endocytosis; break them down; display antigenic fragment on class II MHC proteins - Th cell bind to displayed antigen-MHJC II cpompelx => release cytokiens => B cell to produce clone of plasma cells - Plasma cells then secrete antibodies; completing effector phase of humoral immune response i. MECHANISM of HUMORAL IMMUNE RESPONSE a) Activation phase (1) Antigen taken up by phagocytosis and degraded in lysosome (2) IL-1 (cytokine) activates Th cell (3) A t cell receptor recognizes antigenic fragment bound to class II MHC protein on macrophage (4) Cytokines released by Th cell stimulate it to proliferate ("autocrine") (5) Th cell proliferates and from clone b) Effector phase (6) Binding of antigen tospeciifc IgM receptor triggers endocytosis, degradation, and dispalsy of processed antigen (7) T cell receptor recognizes an antigentic fragment bound to class II MHC protein on B cell (8) Cytokines activate B cell proliferation (9) B cell proliferate and differentiate into plasma cells (10) Plasma cell produces antibodies

1. The 2 types of adaptive immune responses?

a. The humoral immune response - B cell that make antibodies are workhorses of humoral immune response b. The cellular immune response - Cytotoxic (killer) T cells are workhorses of cellular immune response ¬ 2 responses operate simultaneously and cooperatively, sharing many mechanism ¬ key event early in these 2 processes is exposure of nonself antigen´s 3D structure to immune system => this occur when antigenic molecure or fragment of molecule is displayed on surface of cell; unique epitope sturucvtre protrudes fro mcell - where it is exposed to nearby T or B cells ¬ Antigen-presenting cells: cells that can "present " antigen to immune system; ex. Dendritic cells c. Key player integrating humoral and cellular immune response: (1) T-helper (Th) cell => by binding to the antigen on presenting cell => Th cell stimulates events in both responses

The anatomical barriers are very effective in preventing colonization of tissues by microorganisms. However, when there is damage to tissues the anatomical barriers are breached and infection may occur. Once infectious agents have penetrated tissues, another innate defense mechanism comes into play => what is the name f this one?

Biology - Immunology

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