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305 Cards in this Set
- Front
- Back
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OVERVIEW OF IMMUNITY |
OVERVIEW OF IMMUNITY |
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What is the function of the immune system? |
1. prevent and control infections 2. eliminate pathogens and their harmful products |
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What is the human immune system characterized by? |
1. layering= mutliple layers of protection (innate and adaptive)
2. redundancy= single pathogen can be fount by the immune system multiple ways (phagocytosis, antibodies) |
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What components of immune system are found in blood? |
1. leukocytes 2. lymphocytes 3. clotting factors 4. complement 5. antibodies |
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What two activities are in the immune system? |
1. recognition (pathogen present) involving cell surface receptors
2. recruit effector mechanisms to kill/eliminate |
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What does the lymphatic system provide? |
nodes filter interstitial fluids, REMOVE ANTIGENS AND MAKE THEM AVAILABLE TO B and T cells......place where antigens can initiate the immune response, B cells can make ABs and interaction can occur to carry out an immune response |
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What are the branches of immune system? |
1. innate immunity 2. adaptive immunity |
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What is innate immunity? |
1. non specific...elements we are born with and are ALWAYS PRESENT at basal levels.
..recognize things like teichoic acids or LPS on bacteria via PRRs |
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What is adaptive immunity? What is it subdivided into? |
1 immunity acquired by antigen exposure and specific to a given antigen 2. during infection, only lymphaocytes with receptors that recognize the pathogen ae selected to participate (specialized) 3. slower to develope and cause clonal expansion 4. provides memory
Divided into: 1. humoral 2. cell mediated |
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What is the innate immunity comprised of? |
cellular and non-cellular components 1. leukocytes (macrophages) 2. biochemical enzymes 3. skin, blinking, urine 4. proteins (complement, cytokines, chemokines) 5. inflammation (coordinated event b/w cells, cytokines and circulatingproteins that limits the spread of infectious agent and helps repair damaged tissues) |
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What is the key to adaptive immunity? |
discrimination of self and non-self |
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What are the properties that make adaptive immunity effective and protective? |
1. diversity 2. specificity 3. memory |
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What are the cellular components of adaptive immunity? |
1. leukocytes 2. lymphocytes 3. antigen presenting cells |
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What are the non cellular components of adaptive immunity? |
1. antibodies- from B cells 2. cytokines- produced by activated immune cells (mostly T, macrophages, NK cells) 3. complement (circulate around in the bloodstream- liver) |
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What are lymphocytes? What are the diffrent types? |
B and T cells that circulate round the body programmed to respond to a SINGLE foreign antigen and become activated when the antigen is encountered.
1. naive cells: haven't met Salmonella yet 2. effector cells: carry out immune function 3. memory cells: circulate and wait for the next encounter (activated but resting) |
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What are the leukocytes? |
think BEN, M
1. Basophils 2. Eosinophils 3. Neutrophils 4. mast cells |
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What are the antigen presenting cells? |
engulf pathogens, break em down and present them to T (DMB)
1. dendritic cells 2. macrophages 3. B cells |
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What is humoral immunity? |
protects against EXTRACELLULAR pathogens and involved production of antibodies.....consists of B cells and CD4+ TH2 |
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What is cell mediated immunity? |
protects against intracellular pathogens and is involved with CD8+ and CD4+ TH1 |
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What do viral infections do? |
cause production and secretion of IFN which upregulates MHC 1 for better APC to cytotoxic T cells |
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What can complement proteins on surface of antigen hekp with? |
B cell activity enhancement |
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What can cytokines help with? |
cause upregulation of MHCII molecules on phagocytes for better APC to T helper cells |
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What is opsonization? |
antibodies bound to the surface of antigen increasing their uptake by phagocytes |
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STRUCTURE AND FUNCTION OF ANTIBODY MOLECULES |
STRUCTURE AND FUNCTION OF ANTIBODY MOLECULES |
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what is BCR? |
membrane bound form of antibody with same features and antigen specificity but some differences at the C terminal end to allow anchor into cell membrane |
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What do SIg do? |
secreted antibodies recognize and bind extracellular pathogens anf their products to deliver to phagocytes for destruction |
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What have no toxic effects? What is the exception? |
antibodies..
except IgA: can be bactericidal in lysozyme |
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What is the antibody's specificity attributed to? |
the variable region of the antibody
**recognizes specific epitope on a particular pathogen |
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What is the antibody's biological activity attributed to? |
the constant region of the antibody |
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Each L chain is attached to a H chain via?
Each H chain is attached to the other H chain via? |
interchain disulfide linkages |
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How much does a heavy chain weigh? |
50,000 Dalton each |
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How much does a light hain weigh |
25,000 Da each |
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What is the variable region of an antibody? |
N-terminal region of both H and L that contains a variabilitiy in sequence that determines the antigen specificity |
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What is the constant region of an antibody? |
remaining sequence usually unchanged differing only by ISOTYPE. 1. determines the function of the antibody molecule 2. can be subdivided into domains (110 AA each): CH1, CH2, CH3 + 1 CL |
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What is the exception to the three domains? |
IgM and IgE (contain 4 CH domins and no hinge!) |
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What enzyme splits an antibody into two Fabs and one Fc? |
papain. |
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What is Fab? |
the portion of the AB that retains ability to bind an antigen; consists of two sets of: 1. VL, CL 2. VH, CH1 |
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What is Fc? |
ONE piece that contains most of the inge region (CH2,3 and 4 if present) [b/c there of the disulfide bond BELOW the hinge region]
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What are the two distinct functions of Fc? |
1. opsonization (Fab will bind to antigen while Fc is bound by Fc receptors on immune cells that phagocytose the attached antigen)
2. delivers the antibody to specific anatomical sites |
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When is F(ab)2 present? |
created by the gut enzyme PEPSIN |
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What is F(ab)2? |
cut BELOW hinge..single piece containing both Fab regions and hinge held together by S-S bond
*no Fc genetated |
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What is the hinge region? |
AAs found between CH1 and CH2 of the H chain (Pro, Ser, Thr)
- allows 2 Fab arms to open and close (accomodate binding to 2 epitopes with flexibility)
**only found in G, A, D |
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What is J chain? |
glycoprotein associated with igA and igM (polymeric Igs) but NOT HEXAMERIC IgM!
**requird for polymerization (acts like glue) and inteacts with the pIg receptor that transports Abs from basal side to luminal side of mucosal surface (TRANSCYTOSIS) |
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Where do you find polymeric Igs? |
in mucosal and secretory immunity.
* once the enzyme cleaves it off, the pIg receptor segment is now called the Secretory Component and will prevent proteases from killing it |
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What bods form loops within each chain and help give it its globular shape? |
intrachain disulfide bonds |
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Which domains interact in the Fc portion? |
CH3 domains
**ch2 doesnt because of steric hindrance |
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What is the variable region further broken down into? |
1. hypervariable regions 2. framework regions |
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What are hypervariable regions? |
1. found in both VL and VH 2. actually make contact and form bonds with the epitope 3. also known as complementary determining regions (CDR1, CDR2, CDR3) |
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How many CDRs are there in a monomeric antibody? |
12!
-3 from each L chain and 3 from each H chain |
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What are the framework regions? |
remaining 8- AA of the V region, b/w the CDRs **4 of them (FR1-FR4) |
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What are the two types of L chains? |
1. kappa 2. lambda
**both chains in the AB molecule will be identical (one kappa the other one is kappa) |
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what does the H chain do and what can be determined by it? |
1. determines the class (isotype) and function
-G,A,M,E,D |
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What are isotypes? |
determine the class (GAMED)and distinguishes the type of L chain present....nothing to do with specificity |
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What region detemines function and anatomical location? |
constant Heavy! |
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Describe IgM |
1. found as membrane Ig on naive cells 2. first one secreted when B cells are activated by T cells 3. most predominant isotype in response to T-independent antigens **usually a PENTAMER, almost never a Hexamer 4. has CH4 domain 5. most efficient for activating classical complement pathway 6. gengival cervicalar fluid in saliva 7. only isotype made by fetus (20 wks) and until 4-6 months |
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Describe IgG |
1. four of them: 1-4 2. hinge 3. long half life (23 days except IgG 3 = 1 week) 4. most abundant in tissues and serum 5. only one to cross the placenta (1324) 6. activate complement (312) 7. found on Fc receptors to increase opsonization 8. participates in ADCC (antbody depenedent cell mediated cytotoxicity) when bound by Fc receptors on NK cells [e.g. glagella] 9. production begins at 4-6 months of age 10. IgG1 is the best opsonin |
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Describe IgA |
1. two types: IgA 1 and IgA2 2. IgA1 is 5:1 in serum 3. IgA1 directed against protein epitopes; IgA2 directed against polysaccharide epitopes 4. most abundant of ALL antibodies 5. 2nd in serum (GAMDE) 6. Most dominant in secetions on mucosal surfaces 7. can be bactericidal in lysozumes |
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Where do you find monomeric IgA? |
serunm |
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Where do you find polymeric IgA? |
secretions in the dimer form (SIgA)....secreted by salivary glands into the oral cavity |
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Describe IgE |
1. has no hinge 2. most bound to Fc epsilon receptors on surface of mast cells, basophils, eosinophils 3. when Fabs crosslink by binding antigen, activation and release of granules 4. mediate hypersensitivity reactions 6. protect from parasites 7. nost IgE secretin plasma cells are found in the pharyngeal tonsils |
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Describe IgD |
1. found on naive, mature B cells 2. if IgD is missing from surface, self-reactive B cells can enter lymphoid organs and proliferate |
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What is hematopoiesis? |
production of immune cells.....cells of different lineage and function all develop from pluripotent stem cells |
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what can hematopoietic stem cells become? |
1. self renewing stem cell 2. myeloid-erythroid progenitor 3. lymphoid cell |
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what do myeloid progenitor cells develop into? |
1. monocyte/macrophage 2. BEN,M 3. dendritic cell |
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What do lymphoid cells become? |
1. T cell 2. B cell 3. NK cell |
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Where does hematopoeisis take place? |
bone marrow and thymus
**in fetus, begins in yolk sac, goes to liver and spleen where it continue thru infancy |
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What are monocytes? |
circulate in the blood for 1-3 days |
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what are macrophages? |
monocytes that have exited the blood, and become fixed in the tissues (kupfer-liver, microglial-brain alveolar-lung) |
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what are the surface receptors on macrophages? |
1. CR3: complement receptor 3 for complement protein C3b (aids in opsonization) 2. Fc: for the Fc portion of IgG and IgE (aids in opsonization or ADCC) |
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What three ways can macrophages be activated from their resting state? |
1. IFN gamma: produced by TH1, CD8 and NK cells 2. PAMPS (LPS, mannose) 3. opsonization (via C3b, IgG or IgE |
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What are the four main functions of macrophages? |
1. phagocytosis 2. antigen processing and presentation to T cells via MHC 3. production of soluble mediators 4. ADCC |
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What are the three states of a macrophage? |
1. resting= "garbage collectors" sample for foreign invaders and take up dead stuff 2. activated : actively take up foreign invaders via PAMPs or opsonization and APC 3. hyperactivated: secrete cytokines + complement proteins, kill pathogens within macrophage via oxidative burst and APC |
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Describe the production of soluble mediators |
1. usually, macrophages are first phagocell to sense an invading microbe....secrete IL-1, IL-6, TNF-alpha |
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What is ADCC? |
antibody dependent cell mediated cytotoxicity: occurs when the target is coated with IgG antibodies and will directly kill it without phagocytosis
**TOO BIG IT DONT FIT |
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What are the granulocytes |
BENM 1. basophils 2. eosinophils 3. neutrophils 4. mast cells |
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What are neutrophils? |
**aka PMN 1. short lived dedicated killers that circulate in blood until recruited 2. most predominant granulocyte (90% of gran; 60% of WBC 3. have 3 types of granules filled with proteases, cathepshins, collagenases..etc 4. release of enzymes result in killing innocent bystander (immunopathology) 5. live about 2 days or less |
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What are the functions of neutrophils? |
1. phagocytosis (number 1!!): release lytic enzymes and defensins (poke holes in that b***) also oxidative burst 2. cytokine production (IL1, 6, 8, TNF-alpha)
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What are eosinophils? |
1. bilobed nucleus 2. high surface affinity for IgE and low for IgG 3. parasitic infections 4. phagocytc 5. role in allergic reactions (asthma and chronic inflammatory disease) |
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What are basophils? |
1. surface receptor for IgE 2. allerfic reactions 3. cross linking and degranulation 4. granules with histamine, vasodilators |
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What are mast cells? |
1. found mostly in connective tissue and skin 2. surface receptor for IgE 3. major in allergic responses 4. degranulation with histamine and vasodilators |
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What are platelets? |
1. blood clotting and inflammation 2. derived from megakaryocutes 3. surface receptors for: fibrinogen (clot), C3b (complement inflammation), cytokines (CXCR4)
**2/3 found circulating, 1/3 found in spleen |
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What are dendritic cells? |
1. cytoplasmic extensions called dendrites 2. Langerhans cells are in the skin 3. phagocytose then migrate to nearest lymphoid organ and present antigen to T cels which then change their name to interdigitating DCs |
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What are the functions of dendritic cells? |
1. phagocytosis (immature cells only) 2. antigen presentation (NUMBER ONE APC!!)- immature DC phago antigen then migrate now intergitiating now present to T cells 3. negative selection- present self-antigents to thymocytes to see if they're reactive 4. cytokine production |
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What are follicular dendritic cells? |
1. not phagocytic and not related to DCS 2. antigen binds to FDC but not internalized 3. found in germinal centers and follicles 4. APC to B cells but dont express MHC (cant present to T cells) 5. bind antigen-antibody complexes vua Fc which dendrites are covered with Fc receptors to allow presentation of antigens to B cells |
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What are T lymphocytes? |
1. all T cells have a T cell receptor (TCR) that is specific for particular antigen 2. subdivided into CD4+ (T helper) and CD8+ (cytotoxic)
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What does CD4_ T cells become terminally differentiated into? |
T helper cells whose effector function is to produce cytokines |
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What does CD8+ cells terminally differentiate into? |
CTLs whose effector function is to kill infected host cells or tumor cells |
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what do CD4 and CD8 do? |
1. act as antigen coreceptors 2. usually expressed mutually exclusively (CD4 with MHCII, CD8 with MHC1) |
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How are CD4+ T helper cells further divided by? |
cytokine production...
1. IFN gamma (Th1 produced) inhibit TH2 2. IL4 and IL10 (TH2 produced) inhibit TH1 3. IL12 (produced by DC, neutrophils and macrophages)- favor TH1 |
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WHat do TH1 cells do? |
1. produce IL2, IFN gama and TNF beta 2. stimulate CD8+ cells 3. isotype switching in B cells to make (GAG23): IgG2, IgA, IgG3 |
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What do Th2 cells do? |
1. produce IL 4,5,6,10 2. stimulate B cells to make antibodies 3. stimulate isotype switching in B cells to 1GAE: IgG1, IgA, IgE |
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How do you identify a B lymphocyte? |
1. BCR: naive B cells have MD, activated = MAGE 2. express MHC 1 and 2 3. surface receptors for IgG an IgE 4. CD40 (interact with CD40 L on T cells to make 2nd signal for B cells and will signal for isotype switching 5. CD80/86 (B7)- interact with CD28 on T cells as 2nd activation signal for T cells |
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What are the functions of B lymphocytes? |
1, prodution of antibodies 2. immunologic memory 3. antigen presenting |
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What are plasma cells? |
term. differentiated B cells that become antibody factories |
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What are natural killer cells (null lymphocytes) |
1. no TCR or BCR 2. FC gamma receptor 3. express IL2receptor which allows them to proliferate in response to low levels of IL2 (made by T cells) 4. part of innate and adaptive 4, doesnt require APC....kill before cell mediated innumity |
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What are the functions of NK cells? |
1. direct killing of target cells via release of cytotoxic enzymes from granules 2. produce IFN gamma
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NK cells direct kill what? |
1. infected cells (viro or bacto) 2. tumor cells (recognize protein MICA on surface of cancer cells) 3. killing via ADCC when FCgamma receptors bind IgG coated antigen 4. must be told NOT to kill signal through killer inhibitory responses |
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What are killer inhibitory responses |
standown mechanism where timor cells are noted to have NO MHC 1 class gene and are assumed abnorma |
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What are two types oflymphoid organs? |
1. primary: bone marrow, thymus [ where lymphocytes are born and mature"] 2. secondary: spleen, lymph node, MALT [where mature B and T cells interact with antigen and undergo further differentiation and proliferation |
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Whats going on in the bone marrow? |
- contains pluripotent stem cells that become immune....profenitor cells that eventually become B cells remain in the bone marry |
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What's going on in the thymus? |
-progenitor cells that will become mature T cells leave bone marrow and go to thymus - developing T cells undergo thymic selection in which self-reactive T cells are eliminated while those that dont will enter the blood stream |
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What are the functions of the peripheral lymphoid organs? |
1. bring lymphocyte in contact with antigen 2. bring lymphocytes close to each other 3. allow interactions to occur in presence of cytokines that promote proliferation |
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Whats going on n the spleen? |
1. red pulp: filter to remove dead blood cells, remove pathogens 2. white pulp= 25% of body's mature lymphocytes
**pathogen exits blood in red pulp then encounters immune cells in white where response takes place....site where blood-borne pathogens are processed and presented |
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What is going in the lymph nodes? |
1. antigens ener via lymph either as soluble antigen or within phagocyte 2. naive lympocytes enter via blood stream 3. site where antigens from tissues are processed and presented |
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What is MALT? |
1. consists of D-MALT (diffuse- LP), O-MALT (organized- tonsils), GALT (gut- Peyer's pathces) and BALT (bronchus) 2. pathogens arrive in MALT via direct delivery across the mucosa by specialized mucosal epithelial cells (M cells)....sample surroundings and antigen is transcytosed through Mc ells to pocket on the basolateral sie of cell where lymphocytes, DCs and macrophages are. |
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What must happen for antibodies to be made? |
both T and B cells specific for the antigen must interact .....lymphocytes will circulate to maximize opportunities to all meet together. Once they do, they will undergo proliferation and differentiation |
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Where is the majority of lymphocytes? |
lymphoid tissues (not blood) |
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What is interesting about naive T cells? |
have L selectin surface receptors that allow them to enter lymph nodes....migrate into T cell zone where antigens are displayed by APCs.
**if activated, becomes an effector T cell ro memory cell....if not activated, it will reenter lymphatics or blood stream and continue to next lymph node |
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What are effector T cells? |
" experienced " cells that lose their L selectin receptors so they wont enter another lymph node....they will leave the lymph node and enter circulation...prefer to enter to tissues colonized |
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What are memory T cells? |
some will go thru lymph ndes and some will go to sites of infection and will carry out effector functions |
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What is the exception to the rule stating "lymphocytes will circulate thru the body in blood and lymph where they can enter and exit lymphoid tissue"? |
spleen (all pathogens and lymphocytes enter/exit via blood) |
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What is innate immunity? |
1. all elements present from birth-no need for previous exposure 2. actvated rapidly 3. non-specific (responds to common motifs) 4. non adaptive (additional protection not generated once the pathogen comes in....no improvement of response 5. no expansion upon activation 6. no memory |
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What are the physical/physiological barriers? |
1. skin 2. mucosal surfaces 3. mucociliary escalator 4. normal flora 5. tears 6. fever |
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Explain features of the skin |
impenetrable barrier...sloughing of outer layer removes pathogens
**outer layer= keratinized so theres no use for bacteria metabolically
contains: 1. psoriasin (FA w/ antibacterial and chemotactic properties) 2. sebum and FA (lower pH to 4) |
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Is skin an organ of the immune system? |
yes...
- keratinocytes produce cytokines that stimulate cutaneous inflammation - keratinocytes produce chemokines that attract MONOCYTES to site of injury -Langerhans cells |
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What are features of mucosal surfaces? |
-90% of our surface are exposed to pathogens - one cell-layer thick (80% as effective as skin) - bathed in mucus with glycoproteins, proteoglycans, enzymes
**lactoferrins, mucin, lysozyme |
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What is the mucociliary escaltor? |
move mucus trapped particles to the pharynx where they are swallowed/expelled
**Pertussis toxin |
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What is normal flora's features? |
1. prevent binding by occupying the binding sites 2. utilize available nutrients 3. secrete bacteriocidins (kill toxins that are harmful to the other bacteria |
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What are tears? |
wash eye/work w blinking to keep pathogen free.
contain lysozyme |
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What does fever do? |
retard/prevent growth of pathogens that prefer normal body temp
**speeds up hematopoeisis |
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What are some of the enzymatic/protein effectors of the innate immune system? |
1. lysozyme/ lactoperoxidase 2. urease 3. proteases 4. anti-microbial peptides 5. iron sequestering proteins 6. complement |
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Where is lysozyme and lactoperoxidase found? |
tears, mucus, saliva
**breaks down NAG and NAM in bacterial peptidoglycan |
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What does urease do? |
denature proteins |
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what do proteases do? |
cleave and destroy EXTRACELLULAR proteins on pathogen surface
**if adhesin, pathogen cant bind anymor |
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what do antimicrobial peptides do? |
these are called defensins
*found in mucosal secretions + cytoplasmic granules of phagocytosis **destroy by poking holed into membrane |
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on what pathogens are antimicrobial peptides most effective? |
1. gram negative 2. enveloped viruses |
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What are iron sequestering proteins? |
they chelate free iron and remove it from the blood (TRANSFERRIN) or mucosal surfaces (LACTOFERRIN)....makes iron unavailable for bacteria
**test for free iron concentration if low......sign signals induced hypoferremia |
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what is complement? |
roughly 30 serum proteins circulating in the blood......
1. alternative pathway 2. lectin pathway
**both pathways are part of innnate immunity
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What leukocytes are part of the myeloid lineage and mediate most immediate innate function? |
1. neutrophils 2. monocytes/macrophages 3. langerhans cell 4. mast cell |
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what leukocyte of lymphoid lineage mediate some part of the innate response? |
Natural killer cells |
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What is extravastion? |
method in which neutrophils (PMNS) can enter site of infection when "called" to site |
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What are the steps of extravasation? |
1. rolling 2. activation 3. arrest/adhesion 4. transendothelial migration |
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What is rolling? |
formation and breakdown of low affinity interactions with glycoproteins |
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What is activation? |
when chemokines secreted by cells at the site of infection cause PMNs to activate integrins while endothelial cells upregulate high affinity ICAMS |
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What is arrest/adhesion? |
when circulatory cell adhere to the endothelial cells via selectin as well as the integrin/ICAM interactions |
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What is transendothelial migration? |
whn the cell squeezes thru the gap between the endothelial cells into the tissue |
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What are the specialized dendritic cells of the skin? |
langerhans cell
**play a role in adaptive immunity |
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What cells are cytotoxic and useful in immune surveillance against tumors and virally infected hosts? |
natural killer (NK) cells |
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When PRRs recognize PAMPS what happens? |
intracellular portion of the receptor activates a signaling pathway leading to expression of genes important for innate and adaptive immunity |
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What are Toll-like receptors? |
recognize and bind PAMPs (e.g. LPS)
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What are mannose binding leptin receptors? |
recognizes/binds carbohydrates with high mannose content (not on mammalian cells)
**will activate complement system via Lectin pathway |
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What are Nod proteins? |
(nucleotide-binding oligomerization domain proteins)
1. intracellular PAMP receptor 2. detect microbial motifs that ENTER the cell
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What does NOD 1 expression do? |
ubiquitous in adult tissues...recognizes Gram - derived peptidoglycan motifs |
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What does NOD2 expression do? |
expressed in cells of myeloid lineage....recognizes a different peptidoglycan motif
**mutation in NOD2 correlated with increased risk for Crohn's |
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What is inflammation? |
sensing presence of pathogen, macrophages stimulated to secrete cytokines and complements that will attract effector cells (MOSTLY NEUTROPHILS)
1. rubor- red 2. calor- heat 3. dolor-pain 4. tumor- swelling
**achieved thru regulated changes in blood vessels near site of infection |
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what are the functions of inflammation? |
1. remove/limit spread 2. clean up damage 3. repair tissue |
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With inflammation, what things are now possible? |
1. vasodilation/ increased vascular permeability (becomes leaky via cytokines, kinins, histamine, allow complement proteins to leak into tissues and recruit neutrophils into tissues via concentration gradient 2. phagocyte migration (takes 30-60 minutes)....monocytes will follow within 4-6 hours 3. increased phagocytosis 4. cytokine release via IL-1,6, TNF alpha by activated macrophages (cause upregulation of adhesion molecules on the local vascular endothelial cells to help let neutrophils and monocytes know where to slip thru) 5. plasmin (modeling and repair) |
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What is acute phase response? |
- "systemic arm" of inflammatory response from IL 1, 6, TNF alpha changing what proteins will be secreted by hepatocytes:
1. C-reactive protein: binds to LPS and acts like an opsonin which can initiate the classical complement pathway 2. mannose binding lectin: binds to mannose sugars on bacterial and yeast surfaces and activates the Lectin pathway of the complement system |
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What are other components of the acute phase response? |
1. fever (hypothalamus) 2. replace neutrophils/monocytes (bone marrow) 3. replace complement/clotting proteins (liver) 4. induced hypoferremia (use transferrin and lactoferrin) |
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GENETIC BASIS OF ANTIBODY STRUCTURE |
GENETIC BASIS OF ANTIBODY STRUCTURE |
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What is the great dilemma? |
How can we produce greater variety of antibodies than the number of genes we posses?
**how do we generate 10^9-10^11 different antigen receptors when we only have 20000-25000 genes? |
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Two theories that explain our antigenic repertoire? |
1. germline theory 2. somatic mutation/diversification |
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What is germline theory? |
genome contains ONE gene for ONE antigen receptor we make......offered no special genetic mechanism to account
this is BS |
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What is somatic mutation/diversification? |
multiple genes coming together to form unique combinations as a way to increase the variety.
**we have a limited number of genes for variable regions and the diversity is generated thru point mutations/recombination of these gene sets |
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How does a person's antigenic repertoire develop according to somatic mutation/diversification? |
develops as a result of recombining the limited gene sets + high rates of mutation within the genes |
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Where does recombination of these genes occur? |
B cells (IG) and T cells (TCR)
**unique to lymphocytes!
* prior to rearrangement= germline configuration (egg/sperm) * Ig and TCR rearrangement is now somatic recombination bc it happens in somatic cells |
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Describe eukaryotic transcription |
1. entire gene (exons + introns) transcribed into primary RNA transcript 2. enzymes splice genes, remove introns to make single mature mRNA which can be translated ***some cases, exons, introns spliced differently to produce different protein from same primary RNA transcript (alternative splicing) 3. hydrophobic leader sequence takes protein to cytoplasmic compartment (ER) and is told to either go to the cell membrane (BCR or TCR...will keep leader sequence) or go to secretion (kill the leader sequence) |
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Each L chain has what two regions: |
1. variable 2. constant region |
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The VL region is coded for by what 2 genes? |
1. variable (V)= CDR1, CDR2, part of CDR3 2. Joining (J) = remainder of CDR3 |
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Each H chain consists of what 2 regions? |
1. variable VH 2. constant CH |
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The VH region is constructed by what 3 genes? |
1. Variable (V)= CDR1 and CDR2 2. Diversity (D)= part of CDR3 3. Joining (J)= part of CDR3 |
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Rearrangement of the variable regions is: |
- for the light chain : V J recombination - for heavy chain : VDJ recombination
**regulated via RSS (recombination signal sequences) |
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What is the order of the CH genes downstream of the JH genes? |
1. M 2. D 3. G3 4. G1 5. E2* 6. A1 7. G* 8. G2 9. G4 10. E1 11. A2 |
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Which chains rearrange first? |
heavy chains, then L chains after |
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What is the goal of immune system genetics? |
ensure that each lymphocyte produces a receptor of a single specificity but each cell has 2 alleles of each gene, one from MOM and one from DAD |
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What is alleleic exclusion? |
only one of the alleles will be produced and applies to both H and L chains
**if lymphocyte makes a successful arrangement in 1st attempt, the cell will not attempt to rearrange the second one |
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What is isotypic exclusion? |
ensures there will only be one type of L chain (K or lambda) |
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Why is there more chances to screw up in the H chain? |
because any V gene can be placed next to any D gene and any D gene can be placed next to any J gene
**in L chain, any V can be placed next to any J |
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If both H chain alleles fail to make a successful rearrangement, que pasa? |
cell dies by apoptosis |
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After H cell rearrangement goes down, que pasa? |
L chain rearrangement happens....usually Kappa first (60:40) |
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Describe the rearrangement of H chain genes |
1. DJ rearrangement 2. VDJ rearrangement 3. VDJ rearranged DNA transcribed along with M and D genes, creating a primary RNA transcript! 4. primary transcript undergoes alternative splicing making 2 different MATURE mRNA transcripts (IgM and IgD) |
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What is significant of IgM and IgD? |
they are made in membrane form and both found on a mature, naive B cell |
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What is isotype switching? |
when B cell receives a signal from an activated Thelper cell to switch the isotype
*H chain genes will rearrange again, linking the VDJ already made genes next to the appropriate CH gene |
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What is each CH gene followed by? |
short sequence that allows for secretion (spliced out for membrane BCR form) or for membrane tethering (spliced out for secreted form) |
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What is the rearrangement of Kappa light chains? |
1. VJ rearrangement 2. VJ-C rearrangement 3. primary transcript made 4. splicing makes mature mRNA transcript 5. translated kappa L chain moves to lumen of ER where it joins H chains to make complete Ig |
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What is the arrangement of lambda light chains? |
1. V-JC rearrangement 2. primary transcript made 3. splicing makes mature mRNA transcript 4. mRNA translated into protein moved to lumen of ER to join H chains and make complete Ig |
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What is a huge way to regulate Ig gene rearrangement? |
recombination signal sequences (RSS) within the introns that dictate DISTANCE and ROTATION of DNA when bringing antibody genes together and prevent V genes from combining with J genes (in the H chain) |
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RSSs are conserved DNA sequences that: |
flank each V, D, and J gene |
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What are RSSs recognized by? |
recombination activating genes (RAG-1 and RAG-2)
**will bind to the RSS, makes nicks in DNA, remove intervening DNA and allow the genes to become juxtaposed |
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What are the two types of RSSs? |
1. one-turn RSS with a 12 bp spacer 2. two-turn RSS with a 23 bp spacer
*a 12 bp spacer can only combine with a 23 bp spacer (12/23 rule) |
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Describe the Rss and the spacers in the H chain genes |
1. 23-bp behind each V gene 2. 12 bp in front of and behind each D gene 3. 23- bp in front of each J gene
**assures that the V genes can't recombine with J genes (skipping D) or that D genes can't recombine with other D genes
**splicing with remove the spacers and leave only VDJ together in mature mRNA transcript |
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Describe the RSS and spacers in the L chain genes |
1. kappa: 12bp after V and 23 before J 2. lambda: 23 bp after V and 12 before J |
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What is on the base of the triangle in a RSS? |
heptamer
*palindromic and play important role in recombination and diversity....when they re aligned, the DNA of the heptamer is nicked, intervening DNA is removed and the chosen genes are placed adjacent to one another and DNA is thus repaired |
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What is on the tip of a triangle in a RSS? |
nonamer |
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What are 4 other ways to generate antibody diversity? |
1. combinatorial diversity 2. combinatorial association 3. junctional diversity 4. somatic hypermutation |
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What is combinatorial diversity? |
random arrangment of VDJ genes of H chains and random arrangement of VJ genes in the L chains
**at DNA level |
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What is combinatorial association? |
random association of rearranged H and L chains.......any : chain can combine with any H chain
**at protein level |
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If an immune person is born with a mutation in the 12 bp region of a kappa L chain that made it 45 BP long, would AB be produced? Would the person produce mutated or non functional antibodies? |
if mom and dad give K genes, it will move to make lambda and will still have functional antibodies |
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What is junctional diversity? |
occurs during/is part of Ig gene rearrangement
1. P-nucleotide addition 2. junctional diversity 3. N-nucleotide addition |
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What is P-nucleotide addition? |
1. cleavage of DNA w/i palindromic heptamer via RAG enzymes causes formation of hairpin loops in the DNA which need to be clipped off by endonuclease 2. endonuclease is assymmetrical, leaving OVERHANG of nucleotides on one of the DNA strands. 3. DNA polymerase adds nucleotides to the shorter strand *******only CDR3 is affected by this action |
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What is junctional flexibility? |
-hairpin is opened, ends of the DNA are exposed and subject to EXONUCLEASE enzymes that remove nucleotides (1-10) including the P-nucleotides that were just added and the original ones.
**more common in the H chain
****** only CDR3 is affected by this action |
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What is N-nucleotide addition? |
more nucleotides will be added by TdT which will add nucleotides to terminal ends and create the template **only CDR3 is affected **occurs only in H chains (TdT enzyme isn't present when L chain rearrangement occurs) |
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What is somatic hypermutation? |
1. only mechanism of generating diversity that occurs AFTER gene rearranement and AFTER exposure to antigen (periphery) 2. introduce point mutations into the variable regions of H and L chains without altering the # of nucleotides
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What is the main role of SHM? |
produce abs that have a higher affinity for the antigen.....affinity maturation (adaptive immunity)
**can have no effect, + effect (great for memory cells on the next turn) or - effect (apoptose after)
**takes place during the process of ab production by Activated B cell in the follicle of secondary lymphoid organ
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B Cell development |
B cell development |
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What determines the stages of development in B cells? |
1. Ig gene rearrangement 2. expression of specific proteins on cell surface |
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Where does B cell development occur? Describe the ontogeny |
bone marrow and develop independent of antigen, but depend on the stromal cells and soluble factors made by them
**once a B cell leaves the bone marrow, will circulate for days (2--8 weeks) and if no encounter, it dies. If it does, will activate and differntiate into memory or plasma cell
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What is the lineage of B cell maturation? |
pro B cell....large preB....small preB.....immature B cell...naive/mature B cell |
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What are the features of a pro-B cell? |
1. RAG (recombinase activating gene): upregulated to initate VDJ recombination 2. early proB= DJ rearrangement.....late proB= V-DJ rearrangement 3. expression of Ig-alpha and Ig-beta (linked to each other via S-S bonds, but not linked to the Mu chain |
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What are the features of a large Pre-B cell? |
1. synthesis of Mu chain 2. surrogate light chains (14.1 and VpreB) 3. Ig-alpha and beta will send signals to nucleus when the rearrangement of H chain is complete
***BEFORE GOING TO L chain rearrangement, make a lot of copies of large Pre-Bs to increase in number |
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What are the features of small (resting) pre-B cell? |
1, RAG genes initate recombination of L chain genes 2. rearrangement of L chain genes |
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what are the features of immature B cells? |
1. complete BCR expressed as the L chains now linked to the Mu chain + Ig Alpha and beta 2. interaction with self-antigens INSDIE THE BONE MARROW will cause self tolerance 3. leave the bone marrow with IgM on their surface |
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What are the three fates after undergoing self-tolerance teaching? |
1. apoptosis 2. anergic (zombie)....non responsive and still circulate 3. attempt receptor editing: more gene rearrangement of the other L chain alleles and try to make a BCR that will NOT recognize the self-antigen |
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What are the features of a naive/mature B cell |
1. now it left the bone marrow so it gets a few things added....IgD, CR1, CR2, CD40, L-selectin 2. alternative splicing of primary RNA happens here (IgD) 3. everything past this point is considered antigen dependent |
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What is antigen dependent development? |
1. when u recognize the antigen and undergo clonal expansion and become plasma cells + secrete antibodies or become memory cells
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What can activated B cells undergo to become plasma cells? |
1. affinity maturation: of their H and L chain CDRs 2. isotype switching: make G,A, or E |
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What are two ways B cells can be activated? |
1. helped by CD4+ (T dependent) 2. not helped by CD4+ (T independent) |
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What are T-independent antigens? |
1. stimulate AB without help of CD4 help 2. no memory 3. sometimes isotype switching but less than TD (produce mostly IgM) 4. these ABs are usually less specific (no affinity maturation) and less numerous 5. two different types of T-independent antigens: TI-1 and TI-2 |
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What is the required second signal for full activation of B cells into plasma cells? |
IFN-gamma produced by innate immune cells responding to an infection |
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What are TI-1 antigens? |
aka mitogens
- result in non-specific activation of B cells and can activate naive and memory B cells of any specificity! |
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What are TI-2 antigens? |
can only activate antigen specific B cells |
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Describe TI-1 antigens more |
1. tend to be components of bacterial cell wall (LPS) 2. mitogen receptors are like PRRs that have no care of specificity and dont require BCR cross linking (polyclonal activation) 3. mitogen receptors are present and identical on all B cells 4. LPS induced stimulation of B cells also requires IL-1 as cofactor for IgM production |
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Describe TI-2 antigens |
1. large structures with repetitive epitopes (capsular polysaccharides, flagella) 2. binding of repeating epipopes by many BCRs cause cross-linking and strong INTRACELLULAR activation signal (eliminate the need for CD40 interaction with CD40L on CD4 T cell) 3. people who cant respond to TI02 antigens are susceptible to infection of encap. bacteria and immunodef. called Wiskott-Aldrich syndrome |
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TI 2- can activate B cells thru CD21...how? |
many TI 2 antigens are bound by C3 complement products.....C3 complement products bound by CD21 on B cell surface...leads to another mech where carbohydrates are brought to the BCR? |
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The bulk of pathogen-specific antibody responses responses are: |
TD antigen antigens
**occur in the secondary lymphoid tissues where B cells, antigen and CD4+ T cells are brought together |
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What are features of typical B cell activation by TD antigens? |
1. antigen encountered in periphery by dendritic cells (DC) which migrate to the lymph node or spleen and DCs can present both processed antigen (to T cells) and intact whole antigens to surface of B cell 2. DCs are retained in the PARACORTICAL region where processed antigens (MHC class 2) are sampled by CD4+ T cells passing thru |
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What are two ways B cells can encounter antigen via classical activation pathway: |
1. B cells circulate normally into lymph node/spleen and encounter intact antigen on surface of DCs or FDCs
2. B cells encounter and bind antigen in periphery and migrate to to lymph node/spleen where B cell becomes the APC for the CD4+ cell |
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Upon BCR binding to the antigen, what is the first signal for activation? |
Ig alpha and beta send signal |
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Once mIg on B cell encounters the antigen, the antigen specific B cell and antigen specific T cell do what? |
interact thru surface proteins CD40 (B cell) ad CD40L on T cell
**second signal required to activate the B cell |
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What happens to the B cell once it is activated? |
moves from parametrical region into the follicle...now germinal center....andthese 4 things happen:
1. clonal expansion 2. SHM and affinity maturation 3. isotype switching 4. differentiation into plasma and memory cells |
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What happens during affinity maturation? |
B cells mutate BCRs and leave the germinal center to interact with FDCs....if higher affinity BCRs made, they will again receive the CD40 and 40L survival signal from FDC and return to germ center to repeat CLONAL EXPANSION AND SHM (others apoptose) |
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What is significant about isotype switching in the germinal center? |
switching from IgG, IgA, or IgE depends on the cytokines present |
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Whats a difference between the plasma cells and memory B cells? |
plasma cells have larger Golgi and ER bc it secretes 2000 ABs per sec and will do so for 2-4 weeks and then die.
*memory cells can circulate/remain in LN/spleen until next time and only need the first signal to activate again |
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What is sequential activation? |
when B cell is activated after the T cell
**DC or macrophage are the APC for CD4+ then interact with the B cell to activation |
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What is the overview of TD antigen B cell activation? |
1. BCR binds antigen 2. signal 1 sent to nucleus via IgA and IgB 3. Signal 2= CD40 on B cell interacts with CD40L on activated Thelper cell (fully activated)
Move to follicle - clonal proliferation into plasma or memory cell |
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Activation of CD4+ T cell does what? |
release the cytokines that help activate the B cell and lead to further differentiation of the activated T cell (now a TH0) into TH1 or TH2 |
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Describe the CD40 and CD40L interaction |
- increases expression of MHC class 2, CD80, CD86 on B cell
1. required 2nd signal for B cell activation 2. required for isotype switching 3. required for prod. of memory B cells 4. required for affinity maturation |
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What is CD40? |
1. expressed on B cells, DCs and FDCs 2. interact with CD40L and initially causes up regulation of CD86>80 |
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What is CD40L |
1. mostly on CD4+ but can be on CD8+ 2. those who lack functional CD40L can't isotype switch much and suffer from hyper IgM syndrome making them susceptible to infectious agents 3. unregulated when they recognize antigen-MHC complex on APC |
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What is CD80 (B7-1)? |
1. present on all APCs 2. unregulated upon CD40-40L interaction 3. can bind to CD28 and CTLA4 on T cells 4. if it interacts with CD28, it provides second signal required for activation of T cell 5. prefers stimulating TH1 response |
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What is CD86 (B7-2)? |
1. present on all APCs 2. unregulated upon CD40-40L 3. binds to CD28 and CTLA4 4.if it interacts with CD28, it provides second signal required for activation of T cell 5. prefers stimulating TH2 response |
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What is CD28? |
1. presen on T cells 2. interact with 80 or 86 on B cells, providing co-stim signal for full activation of T cell |
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What is CTLA4? |
1. present on T cells 2. unregulated upon T cell activation 3. interact with 80 or 86 and will terminate activation of the T cell |
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Describe the isotype switching in B cells |
- involves changes of Ig genes in activated B cells with same rearranged VDJ but new CH gene (antigen specificity= same, but effector functions, isotype change
**switch region= noncoding region b/w J and C regions |
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What is the mnemonic for the CH regions? |
MD, go get 31, 2 elephant pshhh, and 1 giraffe pssh....go get 24 EA madden 12s
M...D...G3...G1...E2*...A1...G*....G2...G4...E1...A2 |
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T CELL DEVELOPMENT, ACTIVATION and TCR |
T CELL DEVELOPMENT, ACTIVATION and TCR |
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What are the two steps required for development of T cells? |
1. selection FOR self-MHC 2. selection AGAINST those having receptors recognizing self-antigens |
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Describe the ontogeny of th T cell |
1. T lymphocytes mature in the thymus 2. T cell progenitor moves from the bone marrow to the thymus where surface molecules are expressed, TCR rearrangement happens and so does selection based on their ability to BIND to MHC molecules and not bind to self-antigens |
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Describe differentiation of T lymphocytes in the thymus |
1. foreign antigens cannot enter the thymus 2. immature T cells (thymocytes) select based on ability to bind to self antigens complexed on self-MHC molecules 3. T cell progenitors enter thymus at cortex and work their way in (95% die) 4. "Education" to recognize my MHC (MHC restriction) but not my self-antigens.....if not encountered during education, it will be considered foreign 5. T cell differentiation in thymus occurs throughtout life but drops bing time after puberty |
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Describe TCR gene rearrangement |
1. thymocyte enters thymic cortex with TCR genes in germline 2. two types of TCR: alpha-beta and gamma-delta 3. V region of alpha and gamma are V-J genes 4. V region of beta and delta are VDJ genes 5. TCR genes begin rearrangement with DJ 6. follow 12/23 rule with a wrinkle |
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What is the alpha-neat chain? |
more numerous and more diverse than the other form
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What is gamma-delta chain? |
found in specific tissues: peripheral lymphoid tissue and epithelal cells of intestins
**interact with non-classical MHC molecules (CD1) |
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Which chain doesn't follow the rule of allelic exclusion? |
alpha chain ( it is possible to have one T cell with two different TCRs..mom and dad) but same beta chain |
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What genes are located between the alpha genes on the same chromosome? |
delta genes...if a chain rearranges, then delta genes are deleted
**this will prevent individual T cell from having both an alpha-beta and a gamma-delta |
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Which ways can't TCRs generate diversity? |
TCR genes are fixed once rearranged so NO SHM, isotype switching or combinatorial association .....alpha chains will only associate with beta and gamma with delta
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Which ways can TCR generate diversity? |
TCR can generate diversity with:
1. combinatorial diversity (any V with any D with any J) 2. junctional diversity (+,-,+)
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Diversity in CDR1 and 2 occur at lower rate because.... |
this is the part of the TCR that interacts with the MHC molecules so this part will stay constant so it doesn't lose the ability to recognize self-MHC
**most diversity happens at CDR3 since it interacts with different peptides and allow wider variety of antigens that can be recognized |
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What are the new ways where we gain additional diversity in CDR3 region? |
1. more J genes to choose from 2. 12 bp and 23 bp are arranged so that on beta and delta, V genes can skip D genes and go directly to J genes OR there can be multiple genes between the V and J genes |
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What is positive selection? |
double positive thymocytes (4 and 8 on the surface) interact with stomal cells expressing both MHC I and II
- if CD4 interacts with MHCII, then CD8 disappears and makes a CD4+ thymocyte -if CD8 interacts with MHCI, then CD4 disappears making a CD8 thymocyte - if neither then apoptosies
***this step determines MHC restriction as well as EFFECTOR function of the T cell |
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What effector function does CD4+ become? |
cytokine-secreting helper cells |
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What effector function do CD8 cells become? |
cytotoxic effector cells |
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What is negative selection? |
some T cells with TCRs recognizing self antigens survive positive selection so these must be eliminated
-involves presentation of self-peptides complexed to either MHC I or II to single positive thymocytes via DCs and macrophages at CORTICOMEDULLARY junction
-the cells that bind efficiently to MHC-peptide couple will die -interact weakly by recognizing MHC but not peptide will exit as mature, single positive T cell |
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Describe gamma-delta TCR thymocytes |
-not much known but once they rearrange their TCR, they exit thymus without being education or undergoing either selections!
-sometimes they have CD8 co receptor but none have CD4 |
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Summary of steps in T cell development |
1. CD3 and zeta chains made 2. simulataneous VDJ gene rearrangement of beta and delta chains 3. if Beta genes make productive rearragement, then they are chaperoned to surface by CD3 and zero cain (pre-TCR complex) -if failure, then will make delta and form gamma-delta thymocyte and leave! 4. CD4 and CD8 made and expressed on surface making a double positive thymocyte 5. rearrange VJ genes of alpha chain making full TCR complex 6. positive selection (from DP) and negative selection (from single positive) |
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Naive T cell activation takes place in |
peripheral lymphoid organs
-determines type of response that occurs (humoral/cell-mediated) and depends on: 1. type of antigen (exo vs endo) 2. MHC class it is bound to 3. cytokines present |
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Antigen recognition by naive T cells involve: |
multiple cell to cell interactions with APC
1. foreign antigen is trapped in periphery by APCs which migrate to peripheral lymphod organ where they present the antigen to naive T cells or by an APC within the organ 2. once it has recognized the MHC-peptide complex, it will go into TH1 or TH2 of CD4+ or CTL for CD8+....then proliferate and acquire effector funcions |
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Where do antigen activated T cells accumulate? |
at the site of infection
** naive T cells don't remain in specific tissues but migrate thru body to encounter an APC presenting the MHC peptide antigen complex it recognizes |
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Outside of a TCR, what else is required to activate a naive T cell? |
CD3 and the CD4 or CD8 molecule
* CD3 has cytoplasmic tails providing means for signal transduction...CD4 and 8 amplify and help stabilize the interaction between the TCR-MHC interaction.
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What does the CD4 molecule interact with? |
beta 2 domain of the MHC class II molecule |
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What does CD8 interact wit? |
alpha 2 and alpha 3 domains of the MHC class I molecule |
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What is the signaling and activation required to activate native T cells? |
1. 1st signal= TCR recognize and bind MHC-peptide complex with signal sent via CD3 complex 2. 2nd signal = interaction between CD80 or 86 on the APC with CD28 on a T cell or IL-1 secreted by the APC |
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What happens when both signals are received? |
activated T cell makes IL-2 and IL-2R....IL-2 will stimulate proliferation of T cells
**IL-2 is like a growth hormone for T cells |
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What signal is required after a T cell has been previously activated? |
1st signal! |
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MHC COMPLEX! |
MHC COMPLEX! |
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What are the billboards to let T cells see what is going on inside the cell? |
MHC |
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What is the primary function of MHC proteins? |
present antigens to T cells
**reason why graft/transplant rejection occurs |
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What is significant about MHC genes? |
most polymorphic gene system in the body with many allelic variants (continuous locus on chromosome 6)! 10^24different type
**makes it unlikely that 2 random people express same identical sets of MHC proteins |
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How many MHC I and MHC II genes do we have? |
6 MHCI and 6 MHC II ( 3 of each from each parent)
* we inherit a haplotype from mom and dad which are codominant expressed .....1 in 4 chance of siblings being histocompatible but children won't be histocompatible with parents |
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What is promiscuous binds? |
we have 1000s of peptides so each MHC protein has to bind to many different peptides |
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What is the specific name for human MHC genes? |
HLA (human leukocyte antigens)
**mice is H-2 (histocompatability-2 antigens) |
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Humans synthesize what 3 class I MHC molecules? |
1. HLA-A 2. HLA-B 3. HLA-C |
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Humans synthesize what 3 class II MHC molecules? |
1. HLA-DP 2. HLA-DQ 3. HLA-DR |
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What are the three mice class I MHC? |
1. H-2K 2. H-2D 3. H-2L |
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What are the two mice class II MHC? |
1. H-2 IA 2. H-2 IE |
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Describe MHC Class I (HLA-A, HLA-B, HLA-C) |
1. expressed on all NUCLEATED CELLS 2. present to CD*+ T cells |
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What is the structure of class I proteins? |
1. each composed of single polypeptide called alpha chain 2. each alpha chain has 3 domains- alpha1, alpha 2, alpha3 3. each alpha chain pairs with another polypeptide (NON-MHC gene product) called beta2microglobulin......it helps traffic class 1 alpha chain to cell surface |
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T or F: beta2microglobulin is polymorphouse? |
false...
we have different alpha proteins but same b2m |
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What is the b2m covalently linked to? |
alpha3 |
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Describe peptide binding in MHC class I proteins? |
1. binding groove for antigenic peptide is alpha-1 and alpha 2 (alpha 3 anchors protein to cell surface) 2. both ends of groove are closed and will accommodate peptide of 8-10 AA (9 is the best)...longer peptides will bulge out wile remaining anchored at the ends (#2 and 9 specificially) 3. less picky about binding to certain AAs in the middle of peptide sequence 4. some MHC class I molecules prefer basic or hydrophobic residues on the ends...allowing it to bind and present a large # of different peptides 5. different peptides tried on to see if they will bind particular class I molecule...if it doesn't, will return it to the cytoplasm for further degradation
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Where does loading of peptides onto class I molecule occur? |
endoplasmic reticulum |
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Describe antigen presentation for human MHC class I |
1. peptide are from endogenous antigens...made inside the cell and proteins are from intracellular pathogens or from common self-proteins 2. processing of endogenous proteins occurs in cytoplasm by proteasome 3. these peptide antigens will be recognized by CD8+ cells 4. bc our hose cells routinely display peptide fragments (self and foreign), the CTLs can sample and tell when the host cell is infected "see whats going on inside" |
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Describe MHC Class II |
1. DP, DQ, DR 2. each of them are expressed on antigen presenting cells (APCs) 3. present to CD4+ T cells |
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Structure of Class 2 proteins |
-comprised of two polypeptides called alpha and beta (2 domains each) |
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Describe the peptide bonding for Class 2 MHC |
1. binding groove is made up of alpha1 and beta1 (alpha2 and beta2 anchor polypeptides to cell membrane) 2. ends of binding groove are open and accommodate proteins from 13-25 AA in length (13-18 most common) 3. the critical AA for anchoring the antigenic peptide to binding groove are spaced along the peptide (not at ends like MHC1) 4. loading of peptides occurs in the caesural which the internalized antigens were brought to the cell
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From the point at which MHC proteins are translated, assembled and transported to the vesicles for peptide loading, what is the peptide binding cleft occupied by? |
invariant chain to precent the endogenous antigenic peptides from binding during transport |
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Describe antigen presentation for MHC Class II |
1. exogenous antigens! 2. brought into the cell via endocytosis or phagocytosis and remain in vesicles... 3. proteins that become antigenic peptides NOT MADE INSIDE THE CELL but brought fully formed into the cell as part of the whole antigen..........VESICLE merges with ENDOSOME containing proteolytic enzymes (cathepsins) that break it down into small peptides. |
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Where does processing of exogenous antigens occur? |
in the acidic vesicles of the host cell by cathepsin enzymes
**class II molecules will try on the peptides present within the vesicle and once bound will move to surface for presentation to CD4+ |
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ANTIGEN PROCESSING AND PRESENTATION |
ANTIGEN PROCESSING AND PRESENTATION |
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What is class restriction? |
CD4 recognize Class 2 / CD8 recognizes class 1 during T cell development |
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Antigen presentation by class I molecules does what? |
targets cell for destruction by CTLs |
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Antigen presentation by class 2 molecules does what? |
initiate humoral antibody response |
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Describe processing in the endogenous antigen pathway |
1. occurs in cytoplasm 2. proteolysis via proteasome 3. intracellular infection induces cell to make IFN-gamma which induces transcription of MHC locus (sometimes they replace part of regular proteasome and becomes immunoproteasome)....preferentially cleaves proteins AFTER hydrophobic or basic AA residues
^makes it more likely to bind the class I molecules |
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Describe peptide trafficking in endogenous antigen pathway |
1. processed peptides in cytoplams 2. MHC class I proteins translated and assembled in RER where loading of peptides happen 3. translocation from cytoplasm to ER for loading is done via TAP 1 and TAP2 (transporter associated with antigen processing)....part of the MHC locus, upregulated by presence of IFN gamma and will bind and translocate NONAMERIC peptides preferentially.
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What is calnexin? |
chaperine protein that stabilizes the alpha chain-beta2m heterodimer until peptide is loaded
**prevents class I molecule from prematurely exiting the ER before loading |
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What is tapasin? |
chaperone that increases efficiency of loading (brings TAP and class I closer for loading)
**complex dissociated from TAP and tapasin and is sent to cell surface via Golgi after peptide loading
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If PEP is not bound by one of the MHC molecules what happens? |
peptide can be shortened by exoproteases in the RER called ERAP or returned to the cytoplasm for more processing |
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What is the processing in the exogenous pathway? |
1. interalization...then endosome (phagosome) fuses with lysosome [lysosome has proteases/cathepsins and hydrolytic enzymes] 2. pH of fused vesicles decreases to 4.5 and break down the proteins into peptides to be loaded onto MHC class II molecules |
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Can exogenous antigens multiply inside the phagocytic vesicle? |
ye |
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Describe peptide trafficking in MHC class II |
1. translated/assembled in RER 2. during translation, class II molecules associate with invariant chain (binds peptide binding groove of class II molecule, blocks binding cleft from endogenous antigens) 3. classII-invariant chain complex enters Golgi and exits as a membrane-bound vesicle 4. proteases in vesicle cleave in the invariant chain, leaving a small portion associated with peptide binding cleft called CLIP (class II associated invariant peptide) 5. vesicle containing class 2-CLIP complex fuses with endosome 6. HLA-DM removes CLIP and helps with peptide loading (like tapasin) 7. class 2 molecule-peptide complex transported to cell surface for presentation
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What are the 3 functions for invariant chains? |
1. act as chaperone for proper folding of class II polypeptides 2. prevent association of class II molecules with endogenous antigenic peptides in ER 3. help traffic class 2 molecule to endosomal/lysosomal pathway |
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What are non-classical antigens? |
lipid, glycolipid antigens presented to T cells by CD1 cells *mycobacteria series
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CD1 molecules are similar in structure to |
MHC class I |
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CD1 binding cleft is very: |
hydrophobic, binding of hydrophobic lipids |
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The processing pathway of CD1 is similar to: |
class 2/exogenous pathway |
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Is CD1 polymorphic? |
No |
