Cboi Lecture 5 (Ct)

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Antibodies are synthesised by

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plasma cells (lymphoid lineage)

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Antibody-antigen complexes are removed from the circulation primarily through

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phagocytosis by macrophages

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Linus Paulings model proposed that

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a preformed undifferentiated immunoprotein folded over the antigen at different locations at different haptenic groups. Immunoprotein reacted with all antigens but its conformation was different in each case

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Sir Frank MacFarlane Burnet proposed the

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clonal selection theory of acquired immunity

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After clonal deletion what happens

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clonal expansion - activated lymphocytes after selection by antigen

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antibodies are part of which family?

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glycoproteins

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antibodies are composed of

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one or more copies of a characteristic unit that form a Y shape

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define antigen

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any molecules or parts of molecules recognised by the variable antigen receptors of lymphocytes

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define epitope

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the specific region of the antigen bound by the variable region of an immunoglobulin

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define affinity

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measure of the strength of binding of an antigen by an antibody

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what type of binding is antibody to antigen?

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non-covalent and reversible

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the affinity of an antibody for an antigen is related to the ratio of

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the rates of the forward reaction for formation of the complex to back reaction for decay of the complex.

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Each Y contains 4 polypeptides

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two identical heavy chains (55kDa)

Two identical light chains (22kDa)

Held together by disulphide bridges and non-covalent bonds

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Fab fragment stands for

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fragment having the antigen binding site

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Fc fragment stands for

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fragment that crystalises

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The ability for an antibody to bind antigen is determnined by the

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N terminal domains (they are variable)

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There are small regions of hypervariablity within four conserved framework regions

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FR1, FR2,FR3 and FR4

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In 3D structure the hypervariable regions form

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loops that combine together to form the principal antigen binding surfaces.

Called complementarity determining regions

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Papain cleavage separates the

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Fabs from the Fc

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papain cleavage

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pepsin cleavage

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What are the 5 main classes of antibody

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IgG, IgM, IgA, IgE, IgD

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the 5 classes of antibody are divided on the basis of

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the number of Y like units and the type of heavy chain polypeptide they contain

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5 types of heavy chain

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gamma, mew, alpha, sigma and weird backwards 3

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2 light chains

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K or lambda

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one light chain always associates with

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one heavy chain

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In humans, the IgG classes has how many sub classes

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4

these have gamma heavy chains

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In humans the IgA classes have how many sub classes?

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2

these have alpha heavy chains

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IgA is the most prevalent immunoglobulin in

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mucosal secretions

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IgA binds to

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antigens and prevents the uptake of bacteria and toxins

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Epithelial cells in teh intestine mediate the transfer of dimeric serum IgA to the intestinal lumen via

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the polymeric Ig receptor

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IgA dimer binds to the pilymeric Ig receptor via

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the J chain

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Binding of IgA induces ______ of the ploymeric Ig receptor

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transcytosis

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the IgA-pIgR complex is delivered to

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the apical surface of the epithelial cell and into the lumen

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What protects the IgA from the proteases present in mucus and anchors IgA at the desired location

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secretory component

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After opsonisation with IgA, the receptor Fcalpha/microR mediates

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the uptake of organisms by macrophages and dendritic cells

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A second receptor FcalphaRI mediates

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uptake by neutrophils

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What is a common immunodeficiency in humans?

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IgA deficiency

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what can compensate for IgA deficiency by also binding to pIgR

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IgM

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IgM opsonised organisms are phagocytosed via

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Fcalpha/microR

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Activating Fc receptors signal through

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ITAMs

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ITAM stands for

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immunoreceptor tyrosine-based activation motif

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ITAM contains

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two precisely spaced tyrosines within a consensus sequence

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What happens when ITAM is phosphorylated

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the tyrosine residues provide a binding site for one or two closely related intracellular tyrosine kinases

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Examples of tyrosine kinases

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Syk (immune cells)

ZAP-70 (T cells)

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SH2 stands for

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Src Homology 2

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what does SH2 do?

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dock onto two phosphotyrosines, activates signalling events downstream of the receptor

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pIgR stands for

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polymeric Ig receptor

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Src family tyrosine kinase is held in the

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plasma membrane by a lipid tail

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Src family tyrosine kinase does what

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phosphorylates ITAM tyrosines in the receptor Ig-alpha and Ig-Beta chains

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Phosphorylation by Src family tyrosine kinase does what

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creates a binding site for Syk

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Syk binds to

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doubly phosphorylated ITAM sequence

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What does Syk do>

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phosphorylates other signalling proteins which change behaviour of the cell

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Name the mechanisms of antibody mediated toxicity

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Antibody-dependent cell-mediated cytotoxicity (ADCC)

Complement mediated cytotoxicity (CMC)

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What is antibody dependent cell mediated cytotoxicity (ADCC)

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antibody attracts cytotoxic cells by means of their Fc receptors

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What is complement mediated cytotoxicity (CDC)

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antibody binding results in fixation of complement on to the target cell.

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complement consists of

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30 serum and membrane proteins that can mediate a variety of immune reactions

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what can the complement system mediate

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triggering inflammatory responses

attraction of phagocytes to sites of infection

degradation of membranes or virus envelopes

stimulation of antibody production

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What are the three pathways that trigger complement?

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lectin

classical

alternative

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what triggers the lectin pathway

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recognition of carbohydrate moieties by collectins

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what triggers the classical pathway

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antibody binding to antigen in immune complexes

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what triggers the alternative pathway

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directly at microbial cell surfaces

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what does activation of complement trigger?

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initiates a cascade of cleavages - cleaved into small (a) and big (b) fragments

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the b fragment forms what

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a subunit of the protease complex mediating the next cleavage in the pathway

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Are the early events in complement identical for every pathway

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no

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Are the late events in complement identical for every pathway

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yes

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what is the function of the early events in complement>

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generate two functionally equivilant forms of a protease, known as C3 convertase

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What does C3 convertase do?

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initiates the late events

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what is the function of the late events in complement

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produce the effector components of complement

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How does C3 convertase attach to the cell surface

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covalently

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cleavage of C3 convertase leads to

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effector activation

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what are pentraxins

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pentameric serum proteins that participate in innate immunity and activate the classical pathway of complement

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What is MASP

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mannose binding lectin associated seine protease

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Cr1 is activated by

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C1q

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Cr1 cleaves

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C1s which is activated by this

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what are the random letters associated with the lectin pathway

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MASP-2, MASP-3, C4, C4a, C4b, C2, C2a, C2b

C4bC2b C3 convertase cleaves C3

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what are the random letters associated with the classical pathway

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C1s, C1r, C1q, C4, C4a, C4b, C2, C2a, C2b

C4bC2b C3 convertase cleaves C3

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what are the random letters associated with the alternative pathway

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C3b, B, Ba, Bb

C3bBb C3 convertase cleaves C3

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Which surfactents are collectins?

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surfactent protein-A (SP-A)

surfactent protein-D (SP-D)

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What do SP-A and SP-D funtion as

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oposonins that stimulate uptake by phagocytes

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SP-A and SP-D are expressed at highest levels where?

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in the lung

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Collectins structure consists of

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cysteine rich region

collagen like domain

neck region

carbohydrate recognition domain (CRD)

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what is MBL

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mannose-binding lectin.

activates the lectin pathway.