4/26/12. Recap of chapter 3! Antigen recognition by B cells! And by T

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1 ecap of chapter What s the difference between the innate and adaptive immune system? n which way are the epitopes of B and cells different? What does that imply for their role in the immune response? arland cience ntigen recognition by B cells nd by cells

2 ntibodies and -cell receptors have a similar structure ermline organization of C α and β he -cell receptor resembles a membrane-associated ab fragment of immunoglobulin. earrangement of the segments necessary to produce a functional receptor. α-chain consists of and J, β of, D, and J -cell receptor diversity is generated by gene rearrangement ene rearrangement similar for generation of cell receptors and immunoglobulins ain difference: cell receptor C region simpler: only one Cα gene earrangement of immunoglobulin genes occurs in the bone marrow, rearrangement of cell receptor genes in the thymus.

3 he genes were key elements in the origin of adaptive immunity Evolution of reflects the evolution of adaptive immunity genes lack introns and resemble the transposase gene of transposons. mportant for function: ecombination process results in an excision circle rather than a linear (and potentially harmful) element. (D)J recombination arose abruptly during early vertebrate evolution hompson et al. (), mmunity :- he magnitude of potential B and cell receptor diversity he magnitude of potential B and cell receptor diversity omatic recombination results in combinatorial & junctional diversity

4 CD analysis of specific -cells β CD () Jβ %. CPEQ... CQE.. CE... CHQ... CPDEQ... CHEQ... CD... CEQ... CPPH... CEEDQ... CQQEQ... CEEQ... CQEQ... CPPDEQ... CPPDEQ.. cell responses against different viruses defect in (D)J recombination results in severe immunodefiency What do you think happens to an individual who lacks? CD = evere combined immunodeficiency syndrome absence of adaptive immunity ay be caused by mutations in at least different genes, e.g. the genes. fatal in the first years of life because of opportunistic infections herapy only possible if diagnosis is made at birth or shortly thereafter. herapy in the form of bone marrow stem-cell transplantation Buckley () mmunol es. (-):-

5 he composition of the cell receptor complex distinct population of cells expresses a second class of -cell receptor with γ and δ chains Expression of the cell receptor on the cell surface requires association with additional proteins cells either express αβ receptors or γδ receptors ever both cells function by interacting with other cells HC class presents peptide antigens to CD cells HC class presents peptide antigens to CD cells HC = major histocompatibility complex

6 he two classes of HC molecules have very similar structures HC molecules bind a variety of peptides Processing of antigens which bind to HC class or occurs in different cellular compartments Processing of antigens which bind to HC class or occurs in different cellular compartments

7 n infected tissue, cells switch to immunoproteasome for protein degradation HC class binds peptides as part of a peptide-loading complex Prefential cleavage after hydrophobic or basic residues produces peptides that fit the C- terminal binding motif of P and many H allotypes. lein et al. (), at ev mmunol ():- n the E, peptides may be further trimmed from the -terminal end by an amino peptidase he HC class antigen processing pathway HC class molecules are prevented from binding peptides in the endoplasmic reticulum by the invariant chain CP = class -associated invariant-chain peptide

8 Cross-presentation by dendritic cells Differential expression of HC class and molecules professional antigenpresenting cells { yas et al. () at ev mm. :- he major histocompatibility complex Cluster of closely linked genes on chromosome umerous genetic variants of HC class and present in the human population => diversity due to multigene families and genetic polymorphism he human HC: human leukocyte antigen (H) complex ost of the genes in the H class region are involved in the processing and presentation of antigens to cells

9 Human HC regions differ in their number of D genes Diversity of H molecules in human population is caused by copy number variation in concert with polymorphism # of Protein sequences December (/H database) H- H-B H-C enetic mechanisms that generate new HC polymorphisms

10 HC polymorphism affects the binding and presentation of peptide antigens to cells he most polymorphic amino acid residues map to the peptide binding site. Peptide binding motifs of some H class and allotypes Q D C W Q W C * B* anchor residues Q D C W Q W C great variety of binding motifs * B* Q C E D W H C * Q H C * P P C B* D Q E DEW P C E Q D D P W P W P W E D W C B* eemingly small differences may have a big impact on the peptide binding motif * and * have very different peptide binding motifs. C * E C *

11 cell recognition of antigens is HC restricted obel Prize edicine But: ome cells are alloreactive => problem for organ and bone marrow transplantations Peptide determines C diversity HC molecules are expressed in a codominant fashion. Which consequences does that have for an individual?

12 Heterozygous individuals are able to present a more diverse set of peptides to their cells H heterozygosity delays the progression to D raction of H- infected individuals who remain D-free ears since seroconversion Carrington et al. cience ;:- Exposure to pathogens shapes HC gene frequencies Worldwide H class diversity => Balancing selection maintains diversity of H allotypes in populations oulder & Watkins () at ev mm. :-

13 H-association with H- disease outcome H- viral load roughly predicts speed of disease progression pecific H class molecules have been associated with either slow or fast progression to D nother important role of HC class molecules? iepiela et al. () ature :- nother important role of HC class molecules? cell receptor genes cluster in two different regions of the human genome Humans possess more than different cell receptor genes. ndividual cells express different combinations of receptors. C natural killer complex: lectin-like cell receptors C leukocyte receptor complex: immunoglobulin-like receptors ature mmunology () :- ome of them serve as ligands for cell receptors.

14 variety of inhibitory and activating receptors allows cells to identify infected cells. CD: recognizes H-E in complex with a peptide derived from the leader sequence of H-, -B or -C molecules. H-E is non-polymorphic and has a restricted specificity for peptides H-E exclusively binds a peptide derived from the leader sequence of H-, -B, and -C molecules. he amount of H-E on the cell-surface is a measure of the amount of H-, -B, and -C produced by the cell. Clever viral evasion of cell response bind to the same face of the HC class molecules as the cell receptor H: H- and -B are down regulated, but H-C not (dnan et al, Blood,, ). EB: H- and -B are down regulated, but H-E is upregulated (Dutta, et al, Cancer,, ) dapted from Peterlin &rono, at. ev. mmunol,,. pecial function of cells: detect missing self