Immunobiology 7. The Humoral Immune Response

Transcription

1 Janeway Murphy Travers Walport Immunobiology 7 Chapter 9 The Humoral Immune Response Copyright Garland Science 2008 Tim Worbs Institute of Immunology Hannover Medical School 1

2 The course of a typical antibody response 2

3 Antibody responses are primarily directed against extracellular pathogens and their toxic products 3

4 Antibodies participate in host defense by three principal modes of action 4

5 The signalling requirements during B cell activation are determined by the nature of the antigen TD TI-1 TI-2 5

6 The B cell receptor (BCR) complex is formed by membrane-bound Ig and invariant accessory chains 6

7 The activation of B cells requires cross-linking of BCR complexes by multivalent antigens 7

8 Clustering with the B cell co-receptor complex augments BCR signalling 8

9 B cell activation by Thymus-independent (TI-1 and TI-2) antigens 9

10 Characteristic properties of Thymus-dependent (TD) and Thymus-independent (TI-1 and TI-2) antigens 10

11 CD5 + B1 cells and marginal zone B cells prominently contribute to the antibody response against TI-2 antigens 11

12 Armed helper T cells stimulate the proliferation and then the differentiation of TD antigen-binding B cells 12

13 B cells and helper T cells must recognize epitopes of the same molecular complex linked recognition 13

14 Protein antigens attached to polysaccharide antigens allow T cells to help polysaccharide-specific B cells 14

15 Helper T cells deliver membrane-bound stimuli and secreted cytokines in a polarized fashion to individual B cells 15

16 Antigen-binding B cells encounter helper T cells at the border between T cell and B cell zones of secondary lymphoid organs spleen 16

17 Antigen-binding B cells encounter helper T cells at the border between T cell and B cell zones of secondary lymphoid organs lymph node 17

18 Plasma cells secrete antibody at a high rate but can no longer respond to antigen or T cell help 18

19 The differentiation of resting B cells into plasmablasts and plasma cells is accompanied by profound morphological changes 19

20 Plasma cells generated in primary foci and germinal centers migrate to medullary cords, splenic red pulp and bone marrow 20

21 IgG and IgA secreting plasma cells are dispersed within medullary cords, splenic red pulp and bone marrow medullary cords (short-lived days) IgG IgA bone marrow (long-lived month to years) κ light chain λ light chain 21

22 The germinal center is a specialized microenvironment for B cell proliferation, somatic hypermutation and affinity maturation Ki67 FDC CD4 22

23 Activated B cells undergo rounds of mutation and selection for higher-affinity immunoglobulins within germinal centers 23

24 The germinal center reaction results in the generation of plasma cells and memory B cells expressing high-affinity immunoglobulins 24

25 Somatic hypermutation introduces mutations into the rearranged immunoglobulin variable region 25

26 The molecular structure of immunoglobulins 26

27 The complementary-determining regions (CDRs) are hypervariable regions of heavy and light chain V domains 27

28 The hypervariable amino acid sequences of the CDRs form the antigen-binding site of the folded V domains 28

29 Antibodies recognize distinct conformational shapes on the surfaces of intact antigens involving a variety of forces 29

30 Both the affinity and the amount of antibody increase with repeated immunization 30

31 The generation of secondary antibody responses driven by memory B cells is distinct from a primary antibody response 31

32 Class switching leads to the production of IgG, IgA and IgE immunoglobulins 32

33 Class switching is preceded by transcriptional activity at the target heavy-chain C-region genes 33

34 Different cytokines preferentially promote or suppress switching to certain immunoglobulin classes 34

35 Each immunoglobulin class has specialized functional properties and a unique tissue distribution 35

36 The different immunoglobulin classes are selectively distributed in the body 36

37 Secretory IgA is the dominant antibody class within the mucosal immune system 37

38 Transcytosis of IgA (and IgM) across epithelia is mediated by the poly-ig receptor 38

39 Secretory IgA binds to mucins within the intestinal mucus layer and neutralizes pathogens and their toxins 39

40 Secretory IgA has several further functions at epithelial surfaces 40

41 Many common diseases are caused by bacterial toxins 41

42 High-affinity IgG and IgA antibodies neutralize bacterial toxins 42

43 Virus-neutralizing high-affinity IgG and IgA antibodies inhibit the infectivity of viruses 43

44 Antibodies can block the adherence of bacteria to host cells Salmonella spp. adhesins Neisseria gonorrhoeae pilin IgA (mucosal surfaces) / IgG (within tissues) 44

45 Binding to the surface of pathogens induces the staple conformation of IgM exposing binding sites for C1q 45

46 The classical pathway of complement activation is initiated by IgM and IgG bound to bacterial surfaces 46

47 Erythrocyte CR1 contributes to the efficient clearance of immune complexes from the circulation 47

48 Fc receptors specific for the Fc regions of different Ig classes are differentially expressed on accessory cell subsets 48

49 Antigen-bound immunoglobulin binds to Fc receptors with high avidity allowing cross-linking of Fc receptor 49

50 Fc and complement receptors on phagocytes synergize to trigger the uptake and degradation of pathogens 50

51 Eosinophils attacking a schistosome larva in the presence of serum from an infected patient 51

52 NK cells kill antibody-coated target cells by antibody-dependent cell-mediated cytotoxicity (ADCC) 52

53 IgE antibody cross-linking on mast-cell surfaces leads to a rapid release of inflammatory mediators 53

54 The humoral immune response is crucial for clearing primary infections as well as establishing protective immunity 54

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