Basic science of B cell disorders. Stuart Tangye

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1 Basic science of B cell disorders Stuart Tangye

2 Human B-cell development and differentiation

3 Human B-cell development and differentiation X X X X X X Mutations compromising B cell development - agammaglobulinemia BTK (XLA) Ig µ, Igα, Igβ λ5 BLNK X E47, IKAROS ( RAG1/2) X X

4 Kinetics of the Humoral Immune Response

5 B-Cell Activation in Lymphoid Tissues 1. Initiation of 1 response in the T cell zone Short lived cells Extrafollicular reaction

6 Kinetics of the Humoral Immune Response Extrafollicular reaction

7 B-Cell Activation in Lymphoid Tissues 2. Maturation of the B cell response: Germinal centre reaction Outer Zone - differentiation of hi-affinity centrocytes into memory B or plasma cells Bone Marrow Periph blood, 2 lymph tissues, BM Dark Zone - centroblasts - SHM - intense proliferation Light Zone - centrocytes - hi-affinity clones receive survival signals, express survival genes - Recycle to DZ, or exit De Silva & Klein (2015). Nat Rev Immunol 15: 137

8 Kinetics of the Humoral Immune Response GC reaction

9 Why mutate Ig V region genes? allows immune system to select B cells expressing Ag receptors (ie Ig) with increased/improved affinity for the immunising Ag/pathogen generates highly Ag-specific immune response provided B cells with a survival advantage facilitates more rapid elimination of infectious pathogen

10 Why switch Ig isotypes? IgM IgD IgG IgA isotype switching provides secreted Ig with distinct biological activities - IgG : longer t 1/2 than IgM; : binds FcγR to increase phagocytosis : activates complement pathway/system - IgA : produced predominantly in the mucosa : often 1st line of defence against pathogens : dimeric - IgE : binds IgεR to activate mast cells, basophils : important in anti-helminth responses necessary for adaptive Ab responses

11 CSR & SHM: AID-dependent processes Delkeret al., Nat Immunol. 10: 1147

12 GC and memory formation are T-cell dependent nude mice (greatly deteriorated thymus) thymectomised mice anti-cd4 mab treated mice αβ TCR gene deficient mice ALL UNABLE TO MOUNT LONG LIVED Ab RESPONSES Control mice Antibody response But which molecules, interactions and cells are required? Thymectomised mice

13 Role of CD40 During a B-Cell Response IL-21 IL-21 IL-21 IL-21 Van Kooten & Banchereau (1996). Adv. Immunol. 61: 1-77

14 What would happen if the CD40/ CD40L interaction was prevented? IL-21 IL-21 x x IL-21 IL-21 x x Van Kooten & Banchereau (1996). Adv. Immunol. 61: 1-77

15 Hyper-IgM Syndrome (Ig class switch recombination deficiencies) or normal IgM IgG IgA IgE Ie impaired CSR; reduced SHM Extremely susceptible to recurrent bacterial and opportunistic infections Pneumocystis carinii pneumonia, cryptosporidium CMV No germinal centers (ie TD immune responses) Lack of humoral memory X-lined and autosomal forms

16 X-lined Hyper-IgM Syndrome (HIGM-1) ~50% of all cases of HIGM (TRAP = CD40L)

17 Defective GC formation in HIGM1 Control HIGM H&E Ki67 CD23 (FDCs) Facchetti et al., J Immunol. 154: 6624

18 Autosomal recessive HIGM: HIGM3

19 Engagement of CD40 activates NFκB Puel et al Curr. Opin. Immunol. 16: 34

21 Hyper-IgM Syndrome Lack of T-cell help Unable to receive or transmit T-cell help reduced IgM memory B cells, no switched memory B cells Durandy & Honjo (2001). Curr Opin Immunol 13: 543

22 B-cell intrinsic HIGM: mutations in mediators of CSR and SHM

23 or normal IgM IgG IgA IgE impaired CSR (± SHM) B-cell intrinsic HIGM: HIGM2 Hyperplastic lymph nodes/germinal centers Intact T cell function g not susceptible to opportunistic infections Often not recognised til 2 nd or 3 rd decade of life Revy et al (2000). Cell 102: 565

24 B-cell intrinsic HIGM: HIGM2 or normal IgM IgG IgA IgE Impaired CSR (± SHM) Hyperplastic lymph nodes/germinal centers Intact T cell function g not susceptible to opportunistic infections Often not recognised til 2nd or 3rd decade of life

25 Clinical/immunologic features of HIGM syndromes Notarangelo et al., J Allergy Clin Immunol. 117: 855

26 CD40L is predominantly expressed by CD4 + T cells in the outer zone of GC s (Tfh cells) CD40L Ki67 CD4..as is ICOS Casamayor-Palleja et al (1995). J Exp Med. 181: 1293 Hutloff et al (1999). Nature. 397: 263

27 Inducible Co-Stimulator (ICOS) Schwartz (2001). Nature. 409: 31

28 4/36 CVID patients

29 IL-21R/γc/JAK3/STAT3 signalling is necessary for humoral immunity in vivo in humans STAT3 JAK3

30 T follicular helper (T FH ) cells CD4 + CXCR5 hi T cells that localise to B-cell follicles/germinal centres express high levels of many molecules involved in T/B interaction/regulation provide help to B cells via production of specific cytokines Ma et al Immunol Cell Biol. 87: 590 X-HIGM ICOS CVID XLP

31 Correlation between T FH and memory B cells

32 Intrinsic and extrinsic regulators of human B-cell differentiation

33 B-cell differentiation: the role of co-receptors Rolink & Melchers (2002). Curr Opin Immunol. 14: 266

34 CD19: B-cell co-receptor Opsonised Ag - ligates 2 receptors

36 CD19-deficient patients

37 CD19-deficient patients - 6 patients total - 4 unrelated families; different homozygous mutations - recurrent infection, hypogamma, impaired recall responses to vaccine Ags - Memory B cell deficiency - normal GC formation, reduced SHM - reduced B cell responses in vitro - (2 other unrelated CD19 mutant pts been reported; initially diagnosed as B-cell deficient due to lack of CD19+ cells!)

38 Another case of CD19 deficiency?

39 Another case of CD19 deficiency? - phenocopy of CD19-deficiency

40 CD21 deficiency - hypogamma ± recurrent infections, reduced memory B cells, reduced response to polysacch Ag; ± defective B cell responses in vitro - not as severe as CD19-deficiency

41 B-cell differentiation: the role of co-receptors - reduced switched memory B cells - low serum IgG Rolink & Melchers (2002). Curr Opin Immunol. 14: impaired responses to TI Ag (ie PneumoVax) but not TD Ag

42 Novel gene mutations underlying CVID and humoral immune defects

43 Novel gene mutations underlying CVID and humoral immune defects NFKB1 (p50) NFKB2 (p100)

44 B-cell differentiation: the role of co-receptors Rolink & Melchers (2002). Curr Opin Immunol. 14: 266

45 Intrinsic and extrinsic regulators of human B-cell differentiation

B Cells and Antibodies

B Cells and Antibodies Andrew Lichtman, MD PhD Brigham and Women's Hospital Harvard Medical School Lecture outline Functions of antibodies B cell activation; the role of helper T cells in antibody production