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B Cell Tolerance

B Cell Tolerance. Wendy Davidson Ph.D. May 3, 2011 Contact information: Email:davidsonw@niaid.nih.gov Tel:301-402-8399. Factors that contribute to the increased threshold of activation in anergic B cells. HEL and Ars/A1 models: Continuous signaling via self Ag/BCR Decreasd surface IgM

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B Cell Tolerance

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  1. B Cell Tolerance Wendy Davidson Ph.D. May 3, 2011 Contact information: Email:davidsonw@niaid.nih.gov Tel:301-402-8399

  2. Factors that contribute to the increased threshold of activation in anergic B cells HEL and Ars/A1 models: Continuous signaling via self Ag/BCR Decreasd surface IgM Chronic ERK and NFAT signaling Increased intracellular Ca++ Constitutive activation of SHIP-1 and DOK-1 Inhibition of activation of Syk and Akt survival pathway Ferry et.al. 2006. Transplantation 81:308-315

  3. B cell signaling in response to acute and chronic stimulation Mono phosphorylation of ITAMS Dual phosphorylation of ITAMS SHIP1 and DOK activated by LYN, modulate signaling • Chronic BCR signaling required to maintain anergic state • Anergy reversible by removal of Ag • Most relevant to MD4XMD5 and Ars/A1 Tg models Cambier JC, Nature Reviews, 2007

  4. Anergic B cells can be rescued from death if sufficient BAFF is available Fas/FasL and CD40/CD40L interactions also may contribute to the death of anergic B cells Ferry et.al. 2006. Transplantation 81:308-315

  5. Other mechanisms for rescuing autoreactive anergic B cells •  signaling threshold, negative signaling • CD22-/-, SHIP1-/-, FcRIIb-/- mice •  exposure to auto Ag • Transfer autoreactive Tg B cells to auto Ag-free environment • Cross anti-DNA and anti-Sm Tg mice to autoimmune MRL-lpr or B6-lpr mice • Reduce the affinity of the BCR • Defects in cell death pathways (Fas, Bim)

  6. Stages of B cell development and repertoire editing: Checkpoint 2 Checkpoint 1 Newly formed B cells Checkpoint 2 Transitional B cells Checkpoint 3 GC Central tolerance Peripheral tolerance Cambier JC Nature, 2007

  7. Stages of transitional B cells BM Spleen Transitional B cells T1 T2 T3 follicular B cells sIgM ++ ++ + +/++ IgD - ++ ++ ++ CD93 ++ + + - CD23 - + + + CD21 - + + + CD24 ++++ +++ ++ + Rag1,2 - - - - Immature B cells sIgM + IgD- CD93+ CD23- CD21- CD24 ++++ Rag1, Rag2 +/- CD93 = AA4.1 CD24= HSA Non-dividing, half-life 2-4 days

  8. Proposed Model of Human B-Cell Development

  9. Differentiation of transitional B cells in the spleen Dependence on BAFF for survival BM SP Increasing BAFF-R expression T1 T2 Naïve B cell Mature B cell Immature B cells Autoantigens Autoreactive naïve B cell Rescue Induction of anergy Ag removal and decreased stimulation threshold T3 Anergic B cell Death Only ~5% of immature B cells produced in BM enter the mature B cell pool. Significant cell loss J. Cambier, Immunity 2006; M. Cancro, Immunol. Rev. 2004

  10. Properties of BAFF • BAFF (BLyS, TALL-1, THANK, zTNF4) and APRIL, a related cytokine, are members of the TNF super family. • BAFF interacts with three receptors BAFF-R (BR3), BCMA and TACI expressed predominantly on B lineage cells. • APRIL binds to BCMA and TACI only. • BAFF is produced predominantly by myeloid cells and acts on transitional, naive and mature B cells. • BAFF is essential for normal B cell development and survival in the periphery. • BAFF-deficient mice are deficient in B2 cells and MZ B cells but have normal numbers of B1 cells. • BAFF Tg mice have excess mature B cells, especially MZ B cells, and develop systemic autoimmunity and B cell lymphomas with age.

  11. BAFF governs successful transitional B cell differentiation by enhancing survival • Interactions between BAFF and BAFF-R are essential for maturation of transitional B cells. • BAFF-R-deficient mice have severely impeded transitional B cell differentiation and mature B cells with significantly shortened lifespans. TACI and BCMA KO mice exhibit normal transitional B cell differentiation. • BAFF-R expression increases as T1 cells differentiate into T2 cells. • Competition for available BAFF dictates the lifespan of anergic B cells and resting transitional, naïve and mature B cells.

  12. Mechanisms of BAFF-induced survival of B cells • BAFF supports the survival of transitional and mature B cells • without inducing proliferation. • BAFF contributes to B cell survival by inducing the expression of pro-survival members of the Bcl-2 family and interfering with the nuclear translocation of pro-apoptotic PKC to the nucleus. • BCR ligation upregulates expression of BAFF-R, but not TACI or BCMA, on late transitional and mature B cells. • Both BCR- and BAFF-R mediated signals appear to be essential for repertoire selection and survival of mature B cells.

  13. Influence of excess BAFF on the selection of self-reactive B cells Models 1 and 2: Excess BAFF does not rescue cells deleted early in development. Models 3 and 4: Responsiveness to excess BAFF corresponds to a maturational change in T2 cells involving expression of BAFF-R. Thien et. al. 2004. Immunity 20:785-798.

  14. Anergic B Cells are Susceptible to Fas-mediated Death

  15. Differentiation of transitional B cells in the spleen Dependence on BAFF for survival BM SP Increasing BAFF-R expression T1 T2 Naïve B cell Mature B cell Immature B cells Autoantigens Autoreactive naïve B cell Rescue Induction of anergy Ag removal and decreased stimulation threshold T3 Anergic B cell Death Only ~5% of immature B cells produced in BM enter the mature B cell pool. Significant cell loss J. Cambier, Immunity 2006; M. Cancro, Immunol. Rev. 2004

  16. Evidence that anergic B cells and T3 cells have similar properties • Both have a similar surface phenotype (CD93+ CD23+ IgMlo, CD24inter, IgDhi) and lifespan. • Non-autoreactive BCR transgenic mice have few T3 cells suggesting that this population may not represent a developmental stage between T2 and naïve B cells. • Maintenance of the T3 phenotype requires continuous antigen exposure • T1 and T2 B cells are only found in the blood and spleen. Anergic B cells with the phenotype of T3 cells are detectable in spleen, LN and blood. • Anergic B cells and T3 cells have similar abnormalities in BCR signaling and have constitutively activated ERK and DOK-1. • T3 cells from normal mice are enriched for autoreactive specificities and have a similar gene expression profile to HEL Tg anergic B cells.

  17. Potential dangers of having large numbers of anergized B cells produced during B cell selection. • TheT3/anergic B cell population in normal mice ranges from 1-5x106 cells/spleen and ~50% of these are replaced every 4 days (Merrell et.al. 2006.Immunity 25:953-962). • Previous estimates suggest that ~5x106 new B cells arrive in the spleen every 4 days (Rolink et.al. 1998. EJI 28:3738-3748). • Therefore, a significant proportion (upto ~50%) of the B cells entering the spleen every four days from BM may be anergic or become anergic (Merrell et.al. 2006.Immunity 25:953-962). • Since anergy is potentially reversible, having large numbers of anergic autoreactive B cells in the periphery poses a significant risk of autoimmunity. However, under normal circumstances, this danger is likely kept in check by the short half life of anergic B cells. (Merrell et.al. 2006.Immunity 25:953-962).

  18. Possible mechanisms for rescue and activation of autoreactive anergic B cells Increased availability of BAFF Removal of self Ag High avidity Ag stimulation + T cell help TLR signals Defects in Fas, Bim signaling Altered signaling threshold RESCUE AUTOIMMUNITY Ferry et.al. 2006. Transplantation 81:308-315

  19. CHECKPOINT 3: Elimination of autoreactive B cells generated in GC Autoreactive B cells generated in germinal centers by somatic hypermutation normally are eliminated. Possible role for Fas/FasL. Lack of T cell help

  20. Defects in the induction and control of B cell tolerance lead to systemic autoimmunity • Topics for lecture 2: • Sources of autoreactive B cells (incompletely tolerized cells, ignorant B cells) • Sites and mechanisms of activation of autoreactive B cells (antigens, TLRs, extrafollicular responses) • Contributions of autoreactive B cells to disease (effectors and APC)

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