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B Cell Tolerance Wendy Davidson Ph.D. May 3, 2011 Contact information: Tel:301-402-8399.

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Presentation on theme: "B Cell Tolerance Wendy Davidson Ph.D. May 3, 2011 Contact information: Tel:301-402-8399."— Presentation transcript:

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: 1.Continuous signaling via self Ag/BCR 2.Decreasd surface IgM 3.Chronic ERK and NFAT signaling 4.Increased intracellular Ca ++ 5.Constitutive activation of SHIP-1 and DOK-1 6. 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 Cambier JC, Nature Reviews, 2007 Dual phosphorylation of ITAMS Mono 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

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 Cambier JC Nature, 2007 Checkpoint 1 Newly formed B cells Checkpoint 2 Transitional B cells Checkpoint 3 GC Central tolerance Peripheral tolerance

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

8 Proposed Model of Human B-Cell Development

9 Differentiation of transitional B cells in the spleen Immature B cells T1T2 Naïve B cell Autoantigens Anergic B cell T3 Ag removal and decreased stimulation threshold Autoreactive naïve B cell Induction of anergy Increasing BAFF-R expression J. Cambier, Immunity 2006; M. Cancro, Immunol. Rev. 2004 Significant cell loss Only ~5% of immature B cells produced in BM enter the mature B cell pool. Mature B cell Dependence on BAFF for survival BMSP Rescue Death

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 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. Influence of excess BAFF on the selection of self- reactive B cells 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 Immature B cells T1T2 Naïve B cell Autoantigens Anergic B cell T3 Ag removal and decreased stimulation threshold Autoreactive naïve B cell Induction of anergy Increasing BAFF-R expression J. Cambier, Immunity 2006; M. Cancro, Immunol. Rev. 2004 Significant cell loss Only ~5% of immature B cells produced in BM enter the mature B cell pool. Mature B cell Dependence on BAFF for survival BMSP Rescue Death

16 Evidence that anergic B cells and T3 cells have similar properties Both have a similar surface phenotype (CD93 + CD23 + IgM lo, CD24 inter, IgD hi ) 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. The T3/anergic B cell population in normal mice ranges from 1-5x10 6 cells/spleen and ~50% of these are replaced every 4 days (Merrell et.al. 2006.Immunity 25:953-962). Previous estimates suggest that ~5x10 6 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 1. Increased availability of BAFF 2. Removal of self Ag 3. High avidity Ag stimulation + T cell help 4. TLR signals 5. Defects in Fas, Bim signaling 6.Altered signaling threshold Ferry et.al. 2006. Transplantation 81:308-315 RESCUE AUTOIMMUNITY

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

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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