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B Cell Tolerance. Wendy Davidson Ph.D. May 3, 2011 Contact information: Email:[email protected] 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
B Cell Tolerance

Wendy Davidson Ph.D.

May 3, 2011

Contact information:

Email:[email protected]

Tel:301-402-8399

slide2
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

slide3
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

slide4
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

slide5
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)
slide6
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

slide7
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

slide9
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

slide10
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.
slide11
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.
slide12
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.
slide13
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.

slide15
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

slide16
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.
slide17
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).
slide18
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

slide19
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

slide20
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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