Early Preplasma Cells Define a Tolerance Checkpoint for Autoreactive B Cells

Culton, Donna A.; P., O'Conner, Brian; Conway, Kara L.; Diz, Ramiro; Rutan, Jennifer A.; Vilen, Barbara J.; Clarke, Stephen H.

doi:10.4049/jimmunol.176.2.790

Cited by 73 publications

(99 citation statements)

References 56 publications

(61 reference statements)

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“…Autoreactive B cells from SW HEL X HEL 2X mice may have an intrinsic impairment preventing the differentiation into IgG plasma cells due to chronic exposure to the autoAg, especially at the GC level. The existence of a tolerance checkpoint between the GC and plasma cell compartments has been previously suspected in other transgenic mice and in FcRIIb −/− mice [44][45][46].This study reveals control mechanisms that are effective during chronic infection even when self-reactive B cells are activated and pushed to SHM in GCs. Thereby, we provide an explanation for the low prevalence of pathogenic IgG autoAbs in healthy individuals' sera.…”

supporting

confidence: 52%

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

et al. 2015

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The links between infections and the development of B-cell-mediated autoimmune diseases are still unclear. In particular, it has been suggested that infection-induced stimulation of innate immune sensors can engage low affinity autoreactive B lymphocytes to mature and produce mutated IgG pathogenic autoantibodies. To test this hypothesis, we established a new knock-in mouse model in which autoreactive B cells could be committed to an affinity maturation process. We show that a chronic bacterial infection allows the activation of such B cells and the production of nonmutated IgM autoantibodies. Moreover, in the constitutive presence of their soluble antigen, some autoreactive clones are able to acquire a germinal center phenotype, to induce Aicda gene expression and to introduce somatic mutations in the IgG heavy chain variable region on amino acids forming direct contacts with the autoantigen. Paradoxically, only lower affinity variants are detected, which strongly suggests that higher affinity autoantibodies secreting B cells are counterselected. For the first time, we demonstrate in vivo that a noncross-reactive infectious agent can activate and induce autoreactive B cells to isotype switching and autoantigen-driven mutations, but on a nonautoimmune background, tolerance mechanisms prevent the formation of consequently dangerous autoimmunity.Keywords: Affinity maturation r Autoreactive B cell r B-cell tolerance r Germinal center r Infection Additional supporting information may be found in the online version of this article at the publisher's web-site 132Sophie Jung et al. Eur. J. Immunol. 2016. 46: 131-146 Introduction B-cell receptors (BCRs) are assembled in developing B-lymphocyte precursors via a stochastic process of joining immunoglobulin (Ig) genes. These random rearrangements inevitably result in the genesis of multiple receptors that recognize self-antigens (Ags) [1]. Despite the fact that known mechanisms of central tolerance take place in the bone marrow, many self-reactive B cells escape toward the periphery [2][3][4][5]. Most of them are the so-called natural autoimmune B cells with a mature naïve phenotype, which produce-in normal individuals-small amounts of polyreactive low affinity IgM autoantibodies (Abs) devoid of somatic mutations. A recent study performed in mice also suggests that quiescent autoreactive B cells persist in the adult repertoire and could serve as a source of pathogenic autoAbs under circumstances that still have to be defined [6]. Both genetic background and environmental factors could influence B-cell maturation in a way that favors the appearance of high affinity IgG switched autoAbs. Among known environmental factors, epidemiological studies have clearly linked infections with the occurrence of autoimmune diseases in humans and in animal models [7]. In some organ-specific autoimmune diseases, this link is attributed to molecular mimicry between pathogens and self-Ags [8][9][10][11]. The role of such mechanism in the breakdown of B-cell tolerance during systemic auto...

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confidence: 52%

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

et al. 2015

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“…Both SLE patients and lupus-prone mice have alterations in their B-cell subsets, such as an increased proportion of plasmablasts and/or plasma cells, GCs, etc., [39][40][41][42][43] which reflects the disturbed differentiation of B cells in SLE patients and lupus-prone mice. In the present study, we found that compared with wild-type mice, CD138 1 plasmablasts/plasma cells and B220 1 GL-7 1 GC B cells are increased in MRL/lpr mice and are CD180-negative.…”

Section: Discussionmentioning

confidence: 99%

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

You

Dong

et al. 2015

Cell Mol Immunol

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A hallmark of systemic lupus erythematosus (SLE) is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-a (IFN-a) signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between CD180 and IFN-a signaling remains unknown. In the present study, we explored the effect of CD180 on regulating the activation of IFN-a signaling in B cells. We found that the number of CD180-negative B cells was increased in MRL/Mp-Fas(lpr/lpr) lupus-prone mice compared with wild-type mice. Phenotypic analysis showed that CD180-negative B cells comprised CD138 1 plasmablast/plasma cells and GL-7 1 germinal center (GC) B cells. Notably, ligation of CD180 significantly inhibited the IFN-a-induced phosphorylation of signal transducer and activator of transcription 2 (STAT-2) and expression of IFN-stimulated genes (ISGs) in a Lyn-PI3K-BTK-dependent manner in vitro. Moreover, ligation of CD180 could also inhibit IFN-a-induced ISG expression in B cells in vivo. Furthermore, the Toll-like receptor 7 and Toll-like receptor 9 signaling pathways could significantly downregulate CD180 expression and modulate the inhibitory effect of CD180 signaling on the activation of IFN-a signaling. Collectively, our results highlight the close association between the increased proportion of CD180-negative B cells and the activation of IFN-a signaling in SLE. Our data provide molecular insight into the mechanism of IFN-a signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment. Cellular & Molecular Immunology

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Section: A Short History Of Smmentioning

confidence: 99%

“…Expression of the 2-12H transgene in MRL/lpr mice increases the prevalence of the anti-Sm response, accelerates disease, and leads to higher serum anti-Sm levels [65]. Sm-specific B cells from 2-12H mice are arrested at the pre-plasma cell stage, while B cells from the 2-12H/MRL/lpr mice bypass this checkpoint and become activated [93].The presence of class-switched autoantibodies in MRL/lpr mice suggests a breakdown in tolerance within the adaptive immune response. In MRL/lpr mice where somatic hypermutation and isotype switch recombination are blocked (AID −/− ), lupus-like symptoms such as glomerulonephritis, proteinuria, and immune complex deposition are ameliorated [94].…”

mentioning

confidence: 99%

The regulation of autoreactive B cells during innate immune responses

Vilen

Rutan

2008

Immunol Res

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Systemic lupus erythematosus (SLE) highlights the dangers of dysregulated B cells and the importance of initiating and maintaining tolerance. In addition to central deletion, receptor editing, peripheral deletion, receptor revision, anergy, and indifference, we have described a new mechanism of B cell tolerance wherein dendritic cells (DCs) and macrophages (MΦs) regulate autoreactive B cells during innate immune responses. In part, DCs and MΦs repress autoreactive B cells by releasing IL-6 and soluble CD40L (sCD40L). This mechanism is selective in that IL-6 and sCD40L do not affect Ig secretion by naïve cells during innate immune responses, allowing immunity in the absence of autoimmunity. In lupus-prone mice, DCs and MΦs are defective in secretion of IL-6 and sCD40L and cannot effectively repress autoantibody secretion suggesting that defects in DC/MΦ-mediated tolerance may contribute to the autoimmune phenotype. Further, these studies suggest that reconstituting DCs and MΦs in SLE patients might restore regulation of autoreactive B cells and provide an alternative to immunosuppressive therapies. KeywordsSystemic lupus erythematosus; B cell tolerance; Autoimmunity; Dendritic cell; Macrophage; Smith antigen Learning tolerance: a B cell's storyA diverse B cell repertoire is critical in combating pathogens, but inherent in generating diversity is the threat of autoimmunity. In the bone marrow, central tolerance mechanisms such as deletion or receptor editing remove high-affinity autoreactive B cells before they exit to the periphery [1][2][3][4][5][6][7][8][9][10]. Those that escape are subject to receptor revision [8,[11][12][13][14], peripheral deletion [15,16], or a shortened lifespan because they fail to enter B cell follicles [17][18][19][20][21][22]. In rare cases, autoreactive B cells are fully functional but indifferent to their specific antigen [23][24][25]. Finally, many low-affinity autoreactive B cells are maintained in an unresponsive state known as anergy. Anergic B cells do not receive sufficient activation signals to differentiate into plasma cells or secrete immunoglobulin (Ig) in response to antigenic or mitogenic stimulation [26][27][28][29]. Their proliferative responses to B cell receptor (BCR) or toll-like receptor (TLR) signaling as well as their lifespans vary in different models [18,[30][31][32][33][34][35]. Some anergic B cells transduce BCR-derived signals [30, 32,[36][37][38][39][40], while others exhibit desensitized BCRs [30, 33,41]. Quiescence is dependent on chronic exposure to self-antigen and occupancy of the BCR [42,43] The affinity and avidity of the antigen-BCR interaction determines whether developing B cells will be deleted, edited, anergized, or ignored [46]. Self-reactive B cells that survive these developmental checkpoints tend to bind self-antigens with low affinity and they remain anergic in the absence of costimulation by cognate T cells. Many of the early transgenic (Tg) models expressed BCRs with high affinities. However, concerns were raised that these models...

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Early Preplasma Cells Define a Tolerance Checkpoint for Autoreactive B Cells

Cited by 73 publications

References 56 publications

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

The regulation of autoreactive B cells during innate immune responses

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