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

Abstract

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...

The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis

“…By the usual processes of somatic mutation and antibody affinity maturation, the isotype of autoantibody to the peptide backbone of PDC-E2 will switch from IgM to predominantly IgG. (42) We suggest that the coupling of a xenobiotic induces a conformational change that renders the ILD of PDC-E2 distinctly structurally altered to an extent where it is recognized as foreign, but with enough preserved structure such that induced antibodies cross-react to authentic LA-conjugated PDC-E2. This occurs early in the process of tolerance breakdown, explaining why anti 2OA-ILD antibodies are enriched for IgM in early-stage disease.…”

“…As the response progresses, autoantibody to the backbone of PDC‐E2 are produced through epitopes spreading from 2OA to the PDC‐E2 backbone. By the usual processes of somatic mutation and antibody affinity maturation, the isotype of autoantibody to the peptide backbone of PDC‐E2 will switch from IgM to predominantly IgG . We suggest that the coupling of a xenobiotic induces a conformational change that renders the ILD of PDC‐E2 distinctly structurally altered to an extent where it is recognized as foreign, but with enough preserved structure such that induced antibodies cross‐react to authentic LA‐conjugated PDC‐E2.…”

Pseudomonas aeruginosa and acute rejection independently increase the risk of donor-specific antibodies after lung transplantation

“…Ultimately, the inflammatory environment induced by Pseudomonas aeruginosa may promote the clonal expansion of alloreactive T cells and the polyclonal activation of B cells, and upregulation of HLA molecules on airway epithelial cells to amplify the humoral alloimmune response. Pseudomonas aeruginosa is also capable of facilitating affinity maturation and promoting isotype switching and somatic mutations in alloreactive B cells, especially if these antigens are already exposed on the allograft . Moreover, Pseudomonas aeruginosa isolation from the respiratory tract or the resultant clinical treatment with antibiotics may modulate the gut microbiome and result in both protective and deleterious humoral responses .…”

“…Pseudomonas aeruginosa is also capable of facilitating affinity maturation and promoting isotype switching and somatic mutations in alloreactive B cells, especially if these antigens are already exposed on the allograft. 47,48 Moreover, Pseudomonas aeruginosa isolation from the respiratory tract or the resultant clinical treatment with antibiotics may modulate the gut microbiome and result in both protective and deleterious humoral responses. 49,50 Thus, altering the microbiome in itself may modulate the severity of allograft injury.…”

Serum immunoglobulin G4 in Sjögren’s syndrome: a pilot study

“…Immunoglobulin G4 is the least numerous, constituting only about 4% of total IgG. It does not have the ability to opsonize, does not activate the complement directly, and has an affinity to type I, II FcR receptor [1,2]. Its role in the immune process is still not fully understood.…”