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Altered B cell signalling in autoimmunity

Key Points

  • Human genetic variants associated with the development of systemic autoimmunity modulate B cell receptor (BCR) and co-receptor signalling, suggesting a role for dysregulated B cell signalling in promoting disease pathogenesis.

  • Altered B cell signalling probably facilitates a breach in B cell tolerance through distinct effects on B cell selection during the establishment of the naive BCR repertoire and on peripheral activation responses.

  • BCR signalling functions as a 'master regulator' of coordinate co-receptor signalling, facilitating central and peripheral B cell tolerance mechanisms throughout B cell development. Hypomorphic and/or hypermorphic signalling variants affect both the negative and positive selection of autoreactive BCR specificities.

  • During humoral autoimmunity, autoantibody-producing plasma cells are generated through parallel extrafollicular and germinal centre (GC) B cell activation pathways.

  • Activated autoreactive B cells orchestrate the formation of spontaneous, autoimmune GCs by initiating breaks in T cell tolerance and by promoting subsequent T follicular helper cell differentiation. These events are mediated by B cell antigen presentation to cognate CD4+ T cells, probably in concert with B cell co-stimulatory and cytokine signalling.

Abstract

Recent work has provided new insights into how altered B cell-intrinsic signals — through the B cell receptor (BCR) and key co-receptors — function together to promote the pathogenesis of autoimmunity. These combined signals affect B cells at two distinct stages: first, in the selection of the naive repertoire; and second, during extrafollicular or germinal centre activation responses. Thus, dysregulated signalling can lead to both an altered naive BCR repertoire and the generation of autoantibody-producing B cells. Strikingly, high-affinity autoantibodies predate and predict disease in several autoimmune disorders, including type 1 diabetes and systemic lupus erythematosus. This Review summarizes how, rather than being a downstream consequence of autoreactive T cell activation, dysregulated B cell signalling can function as a primary driver of many human autoimmune diseases.

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Figure 1: B cell receptor and co-receptor signalling govern B cell selection and maturation.
Figure 2: Altered B cell receptor and co-receptor signalling promotes increased autoreactivity within the naive B cell repertoire.
Figure 3: T cell-dependent and T cell-independent extrafollicular activation pathways in autoimmunity.
Figure 4: Self-reactive B cells initiate autoimmune germinal centre formation by facilitating breaks in T cell tolerance.
Figure 5: A sequential model of the progression of systemic autoimmunity.

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Acknowledgements

This work was supported by the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (NIH) under award numbers R01HL075453 (to D.J.R), R01A1084457 (to D.J.R.), R01A1071163 (to D.J.R.), DP3DK097672 (to D.J.R.), DP3DK111802 (to D.J.R.), DP3DK097672-01S1 (to G.M.), T32AI106677 (to M.W.-D.) and K08AI112993 (to S.W.J.). The content of this Review is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support of the work was provided by the Benaroya Family Gift Fund (to D.J.R.); a Howard Hughes Medical Institute–NIH Molecular Medicine Training Grant (to G.M.); the American College of Rheumatology Research and Education Foundation Rheumatology Scientist Development Award and Career Development K Supplement (to S.W.J.); an Arthritis National Research Foundation grant (to S.W.J.); a Novel Research Grant from the Lupus Research Alliance (to S.W.J.); and the Arnold Lee Smith Endowed Professorship for Research Faculty Development (to S.W.J.).

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Glossary

CD40

A tumour necrosis factor receptor superfamily member expressed by antigen-presenting cells that transmits activation signals in response to CD40 ligand (CD40L). Binding of CD40 on transitional B cells to CD40L on naive CD4+ T cells activates both the classical and alternative nuclear factor-κB pathways to promote cell survival.

Humoral autoimmunity

Causes a broad range of autoimmune diseases that are characterized by the production of pathogenic antibodies. These disorders frequently share risk alleles. For example, the R620W polymorphism in PTPN22 (which encodes protein tyrosine phosphatase nonreceptor 22) is associated with an increased risk of developing several diseases, including rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, Hashimoto thyroiditis, Addison disease and others.

Extrafollicular B cell activation

In response to infectious challenge, B cell receptor signalling induces the rapid division and differentiation of B cells into short-lived, antibody-secreting plasmablasts at the T cell zone–red pulp border. This extrafollicular B cell response can occur in a T cell-independent or T cell-dependent manner, and is the predominant source of the protective antibodies that are generated early during an infection.

Germinal centre

(GC). A specialized lymphoid structure in which activated B cells cycle between anatomically distinct dark zones and light zones as they undergo iterative rounds of affinity selection, which ultimately leads to the generation of both antigen-specific memory B cells and high-affinity, long-lived plasma cells.

B cell-activating factor receptor

(BAFFR). A tumour necrosis factor receptor superfamily member that promotes the survival and maturation of B cells. Following ligation by B cell-activating factor (BAFF), BAFFR mainly induces the alternative nuclear factor-κB pathway to promote pro-survival signals. Mice that are deficient in BAFF or BAFFR have a block in B cell development at the transitional type 1 stage.

Systemic lupus erythematosus

(SLE). A chronic, multisystem inflammatory disease that is characterized by high-titre, class-switched autoantibodies against nuclear antigens; these autoantibodies are invariably present before disease onset and ultimately lead to the formation of immune complexes that precipitate systemic and/or organ-targeted injury.

Type 1 diabetes

(T1D). An autoimmune disease that is characterized by the destruction of insulin-producing pancreatic islet cells. Although T cells are crucial in this process, high-affinity, somatically mutated autoantibodies that target pancreatic islet antigens are present before disease onset, which emphasizes the importance of B cells in the pathogenesis of T1D.

Rheumatoid arthritis

(RA). A chronic, autoimmune disease that is characterized by symmetrical polyarticular arthritis and the production of rheumatoid factor and autoantibodies against cyclic citrullinated peptides; the appearance of rheumatoid factor and autoantibodies precedes clinical disease, implicating altered B cell responses early in the disease process.

Transmembrane activator and CAML interactor

(TACI). A tumour necrosis factor receptor family member that activates the classical nuclear factor-κB (NF-κB) pathway in response to ligation by multimeric B cell-activating factor (BAFF) or a proliferation-inducing ligand (APRIL; also known as TNFSF13) on developing and mature B cells. TACI signalling promotes T cell-independent antibody responses, and a subset of patients with common variable immunodeficiency have TACI mutations. TACI-deficient animals develop B cell hyperplasia, probably owing to increased serum BAFF levels.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

(IPEX syndrome). A syndrome caused by a lack of functional regulatory T cells that is due to mutations in FOXP3 (which encodes forkhead box P3). It is characterized by severe autoimmunity driven by both activated effector T cells and multiple autoantibodies.

MRL.Faslpr

A strain of mouse generated by breeding multiple mouse strains to select those that exhibit features of lupus-like disease, including lethal autoimmunity and high-titre antinuclear antibodies. The lpr mutation is an autosomal-recessive mutation in Fas, which results in lymphoproliferation and accelerated autoimmunity.

NZB/W mice

F1 mice that are hybrids of NZB (New Zealand black) and NZW (New Zealand white) strains. They develop class-switched antinuclear antibodies, systemic inflammation and immune-complex-mediated glomerulonephritis. Autoimmune susceptibility loci in this strain include polymorphisms in Fcgr2b (which encodes Fcγ receptor IIB) and in signalling lymphocyte activation molecule (SLAM) family genes.

Non-obese diabetic mouse

(NOD mouse). A polygenic animal model of type 1 diabetes characterized by spontaneous leukocyte infiltration within the pancreatic islets and by insulin-dependent diabetes, with a bias towards accelerated disease in female mice. Disease in this model depends on both B cell and T cell activation.

Tlr7-transgenic mice

A mouse model of lupus generated by transgenic overexpression of the gene that encodes Toll-like receptor 7 (TLR7), which results in systemic autoimmunity and high titres of RNA-specific autoantibodies. The phenotype of Tlr7-transgenic mice partially mimics that of lupus-prone strains that express duplicated Tlr7 through the Y-chromosome-linked autoimmune accelerator (Yaa) mutation.

BXSB-Yaa

Lupus-prone male mice that develop accelerated disease due to Y-chromosome-linked autoimmune accelerator (Yaa), a translocation of the telomeric end of the X chromosome to the Y chromosome, which results in the duplication of several genes, including Tlr7 (which encodes Toll-like receptor 7).

Roquin san/san

A strain of mice with an N-ethyl-N-nitrosourea (ENU)-driven 'san' mutation in Roquin (which encodes a RING-type ubiquitin ligase; also known as Rc3h1), resulting in a lupus-like disease that is characterized by spontaneous germinal centre formation, high-affinity double-stranded DNA-specific antibodies, autoimmune thrombocytopenia and immune-complex-mediated glomerulonephritis.

B6.Sle1b

A strain of C57BL/6 mice that has the Sle1b sublocus derived from lupus-prone NZW mice. The Sle1b sublocus contains signalling lymphocyte activation molecule (SLAM) family genes with polymorphisms that are involved in antinuclear antibody production, B cell and T cell activation, and spontaneous germinal centre formation.

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Rawlings, D., Metzler, G., Wray-Dutra, M. et al. Altered B cell signalling in autoimmunity. Nat Rev Immunol 17, 421–436 (2017). https://doi.org/10.1038/nri.2017.24

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