The Autoimmune Risk Variant <i>PTPN22</i> C1858T Alters B Cell Tolerance at Discrete Checkpoints and Differentially Shapes the Naive Repertoire

Metzler, Genita; Dai, Xuezhi; Thouvenel, Christopher D.; Khim, Socheath; Habib, Tania; Buckner, Jane H.; Rawlings, David J.

doi:10.4049/jimmunol.1700601

Cited by 20 publications

(25 citation statements)

References 54 publications

(85 reference statements)

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“…Mice expressing this mutation displayed enhanced BCR and CD40 responses. 91 CD40 seems to be a critical context-dependent co-stimulatory molecule regulating both the full activation of BCR-stimulated B cells as well as their subsequent censoring.…”

Section: Co-stimulation Of Cd40 Effectively Improves B Cell Anergy Inmentioning

confidence: 99%

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

et al. 2020

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Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B cells. Most findings, together with preclinical lupus models, support the concept of B cell hyperactivity in SLE. However, it remains largely unknown whether these specific B cell subsets have pathogenic consequences and whether they provide relevant therapeutic targets. Recent findings indicate a global distortion of B cell functional capability, in which the entire repertoire of naïve and memory B cells in SLE exhibits an anergic or postactivated (APA) functional phenotype. The APA status of SLE B cells has some similarities to the functional derangement of lupus T cells. APA B cells are characterised by reduced global cytokine production, diminished B cell receptor (BCR) signalling with decreased Syk and Bruton’s tyrosine kinase phosphorylation related to repeated in vivo BCR stimulation as well as hyporesponsiveness to toll-like receptor 9 engagement, but intact CD40 signalling. This APA status was related to constitutive co-localisation of CD22 linked to phosphatase SHP-1 and increased overall protein phosphatase activities. Notably, CD40 co-stimulation could revert this APA status and restore BCR signalling, downregulate protein tyrosine phosphatase transcription and promote B cell proliferation and differentiation. The APA status and their potential rescue by bystander help conveyed through CD40 stimulation not only provides insights into possible mechanisms of escape of autoreactive clones from negative selection but also into novel ways to target B cells therapeutically.

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Section: Co-stimulation Of Cd40 Effectively Improves B Cell Anergy Inmentioning

confidence: 99%

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

et al. 2020

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“…Intriguingly, while loss of PTPN22 in B cells does not seem to impact BCR signaling (), multiple reports suggest that the W620 variation results in inhibition of human B cell activation. Although the underlying molecular mechanism remains to be further clarified, these observations suggest that PTPN22‐W620 can impinge on the pathogenesis of autoimmunity by impairing the elimination of autoreactive B cells (). This conclusion is also supported by experiments in humanized mice ().…”

Section: T and B Cell Mechanisms By Which Ptpn22‐w620 May Drive Autoimentioning

confidence: 99%

The Contribution of PTPN22 to Rheumatic Disease

Mustelin

Bottini

Stanford

2019

Arthritis & Rheumatology

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One of the unresolved questions in modern medicine is why certain individuals develop a disorder such as rheumatoid arthritis (RA) or lupus, while others do not. Contemporary science indicates that genetics is partly responsible for disease development, while environmental and stochastic factors also play a role. Among the many genes that increase the risk of autoimmune conditions, the risk allele encoding the W620 variant of protein tyrosine phosphatase N22 (PTPN22) is shared between multiple rheumatic diseases, suggesting that it plays a fundamental role in the development of immune dysfunction. Herein, we discuss how the presence of the PTPN22 risk allele may shape the signs and symptoms of these diseases. Besides the emerging clarity regarding how PTPN22 tunes T and B cell antigen receptor signaling, we discuss recent discoveries of important functions of PTPN22 in myeloid cell lineages. Taken together, these new insights reveal important clues to the molecular mechanisms of prevalent diseases like RA and lupus and may open new avenues for the development of personalized therapies that spare the normal function of the immune system.Dr. Bottini's work was supported by the NIH (grants R01-AI-070544 and R01-AR-066053).

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“…B cells, the frequency of MZ anti-insulin B cells exceeds that of FO anti-insulin B cells in V H 125 SD .NOD mice. Thus, the fate of antiinsulin B cells in NOD mice differs appreciably from anti-insulin B cells in V H 125 SD .B6 mice and other murine models of disease in nonautoimmune (B6) backgrounds, such as B cells that express the Ptpn22 autoimmune risk variant (58), which are characterized by a FO subset predominance (21). Therefore, whereas anti-insulin B cells are competent to enter both MZ and FO subsets, the balance of their developmental fate is governed by the genetic environment.…”

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confidence: 99%

Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes

Felton

Maseda

Bonami

et al. 2018

The Journal of Immunology

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Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.

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The Autoimmune Risk Variant PTPN22 C1858T Alters B Cell Tolerance at Discrete Checkpoints and Differentially Shapes the Naive Repertoire

Cited by 20 publications

References 54 publications

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

The Contribution of PTPN22 to Rheumatic Disease

Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes

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