B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

Zouali, Moncef; Sármay, Gabriella

doi:10.1002/art.20487

Cited by 66 publications

(49 citation statements)

References 59 publications

(70 reference statements)

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“…Thus, mice lacking SHP-1, CD45, CD22, or Lyn produce autoAbs and suffer from immune complex-mediated nephritis (34). Consistently, human lupus B cells that suffer from defective tolerance exhibit abnormal BcR signaling (34,35). Several observations also indicate that the ras-MAPK pathway is defective in lupus patients (36)(37)(38) and aberrantly activated in B cells from lupus mice bearing the Sle1 gene cluster (39).…”

Section: Discussionmentioning

confidence: 89%

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Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

Mazari

Ouarzane

Zouali

2007

Proc. Natl. Acad. Sci. U.S.A.

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Accumulating evidence indicates that epigenetic alterations contribute to exacerbated activation or deregulation of the mechanisms that maintain tolerance to self-antigens in patients with lupus, a systemic autoimmune disease that can be triggered by medications taken to treat a variety of conditions. Here, we tested the effect of hydralazine, an antihypertensive drug that triggers lupus, on receptor editing, a chief mechanism of B lymphocyte tolerance to self-antigens. Using mice expressing transgenic human Igs, we found that hydralazine impairs up-regulation of RAG-2 gene expression and reduces secondary Ig gene rearrangements. Receptor editing was also partially abolished in a dose-dependent manner by a specific inhibitor of MEK1/2. Adoptive transfer of bone marrow B cells pretreated with hydralazine or with a MEK inhibitor to naïve syngeneic mice resulted in autoantibody production. We conclude that, by disrupting receptor editing, hydralazine subverts B lymphocyte tolerance to self and contributes to generation of pathogenic autoreactivity. We also postulate that inhibition of the Erk signaling pathway contributes to the pathogenesis of hydralazine-induced lupus and idiopathic human lupus.autoimmune disease ͉ receptor editing D rug-induced lupus (DIL) is a systemic autoimmune disease that can be induced by over 40 medications, including the antihypertensive drug hydralazine and the antiarrhythmic drug procainamide (1). In the patient, the drug reaches a steady-state concentration within a few hours, but the symptoms require several months to develop and fade with therapy discontinuation. Intriguingly, there is no apparent common chemical structure or pharmacologic property among the various medications that trigger similar laboratory and clinical features, and the disease is clinically indistinguishable from idiopathic lupus. Likewise, the mechanisms underlying the induction of DIL remain unclear.The ability of the immune system to distinguish self from non-self is central to its capacity to protect against pathogens and, at the same time, maintains tolerance to its own components. This seminal property is established at discrete nodes, both during early development and adulthood. In the B lymphocyte compartment, several mechanisms have been identified (2). They include clonal deletion of autoreactive lymphocytes, clonal anergy, which converts autoreactive cells to a state that precludes them from becoming activated, and receptor editing, a mechanism that modifies self-reactive B cells and renders them nonautoreactive (3, 4). This latter process can extinguish autoreactivity by displacing a productively rearranged Ig heavy (H)-or light (L)-chain gene by secondary gene rearrangements, forming edited antigen (Ag) receptors with no, or reduced autoreactivity. Importantly, it also represents a powerful mechanism by which autoreactive cells can be generated or fail to be eliminated (5, 6). Editing depends on the products of recombinase activator genes (RAG-1 and RAG-2), and uses the same recombination machinery ...

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Section: Discussionmentioning

confidence: 89%

“…For example, mice lacking protein kinase C␦, an enzyme implicated in the inhibition of cell growth, differentiation and apoptosis, exhibit increased proliferation of B cells and autoimmunity (reviewed in ref. 35). It will therefore be useful to test the potential effects of the drug on cell cycle regulators.…”

Section: Discussionmentioning

confidence: 99%

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

Mazari

Ouarzane

Zouali

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Only 2 of these hits showed perfect segregation with the disease: UBXN1 (c. G686A, p. Thr229Met) and PRKCD (c.135211G.A) ( Figure 2B and supplemental Figure 1, respectively). While no obvious role for UBXN1 in the patient's disease pathogenesis could be recognized (Supplemental Materials), PRKCD was considered a plausible candidate, because it has a well-established role in B-cell signaling 11,12 and the corresponding Prkcd 2/2 knockout mouse exhibits various autoimmune manifestations together with generalized lymphadenopathy. 13 The murine model also shows splenic lymphocyte hyperproliferation, 13 reminiscent of human autoimmune lymphoproliferative syndrome.…”

Section: Mutation Identification In the Prkcd Genementioning

confidence: 99%

B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ

Salzer

Santos-Valente

Klaver

et al. 2013

Blood

115

102

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Key Points• PRKCD deficiency causes a novel primary immunodeficiency with B-cell deficiency and severe autoimmunity.• Protein kinase C d may represent a key factor controlling immune homeostasis and autoimmunity.Primary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19 1 B cells, a defective class switch indicated by low numbers of IgM-and IgG-memory B cells, as well as increased numbers of CD21 low B cells.Combined homozygosity mapping and exome sequencing identified a biallelic splicesite mutation in protein C kinase d (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity. (Blood. 2013;121(16):3112-3116)

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“…Autoreactive B-cell clones are progressively selected out of the developing B-cell pool in a manner that depends on the magnitude and duration of B-cell receptor (BCR) and B-cell activating factor receptor (BAFFR) signals that serve to enforce these checkpoints (2)(3)(4). Each pathway is independently required for normal B-cell development and survival, and dysregulation of either signaling pathway can cause devastating autoimmune disease (5)(6)(7)(8)(9)(10).…”

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confidence: 99%

Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

Zikherman

Doan

Parameswaran

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The receptor-like tyrosine phosphatase CD45 positively regulates antigen receptor signaling by dephosphorylating the inhibitory tyrosine of the src family kinases. CD45-deficient mice fail to fully unmask the role of CD45 in B cells because of the expression of a partially redundant tyrosine phosphatase, CD148. However, mice that are doubly deficient in CD45 and CD148 exhibit a very early block in B-cell development, thereby obscuring later roles for CD45. To overcome these limitations, here we take advantage of an allelic series of mice in which CD45 expression is titrated broadly (0-180%). Although high expression of CD45 inhibits T-cell receptor (TCR) signaling, we show that CD45 plays a purely positive regulatory role during B-cell receptor (BCR) signaling. In concert with exaggerated BCR signaling, increasing CD45 expression drives enhanced receptor editing in the bone marrow and profound loss of follicular and marginal zone B cells in the spleen. In the context of the IgHEL/sHEL model of B-cell tolerance, such high CD45 expression transforms anergy into deletion. Unexpectedly, elimination of the autoantigen sHEL in this model system in order to block clonal deletion fails to rescue survival of mature B cells. Rather, high CD45 expression reduces B-cell activating factor receptor (BAFFR) expression and inhibits B-cell activating factor (BAFF)-induced B-cell survival in a cell-intrinsic manner. Taken together, our findings reveal how CD45 function diverges in T cells and B cells, as well as how autoreactive B cells are censored as they transit development.antigen receptor signaling | Lyn

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B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

Cited by 66 publications

References 59 publications

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ

Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

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