We show for the first time that gain of function mutations in sodium channel Na(V)1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of Na(V)1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate.

Summary Systemic lupus erythematosus (SLE, lupus) is characterized by a global loss of self-tolerance with activation of autoreactive T and B cells leading to production of pathogenic autoantibodies and tissue injury. Innate immune mechanisms are necessary for the aberrant adaptive immune responses in SLE. Recent advances in basic and clinical biology have shed new light on disease mechanisms in lupus, with this review discussing the recent studies that offer valuable insights into disease-specific therapeutic targets.

Interleukin 17 (IL-17)-producing CD4+ T (TH-17) cells share a developmental relationship with FoxP3+ regulatory T (Treg) cells. Here we show that a TH-17 population differentiates within the thymus in a manner influenced by self-antigen recognition, and by the cytokines IL-6 and transforming growth factor (TGF)-β. Like previously described TH-17 cells, TH-17 cells that develop in the thymus expressed the orphan nuclear receptor RORγt and the IL-23 receptor. These cells also expressed α4β1 integrins and the chemokine receptor CCR6, and were recruited to the lung, gut, and liver. In the liver these cells secreted IL-22 in response to self-antigen and mediated host protection during inflammation. Thus, TH-17 cells, like Treg cells, can be selected by self-antigens in the thymus.

• Peripheral B-cell tolerance is defective in IPEX patients, suggesting that Tregs are involved in the maintenance of B-cell tolerance.• T cells, including Tregs, display an activated phenotype in IPEX patients that may favor the accumulation of autoreactive B cells. Regulatory T cells (Tregs IntroductionImmune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a primary immunodeficiency with severe autoimmunity caused by mutations in the forkhead box protein 3 (FOXP3) gene. 1,2 A similar phenotype is observed in scurfy mice that carry a mutation in their foxp3 gene. FOXP3 encodes a transcription factor essential for the function of natural thymusderived CD4 ϩ CD25 ϩ FOXP3 ϩ regulatory T cells (Tregs), which in turn are critically important in maintaining self-tolerance in both mice and humans. [3][4][5] Multiple and diverse autoantibodies are commonly identified in the sera of IPEX patients, suggesting that Tregs may represent a key regulator for autoreactive B cells. 6 Antibodies are generated during early B-cell development by random joining of immunoglobulin (Ig) gene segments and therefore can result in the assembly of autoreactive antibodies or B-cell receptors (BCRs). It has been previously demonstrated that most developing autoreactive B cells in humans are removed at 2 discrete steps. 7 First, a central checkpoint in the bone marrow between early immature and immature B cells removes the majority of developing B cells that express highly polyreactive antibodies and only a small fraction of clones with low levels of polyreactivity migrate to the periphery. Then, a peripheral B-cell tolerance checkpoint further counterselects autoreactive new emigrant B cells before they enter the mature naive B-cell compartment. 7 The regulation of central B-cell tolerance in humans seems to be mostly controlled by B cell-intrinsic factors, which potentially include self-antigen binding receptors such as BCRs and Toll-like receptors (TLRs). [8][9][10][11] Relatively less is known about the mechanisms that control the peripheral B-cell tolerance checkpoint in humans. The analysis of CD40L-and MHC class II-defective patients demonstrated that while developing autoreactive B cells are properly counterselected in the bone marrow in these patients, their mature naive B cells express a high proportion of autoreactive antibodies, including antinuclear antibodies (ANAs). 12 These findings strongly supported the idea that a CD4 ϩ T-cell population requiring CD40L and potentially self-antigen presentation through MHC class II likely prevent the accumulation of autoreactive B cells in Submitted September 20, 2012; accepted November 14, 2012. Prepublished online as Blood First Edition paper, December 5, 2012; DOI 10.1182 DOI 10. /blood-2012 The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC sectio...