B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL-10 in vitro, the identity of IL-10-producing B cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factors Blimp1 or IRF4 in B lineage cells developed an exacerbated EAE. Furthermore, IRF4 positively regulated IL-10 production that can inhibit dendritic cell functions to generate pathogenic T cells. Our data demonstrate that plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation and emphasize the importance of plasmablasts as IL-10-producing regulatory B cells.

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. Accepted ArticleThis article is protected by copyright. All rights reserved. Running title: Terminology in TTP and TMAsKey words: ADAMTS-13 protein, human; thrombocytopenia; diagnosis, differential; thrombotic microangiopathy; thrombotic thrombocytopenic purpura Essentials• An international collaboration provides a consensus for clinical definitions.• This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP).• The consensus defines diagnosis, disease monitoring and response to treatment.• Requirements for ADAMTS-13 are given. Abstract:Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic Microangiopathy is a broad pathophysiological process that leads to microangiopathic hemolytic anemia, thrombocytopenia and involves capillary and small vessel platelet aggregates. The most common cause being disseminated intravascular coagulation (DIC), which may be differentiated by abnormal Accepted ArticleThis article is protected by copyright. All rights reserved. IntroductionThe elucidation of the pathophysiology of TTP and HUS, in the past 20 years, has transformed our understanding of the phenotypes, genotypes and therapies for these life-threatening conditions. Work on standardization has been addressed [1], but this document aims to develop robust criteria for future clinical use, studies and trials.Clinical and pathophysiologic features of TTP, atypical Hemolytic Uremic Syndrome (aHUS) and disorders with similar presentations, their investigation and subsequent management vary. This consensus document aims to rationalize and standardize definitions. Conditions often included in the initial differential diagnosis of TTP are discussed. Definitions for remission, refractory and relapsing disease are defined.ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assays are central to diagnosis and are discussed. We therefore also describe the minimum requirements for validation of current and future assays. Methods:The development of this document involved key international, primarily clinical, experts in TTP and related TMAs. Accepted ArticleThis article is protected by copyright. All rights reserved.Hemostasis (ISTH) and American Society of Hematology (ASH) and all versions of the document have been reviewed and edited by the authors. Articles were identified by a computer-assisted search of the literature published in English using the National Library of Medicine PubMed database. The authors also undertook a focused review of the available literature. Where there was a lack of robust evidence, the international working group concluded a consensus-based approach was preferable. The conclusions are relevant to both children and adults. Thrombotic MicroangiopathyThe term TMA is a pathological term used to describe occlusive micro...

von Willebrand factor (VWF) is synthesized primarily in vascular endothelial cells and secreted into the plasma as unusually large VWF multimers. Normally, these multimers are quickly degraded into smaller forms by a plasma metalloproteinase, VWF-cleaving protease (VWF-CP). Decreases in the activity of this enzyme result in congenital and acquired thrombotic thrombocytopenic purpura (TTP). The human VWF-CP has recently been purified. Cloning of the corresponding cDNA revealed that the 1,427-aa polypeptide is a member of the ADAMTS gene family, termed ADAMTS13. Twelve rare mutations in this gene have been identified in patients with congenital TTP. Here, we report missense and nonsense mutations in two Japanese families with Upshaw-Schulman syndrome, congenital TTP with neonatal onset and frequent relapses. The comparison of individual ADAMTS13 genotypes and plasma VWF-CP activities indicated that the R268P, Q449stop, and C508Y mutations abrogated activity of the enzyme, whereas the P475S mutant retained low but significant activity. The effects of these mutations were further confirmed by expression analysis in HeLa cells. Recombinant VWF-CP containing either the R268P or C508Y mutations was not secreted from cells. In contrast, Q449stop and P475S mutants were normally secreted but demonstrated minimal activity. Genotype analysis of 364 Japanese subjects revealed that P475S is heterozygous in 9.6% of individuals, suggesting that approximately 10% of the Japanese population possesses reduced VWF-CP activity. We report on a single-nucleotide polymorphism associated with alterations in VWF-CP activity; it will be important to assess this single-nucleotide polymorphism as a risk factor for thrombotic disorders.