Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists.

Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists.

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.

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Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,492 SLE cases and 12,675 controls from six East-Asian cohorts, to identify novel and better localize known SLE susceptibility loci. We identified 10 novel loci as well as 20 known loci with genome-wide significance. Among the novel loci, the most significant was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta=3.75×10−117, OR=2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We localized the most likely functional variants for each locus by analyzing epigenetic marks and gene regulation data. Ten putative variants are known to alter cis- or trans-gene expression. Enrichment analysis highlights the importance of these loci in B- and T-cell biology. Together with previously known loci, the explained heritability of SLE increases to 24%. Novel loci share functional and ontological characteristics with previously reported loci, and are possible drug targets for SLE therapeutics.

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that predominantly affects women. Previous findings that duplicated Toll-like receptor 7 (Tlr7) promotes lupus-like disease in male BXSB mice prompted us to evaluate TLR7 in human SLE. By using a candidate gene approach, we identified and replicated association of a TLR7 3′UTR SNP, rs3853839 (G/C), with SLE in 9,274 Eastern Asians (P combined = 6.5 × 10 −10 ), with a stronger effect in male than female subjects [odds ratio, male vs. female = 2.33 (95% CI = 1.64-3.30) vs. 1.24 (95% CI = 1.14-1.34); P = 4.1 × 10]. G-allele carriers had increased TLR7 transcripts and more pronounced IFN signature than C-allele carriers; heterozygotes had 2.7-fold higher transcripts of G-allele than C-allele. These data established a functional polymorphism in type I IFN pathway gene TLR7 predisposing to SLE, especially in Chinese and Japanese male subjects. functional polymorphism | disease susceptibility | autoimmunity | type I interferon S ystemic lupus erythematosus [SLE; Online Mendelian Inheritance in Man (OMIM) no. 152700] is a multisystem, autoimmune disease with strong genetic and environmental components (1). SLE predominantly affects women, with a female-to-male ratio of approximately 9:1. Male patients with SLE, although rare, tend to have more severe disease and poorer outcome (2), suggesting potential sex dimorphism in the disease development. Although the sex effect has often been attributed to sex hormones, the fact that XXY male subjects have approximately a 14-fold higher risk of developing SLE than 46 XY men indicates that X-linked genes may be risk factors for human SLE (3).Located at Xp22.2, Toll-like receptor 7 (TLR7; OMIM no. 300365) and its functionally related gene TLR8 (OMIM no. 300366) encode proteins that play critical roles in pathogen recognition and activation of innate immunity (4). They recognize endogenous RNA-containing autoantigens and induce the expression of type I IFN, a pivotal cytokine in the pathogenesis of SLE (5). In lupus-prone BXSB mice, the translocation of a segmental duplication of X chromosome to Y chromosome creates the Y-linked autoimmune accelerator (Yaa) locus, which was associated with autoreactive B cell responses to RNA-related antigens and exacerbation of glomerulonephritis in male mice (6). Although translocated X chromosome segment in Yaa may contain as many as 16 genes, the major gene for causation of the autoimmune phenotypes was identified to be TLR7 (7), making it a potential susceptibility gene for SLE. By using a candidate gene approach, we report herein that a functional polymorphism in 3′UTR of TLR7 is associated with SLE in Chinese and Japanese populations, with a stronger effect in male than female subjects. ResultsDiscovery and Replication of the Association of a TLR7 3′UTR SNP with SLE in Eastern Asian Population. We genotyped 27 SNPs from the TLR7-TLR8 region (12 in TLR7 and 15 in TLR8) in 1,434 SLE cases and 1,591 control subjects of Eastern Asian ancestry using the Beadstation Infinium II...

This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

S Ul-lfuTlary A novel subset ofT ceils characterized by the expression of an invariant T cell antigen receptor (TC1L) encoded by V0t24J~xQ gene segments was investigated in patients with systemic sclerosis (SSc). Polymerase chain reaction analysis demonstrated that the Vot24 TClL repertoire was selectively used in CD4-CD8-double-negative T cells both in patients and in healthy individuals, while almost all families of TCR.Vot were expressed in single-positive T cell fractions. The Vor + double-negative T cells were increased by approximately fivefold in patients. However, sequence analysis clearly showed significant differences in the Vo~24 TC1L repertoire dominating in patients and healthy donors. In healthy individuals, the invariant Vot24JoLQ was expanded and comprised 20-50% of the total TCR-ot, while their selective reduction was observed in SSc patients who also showed expansion of invariant Vex24 TCR other than Vot24JcxQ. Analogous to murine invariant V~14JoL281 TC1L, these results suggest that T cells with invariant V&24JotQ TCR would function as regulatory T cells, whereas T cells bearing other invariant Vex24 TCR in SSc patients could be autoaggressive T cells in nature. Recent studies by Porcelli et al. (6) and Dellabona et al. (7,8) indicate that the invariant Vcx24J~xQ sequence is preferentially expressed on DN ot/]3 T cells from healthy individuals. The homology of the nucleotide sequences is found to be 75% in the V0t24 and 90% in the CDR3 regions compared with murine Vo~24 TCR (9). Therefore, the human V&24 sequence is a homologue of murine V&14 TCP,. Another striking similarity to murine invariant V~14 T cells is that human peripheral DN T cells also express a limited TCR.-[3 repertoire including V [32, V[38, VI311,10). Interestingly, the decrease in invariant Vod4Jo~281 TCR expression in autoimmune prone mice correlates with disease development. It is thus likely that Vot14 § NK T cells play a role in the regulation ofautoimmune disease development.