Concept: Systemic lupus erythematosus
Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19(+)CD24(hi)CD38(hi) (immature) B cells into IL-10-producing CD24(+)CD38(hi) Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24(+)CD38(hi) Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24(+)CD38(hi) Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24(+)CD38(hi) Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24(+)CD38(hi) Breg cell interaction contributes to the pathogenesis of SLE.
Genetic diversity across different human populations can enhance understanding of the genetic basis of disease. We calculated the genetic risk of 102 diseases in 1,043 unrelated individuals across 51 populations of the Human Genome Diversity Panel. We found that genetic risk for type 2 diabetes and pancreatic cancer decreased as humans migrated toward East Asia. In addition, biliary liver cirrhosis, alopecia areata, bladder cancer, inflammatory bowel disease, membranous nephropathy, systemic lupus erythematosus, systemic sclerosis, ulcerative colitis, and vitiligo have undergone genetic risk differentiation. This analysis represents a large-scale attempt to characterize genetic risk differentiation in the context of migration. We anticipate that our findings will enable detailed analysis pertaining to the driving forces behind genetic risk differentiation.
We previously reported that the G allele of rs3853839 at 3'untranslated region (UTR) of Toll-like receptor 7 () was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [ = 6.5×10, odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the region exhibiting consistent and independent association with SLE ( = 7.5×10, OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. 3'UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate expression. Indeed, miR-3148 levels were inversely correlated with transcript levels in PBMCs from SLE patients and controls (R = 0.255, = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by 3'UTR segment bearing the C allele ( = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries ( = 2.0×10, OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
Systemic lupus erythematosus (SLE) patients exhibit immense heterogeneity which is challenging from the diagnostic perspective. Emerging high throughput sequencing technologies have been proved to be a useful platform to understand the complex and dynamic disease processes. SLE patients categorised based on autoantibody specificities are reported to have differential immuno-regulatory mechanisms. Therefore, we performed RNA-seq analysis to identify transcriptomics of SLE patients with distinguished autoantibody specificities. The SLE patients were segregated into three subsets based on the type of autoantibodies present in their sera (anti-dsDNA+ group with anti-dsDNA autoantibody alone; anti-ENA+ group having autoantibodies against extractable nuclear antigens (ENA) only, and anti-dsDNA+ENA+ group having autoantibodies to both dsDNA and ENA). Global transcriptome profiling for each SLE patients subsets was performed using Illumina® Hiseq-2000 platform. The biological relevance of dysregulated transcripts in each SLE subsets was assessed by ingenuity pathway analysis (IPA) software. We observed that dysregulation in the transcriptome expression pattern was clearly distinct in each SLE patients subsets. IPA analysis of transcripts uniquely expressed in different SLE groups revealed specific biological pathways to be affected in each SLE subsets. Multiple cytokine signaling pathways were specifically dysregulated in anti-dsDNA+ patients whereas Interferon signaling was predominantly dysregulated in anti-ENA+ patients. In anti-dsDNA+ENA+ patients regulation of actin based motility by Rho pathway was significantly affected. The granulocyte gene signature was a common feature to all SLE subsets; however, anti-dsDNA+ group showed relatively predominant expression of these genes. Dysregulation of Plasma cell related transcripts were higher in anti-dsDNA+ and anti-ENA+ patients as compared to anti-dsDNA+ ENA+. Association of specific canonical pathways with the uniquely expressed transcripts in each SLE subgroup indicates that specific immunological disease mechanisms are operative in distinct SLE patients' subsets. This ‘sub-grouping’ approach could further be useful for clinical evaluation of SLE patients and devising targeted therapeutics.
Over the last few years, dermoscopy has been shown to be a useful tool in assisting the noninvasive diagnosis of various general dermatological disorders. In this article, we sought to provide an up-to-date practical overview on the use of dermoscopy in general dermatology by analysing the dermoscopic differential diagnosis of relatively common dermatological disorders grouped according to their clinical presentation, i.e. dermatoses presenting with erythematous-desquamative patches/plaques (plaque psoriasis, eczematous dermatitis, pityriasis rosea, mycosis fungoides and subacute cutaneous lupus erythematosus), papulosquamous/papulokeratotic dermatoses (lichen planus, pityriasis rosea, papulosquamous sarcoidosis, guttate psoriasis, pityriasis lichenoides chronica, classical pityriasis rubra pilaris, porokeratosis, lymphomatoid papulosis, papulosquamous chronic GVHD, parakeratosis variegata, Grover disease, Darier disease and BRAF-inhibitor-induced acantholytic dyskeratosis), facial inflammatory skin diseases (rosacea, seborrheic dermatitis, discoid lupus erythematosus, sarcoidosis, cutaneous leishmaniasis, lupus vulgaris, granuloma faciale and demodicidosis), acquired keratodermas (chronic hand eczema, palmar psoriasis, keratoderma due to mycosis fungoides, keratoderma resulting from pityriasis rubra pilaris, tinea manuum, palmar lichen planus and aquagenic palmar keratoderma), sclero-atrophic dermatoses (necrobiosis lipoidica, morphea and cutaneous lichen sclerosus), hypopigmented macular diseases (extragenital guttate lichen sclerosus, achromic pityriasis versicolor, guttate vitiligo, idiopathic guttate hypomelanosis, progressive macular hypomelanosis and postinflammatory hypopigmentations), hyperpigmented maculopapular diseases (pityriasis versicolor, lichen planus pigmentosus, Gougerot-Carteaud syndrome, Dowling-Degos disease, erythema ab igne, macular amyloidosis, lichen amyloidosus, friction melanosis, terra firma-forme dermatosis, urticaria pigmentosa and telangiectasia macularis eruptiva perstans), itchy papulonodular dermatoses (hypertrophic lichen planus, prurigo nodularis, nodular scabies and acquired perforating dermatosis), erythrodermas (due to psoriasis, atopic dermatitis, mycosis fungoides, pityriasis rubra pilaris and scabies), noninfectious balanitis (Zoon’s plasma cell balanitis, psoriatic balanitis, seborrheic dermatitis and non-specific balanitis) and erythroplasia of Queyrat, inflammatory cicatricial alopecias (scalp discoid lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia and folliculitis decalvans), nonscarring alopecias (alopecia areata, trichotillomania, androgenetic alopecia and telogen effluvium) and scaling disorders of the scalp (tinea capitis, scalp psoriasis, seborrheic dermatitis and pityriasis amiantacea).
Background A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. Methods Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. Results We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. Conclusions In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).
Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus, and an important cause of both acute kidney injury and end-stage renal disease. Despite its aggressive course, lupus nephritis is amenable to treatment in the majority of patients. The paradigm of immunosuppressive treatment for lupus nephritis has evolved over the past few decades from corticosteroids alone to corticosteroids combined with cyclophosphamide. Sequential treatment regimens using various agents have been formulated for induction and long-term maintenance therapy, and mycophenolate mofetil has emerged as a standard of care option for both induction and maintenance immunosuppressive treatment. The current era has witnessed the emergence of multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents that target key pathogenetic mechanisms of lupus nephritis. Clinical outcomes have improved in parallel with these therapeutic advances. This Review discusses the evidence in support of current standard of care immunosuppressive treatments and emerging therapies, and describes their roles and relative merits in the management of patients with lupus nephritis.
GARDASIL (Merck & Co., Inc., Whitehouse Station, NJ, USA) is a quadrivalent human papillomavirus (HPV4) vaccine. An epidemiological study was undertaken to evaluate concerns about the potential for HPV4 vaccination to induce serious autoimmune adverse events (SAAEs). The vaccine adverse event reporting system (VAERS) database was examined for adverse event reports associated with vaccines administered from January 2006 through December 2012 to recipients between 18 and 39 years old with a listed residence in the USA and a specified female gender. It was observed that cases with the SAAE outcomes of gastroenteritis (odds ratio (OR) = 4.6, 95 % confidence interval (CI) = 1.3-18.5), arthritis (OR = 2.5, 95 % CI = 1.4-4.3), systemic lupus erythematosus (OR = 5.3, 95 % CI = 1.5-20.5), vasculitis (OR = 4, 95 % CI = 1.01-16.4), alopecia (OR = 8.3, 95 % CI = 4.5-15.9), or CNS conditions (OR = 1.8, 95 % CI = 1.04-2.9) were significantly more likely than controls to have received HPV4 vaccine (median onset of SAAE symptoms from 6 to 55 days post-HPV4 vaccination). Cases with the outcomes of Guillain-Barre syndrome (OR = 0.75, 95 % CI = 0.42-1.3) or thrombocytopenia (OR = 1.3, 95 % CI = 0.48-3.5) were no more likely than controls to have received HPV4 vaccine. Cases with the general health outcomes of infection (OR = 0.72, 95 % CI = 0.27-1.7), conjunctivitis (OR = 0.88, 95 % CI = 0.29-2.7), or diarrhea (OR = 1.01, 95 % CI = 0.83-1.22) were no more likely than controls to have received HPV4 vaccine. Previous case series of SAAEs and biological plausibility support the observed results. Additional studies should be conducted to further evaluate the potential biological mechanisms involved in HPV4 vaccine-associated SAAEs in animal model systems, and to examine the potential epidemiological relationship between HPV4 vaccine-associated SAAEs in other databases and populations.
To evaluate the safety and efficacy of hCDR1 (Edratide) in patients with systemic lupus erythematosus (SLE).
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to >4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.