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Scooped by
Gilbert C FAURE
December 21, 2018 3:10 PM
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Nakazawa and colleagues describe advances in our understanding of anti-neutrophil cytoplasmic antibody-associated vasculitis. These insights have already generated promising new treatments that target B cells, T cells and cytokines; potential novel approaches targeting additional cells or molecules are also discussed.
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Suggested by
LIGHTING
December 20, 2018 12:06 PM
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Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered to have an unspecified IgG4-driven autoimmune genesis, while secondary MN has been associated with other diseases, most notably cancer, and not linked to IgG4. Immunologic mechanisms of primary and malignancy-associated MN are assumed to be different, however, this has never been systematically evaluated. The identification of Phospholipase A2 Receptor 1 (PLA2R1) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) as target antigens in MN allows a pathogenesis-driven differential diagnosis. Recent data showing a molecular link between increased THSD7A-expression in tumors and THSD7A-antibody positive MN suggest a similar pathogenesis of malignancy-associated and primary MN. In order to better define the underlying immunologic processes, we systematically analyzed circulating antigen-specific IgG subclasses in the serum of 76 patients with PLA2R1-associated MN and 41 patients with THSD7A-associated MN in relationship to concurrent malignancy and disease outcome. Twenty-three patients in the study had malignancy-associated MN. We analyzed antigen-specific IgG subclasses in the serum of all patients at baseline and in 55 patients during follow-up by Western blot applying antigens derived from human kidney and lung. At baseline all 117 patients were positive for IgG4-antibodie
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Scooped by
Gilbert C FAURE
December 18, 2018 1:06 PM
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It was with much interest that we read the recent European League Against Rheumatism/American College of Rheumatology classification criteria for idiopathic inflammatory myopathies.1 These criteria include Jo-1 autoantibodies, and the authors discussed that future updates of the criteria should also...
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Gilbert C FAURE
December 18, 2018 5:08 AM
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Eur J Immunol. 2018 Dec 3. doi: 10.1002/eji.201847717.[Epub ahead of print]...
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Scooped by
Gilbert C FAURE
December 17, 2018 2:19 PM
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Images in Clinical Medicine from The New England Journal of Medicine — Neonatal Lupus...
Non‐classical monocytes infiltrate the kidney parenchyma and participate in tissue damage in patients with lupus nephritis (LN). Circulating microparticles (MPs) seem to play critical roles in the activation of monocytes in systemic lupus erythematosus (SLE) patients. This study aims to characterize the phenotypes of MPs and monocyte subsets in LN patients and to determine their potential to discriminate between SLE patients with and without LN. Blood and urine samples from SLE patients were collected. In monocyte subsets from whole blood samples several phenotypic markers were evaluated. MPs were isolated from platelet‐poor plasma and urine by centrifugation. This phenotypic marker characterization was performed using multiparametric flow cytometry. We observed that patients with active LN have lower counts of non‐classical monocytes than do those without renal involvement. All monocyte subsets exhibited lower expression of CX3CR1 and ICAM‐1 in LN than in patients without LN. High frequencies of MP‐HMGB1+ and MP‐HLA‐DR+ were detected in circulation and urine of LN patients. Although MP‐HMGB1+, MP‐HLA‐DR+, and MP‐CX3CR1+ from urine were able to discriminate between patients with and without LN, only urinary MP‐HMGB1+ were different between patients with active and inactive LN. Therefore, these vesicles may be useful as biomarkers of LN. This article is protected by copyright. All rights reserved
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
December 13, 2018 3:04 PM
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The treatment of systemic lupus erythematosus involves a balance between control of disease activity and prevention of therapeutic harm that requires careful optimization. In this Review, the authors discuss available and emerging therapeutic strategies that exploit the current drug armamentarium.
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Scooped by
Gilbert C FAURE
December 13, 2018 4:20 AM
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La Jolla Institute for Immunology. We have relied on the strength of our people and the quality of our research.
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Scooped by
Gilbert C FAURE
December 10, 2018 11:42 AM
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As part of studies of the pancreas and islets from individuals with T1D (10–12), we were surprised to find that analysis of sections from the head, body, and tail regions of one donor’s pancreas showed that all islets contained insulin-positive β cells (Figure 1A and Supplemental Figure 1A and insets, and Supplemental Tables 1, 3, and 4; supplemental material available online with this article; https://doi.org/10.1172/JCI121994DS1), but lacked insulitis typical of T1D (infiltration of CD45+ cells) (13). Figure 1 Histological and functional analysis of HNF1A+/T260M pancreas and islets. (A) Example of expression of insulin (INS), glucagon (GCG), and somatostatin (SOM) in donor’s native pancreatic tissue compared with control. Scale bar: 50 μm. (B) β and α cell mass (grams) in HNF1A+/T260M pancreas compared with controls (n = 7 donors; ages 10–55 years). Each data point represents the average mass across the combined pancreatic head, body, and tail regions. (C) Insulin secretion in islets isolated from the HNF1A+/T260M pancreas compared with controls (n = 6 donors; ages 8–55 years) and normalized to overall islet cell volume (expressed as islet equivalents, IEQs). Islets were teated with 5.6 mM glucose (G 5.6); 16.7 mM glucose (G 16.7); 16.7 mM glucose plus 100 μM isobutylmethylxanthine (G 16.7 + IBMX 100); 1.7 mM glucose plus 1 μM epinephrine (G 1.7 + Epi 1); or 20 mM potassium chloride (KCl 20) at the indicated times. Insets show average insulin response of controls and HNF1A+/T260M donor to 30-minute stimulation with 16.7 mM glucose. (D) Integrated insulin secretion was calculated as the area under the curve (AUC) for the indicated secretagogue (shaded to correspond to color-matched regions of perifusion trace in panel C). Results of control samples are expressed as mean ± SEM. Donor pancreas had normal β cell mass, but β cells were functionally impaired. The donor pancreas had β and δ cell mass within the normal range, with slightly elevated α cell mass (Figure 1B and Supplemental Figure 1B) and an increased α/β cell ratio (Supplemental Figure 1, C, G, and H). No β cell apoptosis (TUNEL) or proliferation (Ki67) was detected (Supplemental Figure 1D). In a dynamic perifusion system, isolated donor islets had normal insulin content but had higher basal insulin secretion, lacked biphasic glucose-stimulated insulin secretion (GSIS), and had a decreased secretory response to KCl-mediated membrane depolarization (Figure 1C and inset, Figure 1D, and Supplemental Figure 1G). Despite the lack of GSIS, the donor’s islets responded normally to high glucose coupled with the phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX). Moreover, glucagon secretion from donor islet α cells had an abrogated response to potent α cell stimuli such as low glucose (1.7 mM) and epinephrine (1 μM) and, strikingly, showed an inhibitory response to membrane depolarization by KCl (Supplemental Figure 1, E, F, and H). Donor pancreas islet innervation and vasculature, important for coordinated islet function in vivo (8, 14), were normal (Supplemental Figure 1I). Because of these unexpected histological and functional findings, we sequenced the donor DNA for variants associated with monogenic diabetes and uncovered a heterozygous, disease-associated variant in a conserved region of the POUH DNA binding domain of HNF1A (c.779C>T, p.Thr260Met) (15) (Supplemental Table 2 and Supplemental Figure 1J). Variants in HNF1A comprise the most common form of maturity-onset diabetes of the young 3 (termed MODY3) (16). HNF1AT260M displayed compromised DNA binding. Nuclear HNF1A protein was detected in both the exocrine and endocrine compartments of the donor pancreas, with normal expression in β cells and α cells (Figure 2A and Supplemental Figure 2, A and B). The DNA binding capacity of the altered HNF1AT260M protein, as assessed by electrophoretic mobility shift assay (EMSA), was severely compromised compared with HNF1AWT protein (Figure 2B and Supplemental Figure 2, C–E). Accordingly, HNF1AT260M had little to no ability to stimulate MAFA region 3 enhancer-driven reporter activity relative to HNF1AWT in cotransfection assays (Supplemental Figure 2, F and G). Notably, each of these proteins was expressed at similar levels, and WT activation was dependent on HNF1A-site binding, as described previously (17). Furthermore, HNF1AT260M decreased HNF1AWT activation in a dose-dependent manner, providing evidence that the dominant-negative action of HNF1AT260M is due to dimerization with HNF1AWT (Supplemental Figure 2, F and G). Moreover, protein modeling predicted that disrupted DNA binding results from the missing hydrogen donor at position 260 in the variant protein, which destabilizes the DNA-binding Arg-263 residue (Figure 2C), yet leaves the distinct dimerization domain in the transcription factor intact (18). Figure 2 Expression and functional characterization of HNF1AT260M variant. (A) Analysis of donor’s native pancreatic tissue for HNF1A compared with controls (n = 4 donors; ages 10–55 years) revealed HNF1A protein in donor β cells. Scale bar: 50 μm. (B) Electrophoretic mobility shift assay (EMSA) shows that the HNF1AT260M variant has impaired DNA binding, with loss of the HNF1A-specific DNA binding complex (arrow) in Myc-tagged HNF1AT260M–transfected HeLa cells compared with Myc-tagged HNF1AWT. Specificity of this complex (arrow) was shown by exclusive elimination of these species by adding either Myc antibody (Myc-Ab) or unlabeled oligonucleotide (WT Oligo) containing the HNF1A consensus recognition motif, but not a mutated form of this oligonucleotide (Comp Oligo). Moreover, HNF1A antibody (HNF1A-Ab) only supershifted (s.s.) this complex. All samples in B include oligonucleotide labeled with 32P as described in the supplemental material. Asterisk indicates nonspecific complexes. NT, nontransfected HeLa cells. One representative experiment of 3 is shown. (C) Molecular modeling of the HNF1AT260 variant in PyMOL predicts that the hydroxyl group (red) on threonine 260 (Thr-260) stabilizes arginine 263 (Arg-263) by hydrogen bonding to nitrogen (blue). Arg-263 H-bonds to the DNA backbone of the fifth adenosine of the HNF1A consensus recognition motif (5′-CTTGGTTAATAATTCACCAGA-3′) in control conditions (18). A missense mutation from threonine to methionine at position 260 is predicted to result in the loss of this interaction by destabilizing Arg-263 and subsequently DNA binding. Results of control samples are expressed as mean ± SEM. See complete unedited blots in the supplemental material. HNF1A+/T260M β cells have preserved markers of β cell identity, but changes in processes critical for GSIS. RNA-sequencing and transcriptional profiling of purified HNF1A+/T260M β cells (Figure 3, A and B) showed relatively preserved expression of INS mRNA and transcription factor markers of β cell identity (PDX1, NKX2.2, and NKX6.1), which was confirmed by protein expression analysis (Supplemental Figure 2H). However, decreased expression of other transcription factors associated with mature β cell function (i.e., MAFA, SIX3, and RFX6; refs. 17, 19, and 20, respectively) suggests that the HNF1AT260M variant impacts transcriptional regulatory networks required for β cell function rather than maintaining identity. Decreased expression of known (e.g., MLXIPL, HNF4A, PKM, OGDH, PPP1R1A, G6PC2, and TMEM27) (21) and previously undescribed HNF1A targets (IAPP, ABCC8, KCNJ11, TMEM37, SYNGR4, and FOXRED2) likely contributes to the loss of GSIS identified by islet perifusion (Figure 3C). Notably, most voltage-gated calcium channels, such as L-type and P/Q-type, were not changed in HNF1A+/T260M β cells, but ATP-sensitive channels were decreased (ABCC8, KCNJ11, KCNJ8, and FXYD2). Pathway analysis of HNF1A+/T260M β cells revealed changes in glucose metabolism and ATP production important in glucose-mediated insulin secretory processes as well as in core cellular pathways such as gene transcription, intracellular protein transport (i.e., synthesis, ubiquitination, and exocytosis), cell stress response, and cell signaling (Figure 3D and Supplemental Tables 5 and 7). Approximately 50% of the genes differentially expressed in HNF1A+/T260M β cells were also altered in donor α cells (Supplemental Figure 3, A–G), suggesting that HNF1A dysfunction is a common effector in both cell types (Supplemental Tables 5–7). We also noted that other processes such as amino acid nutrient sensing and metabolism, cell cycle regulators, and cell adhesion/motility were altered in HNF1A+/T260M islet cells (SLC38A4, GLUL, IGFBP5, and CREB3L1). Figure 3 Transcriptomic analysis of HNF1A+/T260M β cells. (A) Principal component analysis (PCA) plot depicts clustering of control β cells (n = 5 donors; ages 26–55 years) (31) separate from HNF1A+/T260M β cells. (B) The volcano plot demonstrates transcripts differentially expressed between control and HNF1A+/T260M β cells (red, upregulated gene expression; green, downregulated gene expression). Differential expression was calculated based on fold change (FC) ≥1.5 with a P-value cutoff of <0.05 for calculated Z score. (C) Genes of interest and HNF1A targets are significantly downregulated in HNF1A+/T260M β cells. The vertical dotted line represents FC = 1.5 times the threshold; P < 0.05 for all values shown. (D) Significant processes identified by Gene Ontology (GO) term-enrichment analysis are grouped and displayed by their P value on a log2 scale. This report highlights how molecular and functional findings in unique human samples, even in a single case, can contribute to our understanding of physiology and disease pathogenesis. Levels of HNF1A gene transcript in the human pancreas are substantially lower compared with mouse (22), such that mouse models of heterozygous HNF1A do not phenocopy the human disease (4–6). Missense mutations in the HNF1A dimerization and DNA binding domains account for the majority of described pathogenic HNF1A variants (23). Our modeling predicted that the T260M change would impair DNA binding of HNF1A, rendering this transcriptional factor nonfunctional, which was demonstrated by EMSA analysis. The dose-dependent decrease in transcriptional activity in WT HNF1A–dependent MAFA gene activation by HNF1AT260M suggests that the dimerization between these proteins leads to impaired DNA binding activity and reduced HNF1A target gene expression in individuals carrying this variant. In one of the first direct studies of human islets from an individual with a heterozygous, missense variant in the HNF1A locus, we show that this HNF1A+/T260M donor had relatively normal β cell mass and maintained many key markers of β cell identity but lacked an insulin secretory response to glucose challenge. This insulin secretory deficit was accompanied by alterations in genes encoding pathways of glucose metabolism and ATP production, which were also coupled with changes in core metabolic functions, such as gene transcription, protein synthesis and degradation, unfolded protein response, and intracellular and cell-cell communications in HNF1A+/T260M β cells. From this data set, we propose that this class of loss-of-function variants in HNF1A leads to insulin-insufficient diabetes, not by significant loss of β cell mass, but rather by impacting β cell transcriptional regulatory networks (HNF4A, MAFA, RFX6, SIX3, FOXA2, and MLXIPL) that results in impairment of β cell pathways necessary for a normal insulin response to glucose (Figure 4). Figure 4 Model of HNF1A dysfunction in human β cells. From these results, we propose that dysfunction of HNF1A leads to decreased expression of direct targets, which encompass both enzymatic and gene regulatory products, producing broad changes in transcriptional regulation, glucose metabolism, and hormone secretion. These processes ultimately lead to β cell dysfunction and result in clinical manifestation of insulin-insufficient diabetes. Furthermore, by investigating hormone secretion in isolated pancreatic islets, we discovered that depolarization by KCl, which directly stimulates hormone secretion by activating voltage-dependent calcium channels, was impaired in HNF1A+/T260M α and β cells, in contrast to results from mouse models (4). Interestingly, elevated basal insulin secretion was observed in islets from this donor, consistent with decreased expression of genes associated with glucose sensitivity of insulin secretion (G6PC2 and SLC37A4) (24). Our data also revealed a previously unrecognized role for HNF1A in α cell function, as HNF1A+/T260M impacted expression of many shared genes involved in hormone-regulated secretion (Supplemental Figure 3C). Transcriptomic analysis also uncovered HNF1A-regulated gene targets in β cells, such as PPP1R1A and RFX6, and pathways, like protein synthesis and amino acid metabolism. In addition, a number of genes differentially regulated in HNF1A+/T260M β cells included those identified in β cell subpopulations by Dorell and colleagues (HCN4, SPP1, KCNJ8, RFX6, SIX3, PPP1R1A, FAM159B, and G6PC2), suggesting that HNF1A may participate in the development of these β cell populations (25). Preserved β cell mass in a pancreas with 17 years of MODY3 highlights the importance of clinical identification and intervention even years after the diagnosis of diabetes. Low-dose sulfonylurea therapy produces effective glycemic control in some individuals with MODY3 (26) by stimulating this existing β cell reservoir; however, our data provide rationale for a therapeutic alternative to current treatment. Sulfonylureas likely have clinical efficacy by initiating membrane depolarization with potassium channel closure and bypassing effects from impaired ATP production, producing insulin responses comparable to control subjects (27). However, individuals with MODY3 are more sensitive to sulfonylureas (28), which may lead to hypoglycemia and limit this treatment; this might result in part from impaired glucagon secretion related to α cell depolarization (Supplemental Figure 1E). The islet perifusion data from this donor suggest that targeting cAMP-dependent pathways of insulin secretion, such as with glucagon-like peptide 1 (GLP-1) agonists, would have advantages over sulfonylureas, as this pathway of insulin secretion is preserved and accompanied by an intact glucagon response, thus lowering the risk of hypoglycemia in such MODY3 patients (29) (Figure 1C and Supplemental Figure 1E). Clinical and pathogenic heterogeneity in clinically diagnosed T1D is now increasingly apparent with the ability to study affected human pancreatic tissue (13, 30). Clinical features of many MODY phenotypes, which make up 1%–5% of all diabetes cases, can be easily mistaken for T1D. Lack of islet-related humoral autoantibodies, significant family history of insulin-deficient diabetes, and/or a low renal threshold for glucose should prompt genetic testing for HNF1A variants and other monogenic forms of diabetes. Because of this, in collaboration with the Vanderbilt Institutional Review Board (IRB), we are working to communicate our findings to the deidentified donor’s family and recommend diagnostic MODY genetic testing in potentially affected family members. Overall, this report shows how integrating clinical information with molecular and cellular analyses identified what appeared to be T1D was in fact part of a broader spectrum of insulin-deficient diabetes and provides translational insight into an incompletely understood form of human diabetes.
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Scooped by
Gilbert C FAURE
December 8, 2018 4:07 AM
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Since type 1 diabetes was first proposed to be an autoimmune disease in the 1970s,
the search has been on to identify the key pathogenic determinants and immune cell
types involved. The Immunology of Diabetes Society Congress in October, 2018 (London,
UK) featured a debate questioning the Achilles' heel of type 1 diabetes: is it regulatory
T-cell dysfunction, misdirected cytotoxic T cells, autoimmune B cells, type 1 interferon,
or a viral infection? The audience—comprising many of the world's leading experts
on the disease—could not agree.
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Scooped by
Gilbert C FAURE
December 7, 2018 2:42 PM
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Epitope mapping of anti-Ro52 antibodies (Abs) has been extensively studied in patients with Sjögren’s syndrome (SjS) and systemic lupus erythematosus (SLE). Comprehensive epitope mapping in systemic sclerosis (SSc), where anti-Ro52 antibodies are also frequently detected, has not been performed. The aim of the present study was to fully characterize Ro52 epitopes in anti-Ro52-positive SSc using Ro52 fragments spanning the full antigen. Further analysis was made according to anti-Ro60 status. Epitope mapping was performed in 43 anti-Ro52-positive SSc patients. Seventy eight anti-Ro52-positive pathological controls, including 20 patients with SjS, 28 patients with SLE, 15 patients with dermatomyositis (DM) and 15 patients with primary biliary cholangitis (PBC), and 20 anti-Ro52-negative healthy individuals as normal controls were also tested. Five recombinant Ro52 fragments [Ro52-1 (aa 1-127), Ro52-2 (aa 125-268), Ro52-3 (aa 268-475), Ro52-4 (aa 57-180), and Ro52-5 (aa 181-320) were used to test reactivity by line-immunoassay and in house ELISA. Anti-Ro60 reactivity was tested by ELISA. All anti-Ro52 positive sera reacted with Ro52-2; none recognized Ro52-3. Antibodies against Ro52-1 were less frequently found in SSc than in SjS/SLE (11.6% vs 41.7%, p=0.001); and antibodies against Ro52-4 were less frequently found in SSc than in SjS/SLE (27.9% vs 50%, p=0.03). In SSc patients, reactivity against Ro52-1 was more frequent in anti-Ro52+/anti-Ro60+ than i
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Scooped by
Gilbert C FAURE
December 7, 2018 11:38 AM
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Breaking tolerance is a key event leading to autoimmunity, but the exact mechanisms responsible for this remain uncertain. Here we show that the alarmin IL-33 is able to drive the generation of autoantibodies through induction of the B cell survival factor BAFF. A temporary, short-term increase in IL-33 results in a primary (IgM) response to self-antigens. This transient DNA-specific autoantibody response was dependent on the induction of BAFF. Notably, radiation resistant cells and not myeloid cells such as neutrophils or dendritic cells were the major source of BAFF and were critical in driving the autoantibody response. Chronic exposure to IL-33 elicited dramatic increases in BAFF levels and resulted in elevated number of B and T follicular helper cells as well as germinal center formation. We also observed class-switching from an IgM to an IgG DNA-specific autoantibody response. Collectively, the results provide novel insights into a potential mechanism for breaking immune-tolerance via IL-33-mediated induction of BAFF.
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Scooped by
Gilbert C FAURE
December 3, 2018 1:24 PM
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Antineutrophil cytoplasmic antibody-associated vasculitis, update on molecular pathogenesis, diagnosis, and treatment Farid Arman,1 Marina Barsoum,1 Umut Selamet,1 Hania Shakeri,1 Olivia Wassef,1 Mira Mikhail,2 Anjay Rastogi,1 Ramy M Hanna1 1Department of Medicine, Division of Nephrology, UCLA...
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Suggested by
LIGHTING
December 21, 2018 2:51 PM
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Join Dr Furie and colleagues in a discussion of best practices in the multidisciplinary care of patients with SLE.
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Scooped by
Gilbert C FAURE
December 19, 2018 1:27 PM
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A team from Scripps Research has found a molecular cause of a group of rare autoimmune disorders in which the immune system attacks the body's own healthy cells.
Abstract
Sometimes new ideas come from old places. Complement's central role in lupus pathogenesis has been known for years, and a reduction in C3 and C4 levels is one of the strongest biomarkers for increased lupus disease activity. However, every rheumatologist knows that some patients with no symptoms of active lupus will present with low complement levels, whereas some patients with aggressive disease have levels that never budge from the “normal” range. How can we better utilize the biomarkers associated with the complement system to guide therapy in lupus – both to predict lupus flares so that damage from unwanted inflammation can be prevented and to allow withdrawal of therapy after inflammation has resolved so as to minimize harm from toxic immunosuppressants?
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
December 17, 2018 2:20 PM
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Summary Systemic sclerosis (SSc) is an idiopathic systemic autoimmune disease. It is characterized by a triad of hallmarks: immune dysfunction, fibrosis and vasculopathy. Immune dysfunction in SSc is characterized by the activation and recruitment of immune cells and the production of autoantibodies and cytokines. How immune abnormalities link the fibrosis and vasculopathy in SSc is poorly understood. A plethora of immune cell types are implicated in the immunopathogenesis of SSc, including T cells, B cells, dendritic cells, mast cells and macrophages. How these different cell types interact to contribute to SSc is complicated, and can involve cell‐to‐cell interactions and communication via cytokines, including transforming growth factor (TGF)‐β, interleukin (IL)‐6 and IL‐4. We will attempt to review significant and recent research demonstrating the importance of immune cell regulation in the immunopathogenesis of SSc with a particular focus on fibrosis. Introduction Systemic sclerosis (SSc) is an idiopathic systemic autoimmune disease. The pathogenesis of SSc is mostly unknown. Immunological abnormality, which includes autoimmunity and infiltration and activation of immune cells, is one of three key features of the disease. The other two hallmarks of SSc are fibrosis and vasculopathy. How autoimmunity is linked to fibrosis and vascular damage remains poorly understood, with no single hypothesis or mechanism to explain the links. It is therefore likely that a combination of mechanisms is involved in the pathogenesis of SSc, and picking apart these mechanisms to establish how the triad of fibrosis, vasculopathy and immune cell activation progress in SSc is a mammoth task. Many studies have linked immune abnormality as a cause of or at least a contributor to fibrosis in SSc, while fibrosis may also contribute to immune cell activation. Fibrosis in SSc occurs mainly in the skin but may progress to visceral organs, including heart and lungs. Fibrosis is the result of activation of fibroblasts and excessive extracellular matrix (ECM) deposition, both of which are hallmarks of SSc. As well as fibrosis, immune abnormalities are also linked to vasculopathy in SSc, with most research implicating vascular damage as an activator of immune cells. However, this review will focus mainly on the role of immunological abnormalities in the development of fibrosis in SSc; we recommend the paper by Asano and Sato for a comprehensive review of vasculopathy in SSc 1. Multiple different cell types of the immune system have been implicated in SSc, including T cells, B cells, dendritic cells, mast cells and macrophages. It appears that both innate and adaptive immunity is critical in the disease. We will attempt to review the old and emerging literature to examine the potential roles of these individual cell types in the immunopathogenesis of SSc. First, we will summarize major cytokines implicated in the immunopathogenesis of SSc, because these major players reappear in many studies, linking immune cell activation with other phenotypes in SSc, especially fibrosis. Cytokines in SSc Many cytokines are elevated in SSc, but interleukin (IL)‐4, transforming growth factor (TGF)‐β and IL‐6 are considered to be the major fibrogenic cytokines, or are at least the most studied. Genetic deletion of both IL‐4 and TGF‐β prevents skin fibrosis in a mouse model of SSc 2. Many other in‐vitro studies support the idea that IL‐4 promotes fibrosis through its ability to enhance the production of collagen 3, 4 and other ECM proteins 5, 6 while antibodies against IL‐4 prevent dermal fibrosis in the tight skin (Tsk) mouse model 7 targeted deletion of IL‐4 receptor in the Tsk mouse also reduces fibrosis 2. Skin and lung in SSc have high levels of IL‐4 8 and increased levels of IL‐4 in the blood are a common feature in patients with SSc 9-11 suggesting systemic release. TGF‐β is a well‐known potent inducer of fibrosis, with TGF‐β‐stimulated fibroblasts resembling those from SSc patients 12. Activation of the TGF‐β receptor following the binding of TGF‐β results in the phosphorylation and activation of SMAD proteins in the cytoplasm 13. TGF‐β also activates the three mitogen‐activated protein kinase (MAPK) signalling branches, c‐Jun N‐terminal kinase (JNK), p38 and extracellular signal‐regulated kinases 1 and 2 (ERK1 and 2) 12 all of which can promote inflammatory signalling. TGF‐β‐induced collagen production from both healthy and SSc dermal fibroblasts was found to be dependent on p38 14. JNK activation has also been implicated in fibrosis 15. However, in one study ERK activation inhibited skin fibroblast collagens I and III production while, p38 activation up‐regulated collagen I 16. IL‐6 is a classic proinflammatory cytokine and is also considered to be an important protein in the immunopathogenesis of SSc. For example, IL‐6 levels are increased in SSc patient sera 9 and skin 17. IL‐6 levels also correlate with SSc disease severity 18. A mouse model with development of autoimmune disease with SSc‐like skin thickening and lung fibrosis was found to be mediated by IL‐6 signalling 19. Bleomycin‐induced lung inflammation with collagen deposition was significantly attenuated in IL‐6‐deficient mice 20. IL‐6 signalling through trans‐signalling appears to be important, and we found that IL‐6 and the soluble form of the IL‐6 receptor are necessary for collagen production 21. We further showed in the same study that this was critical, dependent on the downstream signalling molecule signal transducer and activator of transcription (STAT)‐3. A crucial early step hypothesized to trigger the immune abnormalities and fibrosis in SSc is vasculopathy, including the damage and apoptosis of endothelial cells, resulting in the release of internal damage‐associated molecular patterns (DAMPs), which go on to activate and recruit immune cells 22. IL‐6 was found to mediate endothelial activation and apoptosis caused by the serum of patients with SSc 23, suggesting that it may play a major role in the very early stages of SSc. However, IL‐6 was found to be up‐regulated at the late stage of the disease using immunohistological analysis of skin biopsies from SSc patients 17. In both IL‐6 knock‐out (KO) mice and mice exposed to an IL‐6 blocking antibody, bleomycin‐induced dermal fibrosis was greatly induced by supressing fibroblast activation 24. The anti‐IL‐6 receptor antibody tocilizumab has had promising results with softening of the skin in two patients with SSc in one study 25 while a Phase II trial provided SSc patients with improvement in fibrosis of the skin 26 although statistically this was not significant. Thus, IL‐6 antibody therapy could be the first biological licensed for SSc. T cells T cells have been identified early in SSc progression before any evidence of fibrosis 27. SSc skin has a greater propensity to recruit/adhere T cells compared to healthy controls because of a greater expression of intercellular adhesion molecule (ICAM‐1), which is a ligand for the lymphocyte function‐associated antigen 1 (LFA1) receptor found on the surface of lymphocytes such as T cells 28. T cells from SSc skin biopsies have increased expression of the early T cell activation marker CD69 29. TGF‐β, which is elevated in SSc, was also found to be important for the recruitment of T cells to the skin in an SSc mouse model 30. A recent paper demonstrated that abatacept, which is an antibody that interferes with T cell activation, reduced fibrosis in not one, but two animal models of fibrosis 31. This was associated with reduced T cell activation and reduced levels of IL‐6, which may be mediated by blockade of cross‐talk between T cells and antigen‐presenting cells such as monocytes. Abatacept works by blocking the interaction of CD80/86 with cytotoxic T lymphocyte antigen (CTLA)‐4 on T cells, which is required for co‐stimulatory activation of T cells alongside major histocompatibility complex (MHC) and antigen presentation from antigen‐presenting cells such as dendritic cells, macrophages and B cells 32 Abatacept was initiated in three patients with morphea, and all three showed regression of the modified Rodnan skin score 33. T cells can be further classified into diverse subsets characterized by their distinct function, activators and the cytokines they subsequently release. Some of these T cell types have been found to play a role in SSc, which has been reviewed in more detail 34. However, many studies have identified the T helper type 2 (Th2) subtype as playing the largest role in SSc. Th2 cells are a major IL‐4‐producing cell type, but also secrete IL‐5, IL‐6, IL‐10 and IL‐13. Depletion of CD3+ T cells in a bleomycin mouse model reduced both fibrosis and IL‐4 secretion 35. As described above, IL‐4 can directly induce fibroblasts to promote fibrosis, but in addition IL‐4 can induce TGF‐β production in fibroblasts 36 and macrophages 37, which then leads to further signalling to fibroblasts to produce more collagen. Therefore, it is very likely that T cells have a major role to play in the onset of fibrosis in SSc through activation of macrophages and fibroblasts. An unusual population of CD4+CD8+ double‐positive T cells has been described in the skin that has very high levels of IL‐4 38. Gross et al. showed almost 30 years ago that IL‐4 is required to induce naive T cells to produce further IL‐4 39. If IL‐4 is required for T cells to produce IL‐4, this leads to the question: ‘what is the initial source of IL‐4 in SSc?’. This question remains unanswered, but potentially implicates other immune cells in the onset or progression of SSc. IL‐13 is produced predominantly by activated Th2 cells 34. IL‐13 was established as a major profibrotic agent in a model of hepatic fibrosis 40. IL‐13 inhibited IL‐1β‐induced matrix metalloproteinase (MMP)‐1 and MMP‐3 production and enhanced tissue inhibitor of metalloproteinase (TIMP)‐1 and collagen generation in fibroblasts 41. In the bleomycin model of SSc pulmonary fibrosis IL‐13 levels increased with pathogenesis, while neutralization of IL‐13 attenuated bleomycin‐induced pulmonary fibrosis 42. The potent fibrosis‐inducer, TGF‐β, may also contribute to an increase in Th2‐originating IL‐13 because TGF‐β up‐regulates GATA binding protein 3 (GATA‐3) expression in the T cells of patients with SSc, resulting in an increase in IL‐13 synthesis 43. As well as CD4+CD8+ double‐positive T cells, CD8+ single‐positive cells have been described that produce exuberant levels of IL‐13 44. These cells appear to be memory CD8+ T cells 45. We have shown that IL‐13 is directly profibrotic and is STAT‐6‐dependent 46. Thus, IL‐13 produced from T cells probably contributes to fibrosis in SSc and a monoclonal IL‐13 clinical‐grade antibody exists. Very recently, IL‐13 was shown to decrease MMP‐1 expression in both healthy and SSc fibroblasts and therefore may have an anti‐fibrotic role 47. However, this was only demonstrated in tumour necrosis factor (TNF)‐α‐induced fibroblasts, thus the effect of IL‐13 may be specific to the mechanism with which TNF‐α induces MMP‐1 expression. Another cytokine, IL‐17, prevalent in the serum of SSc patients in some studies, also implicates T cells 48. Th17 cells, which are characterized by their production of IL‐17A, IL‐17F, IL‐21 and IL‐22, are elevated in SSc skin compared to healthy controls 49, 50. Thus, Th17 cells and the IL‐17 they produce may play an important role in SSc. However, the roles of Th17 and IL‐17 in SSc are controversial, and have been recently reviewed in detail 51. Importantly, some studies have not detected differences in IL‐17 levels between SSc patients and healthy controls 52, 53 while IL‐17 has been shown to both increase 50 and decrease 54, 55 collagen production. The reasons for the differences in these studies between pro‐ or anti‐fibrotic effects of IL‐17 are not clear, and may reflect the source of the recombinant protein. A reduction in regulatory T cells has been recorded in the skin lesions of patients with SSc 56 suggesting that there is compromised capacity to regulate immune responses in SSc. A recent study identified an imbalance of regulatory T cells and Th17 cells, with a decrease in the former and an increase in the latter in the peripheral blood of SSc patients compared to healthy controls 57. In addition, a more recent study has confirmed that Th2 and Th17 cells are found in higher frequencies in SSc patients, and this was found to positively correlate with IL‐35 levels, although a causal link has not been established 58. Further evidence of disruption to T cell homeostasis comes from a recent study showing that SSc patients displaying severe peripheral vascular complications have an expansion of the recently discovered angiogenic T cells 59. This expansion in angiogenic T cells may also demonstrate a link between immune cell activation and vasculopathy in SSc. Macrophages More than 30 years ago circulating monocytes were found to be strongly activated in patients with SSc 60. Since then, many studies have found evidence of monocyte/macrophage activation in SSc. Higher numbers of macrophages have been observed in skin from SSc patients 27, 61 while cells positive for CD163, a putative marker for M2 macrophages 62, have been found to be increased in the serum of SSc patients 61, 63-65. M2 macrophages are therefore prominent in SSc, with a very recent study involving more than 200 SSc patients, not only confirming this but also demonstrating that soluble CD163 (sCD163) is significantly elevated in the serum of SSc patients and therefore may be of use as a biomarker 66. Microarray gene expression data have also supported a role for monocytes/macrophages in the immunopathogenesis of SSc, with studies demonstrating that peripheral blood mononuclear cells (PBMCs) from SSc patients have an increased expression of genes associated with monocyte/macrophages 67-69. Such large‐scale genomic studies have identified multiple innate immune regulators in SSc. Macrophages are also a major source of TGF‐β 70, which is a potent inducer of fibrosis 71. Many studies have implicated macrophages in the initiation or progression of fibrosis in SSc. Microarray data from SSc lung tissue confirm what has been observed in the blood with markers of macrophage activation 72 and emigration, which correlate with progressive lung fibrosis 73. In another recent study, a novel multi‐network approach to compare gene expression profiles has identified a gene expression signature indicative of profibrotic M2 macrophages in SSc tissues 74. Interestingly, the profibrotic macrophage gene expression profile differed between skin and lung, suggesting that although a role for macrophages in the immunopathogenesis of fibrosis in SSc seems likely in both skin and lung, there may still be subtle differences in what those roles are. Recently nintedanib, an inhibitor of the receptor tyrosine kinase platelet‐derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor, blocked myofibroblast differentiation and subsequent fibrosis in a mouse model of SSc. Interestingly, these nintedanib‐mediated anti‐fibrotic effects were associated with reduced numbers of M2 macrophages 75. Many chemokines which both recruit and can be primarily secreted by macrophages are up‐regulated in SSc skin 76-79 which is not surprising, given that infiltration of macrophages in SSc skin has been known since the early 1990s 80. However, the chemokine (C‐C motif) ligand 19 (CCL19) was up‐regulated in SSc skin and co‐localized with CD163‐positive macrophages, suggesting that it has a role in the recruitment of macrophages 76. The authors of the study also suggest that macrophages are the source of the CCL19, and in‐vivo experiments demonstrate that Toll‐like receptor (TLR)‐3, ‐4 or ‐9 activation is required for CCL19 expression in monocytes. TLR activation is considered a major event in the immunopathogenesis of SSc 81, 82. Cell types which highly express TLRs such as macrophages are thought to play a major role in SSc. However, many different cell types express TLRs, and thus TLR‐mediated signalling in the immunopathogenesis of SSc may not be limited to macrophages. It is possible that TLR activation in any cell type expressing TLRs is also a source of CCL19, and therefore a potential cause of macrophage recruitment in SSc. Indeed, Mathes et al. also observed that CCL19 expression was up‐regulated from TLR activation in T cells and other cell types from PBMCs, but monocytes gave the most robust increase 76. We have found that macrophages that respond to the TLR‐8 stimulus single‐stranded RNA in SSc result in up‐regulation of TIMP‐1 that is functional and leads to increased collagen deposition 83. Interestingly, these monocytes seemed to be perivascular. IL‐6 appears to play an important part in the role of macrophages in SSc because inhibition of phosphodiesterase‐4, which blocks M2 differentiation, also inhibits IL‐6 production, fibroblast activation and fibrosis in an SSc mouse model 84. IL‐6 may also be an important activator of M2 macrophages, as indicated by IL‐6 receptor blockage by tocilizumab 85 causing down‐regulation of genes associated with M2 macrophages in SSc skin. Oncostatin M is another IL‐6‐like cytokine that appears to be involved in fibrosis, as cells treated with OSM induced ECM accumulation in fibroblasts 86. SSc patients with higher expression of the M2 macrophage marker, MRC1, were also found to have elevated levels of IL‐13 in their plasma 69 suggesting that macrophage activation in SSc results in production of cytokines from macrophages themselves or indirectly through interaction with other immune cells, because macrophages can both secrete IL‐13 87 and, through being antigen‐presenting cells, can activate T cells which could lead to IL‐13 production. There have been more than 30 years of research implicating macrophages in the immunopathogenesis of SSc, with various cytokines produced by macrophages and other immune cells, internal molecules from damaged endothelial cells and chemokines all contributing to the recruitment and activation of macrophages, resulting in a profibrotic environment (Fig. 1). However, how macrophages are recruited to and activated in the tissues of SSc patients is not fully understood. What role is played by macrophages in the progression of fibrosis is also not fully known, but activation of TLRs and the subsequent profibrotic signalling remains an obvious choice. Targeting of TLRs may be a therapeutic option. B cells B cells are heavily implicated in the immunopathogenesis of SSc. B cells are known inducers of fibrosis generally and in SSc 88 and mounting evidence suggests that they are modified and activated in patients with SSc. SSc patients have abnormalities of B cell homeostasis in the blood, which includes an expansion of naive B cells and activated but diminished memory B cells 89. The cytokine B cell activating factor (BAFF), which belongs to the TNF ligand family, is a potent activator of B cells 90. Not only are BAFF levels elevated in SSc; levels also correlate with disease severity, while B cells isolated from SSc patients produce more IL‐6 when exposed to BAFF 91. A BAFF antagonist inhibited IL‐6 and IL‐10 expression in the skin of the Tsk mouse model of SSc, while stimulation of B cells with BAFF greatly increased IL‐6 92. IL‐6 can direct the differentiation of T cells into IL‐4‐producing Th2 cells 93, therefore B cell‐secreted IL‐6 could contribute to the Th2 phenotype detected in SSc. As well as being involved in IL‐6 cytokine production, B cells are also suggested to play an important role in fibrosis. Co‐cultures of B cells and fibroblasts from SSc patients induced a fibrotic response, including collagen, TGF‐β1 and IL‐6 secretion. Exposure of co‐cultures to BAFF (and anti‐IgM) further increased secretion of the profibrotic compounds 88. The majority of B cells are IL‐6‐producing, termed B effector cells (Beffs), and have a proinflammatory and autoimmunity role. However, a small subset of B cells termed regulatory B cells (Bregs) are potent negative regulators of inflammation and autoimmunity, in part through their ability to express IL‐10 94. These Bregs therefore have the potential to inhibit diseases with immune abnormalities such as SSc. Indeed, Bregs were able to inhibit the initiation of a mouse model of multiple sclerosis and depletion of Bregs increased symptom severity 95. Interestingly, the frequency of blood Bregs was found to be significantly lower in SSc patients compared to healthy controls 96 while in a very recent study by Matsushita et al., Bregs were found to have a similar role in a mouse model of SSc. Depletion of IL‐6‐producing Beffs reduced skin and lung fibrosis, while depletion of IL‐10‐producing Bregs caused more severe fibrosis 97 backing up findings from a previous study that Bregs can suppress skin fibrosis in a graft‐versus‐host disease mouse model of SSc 98. A tipping of the balance of Bregs and Beffs in favour of fewer Bregs is therefore a potential important event in the initiation of fibrosis in SSc. However, the cause of this shift in B cell homeostasis remains unknown, and future studies to identify the trigger/s may provide useful early therapeutic targets. Various response regulators on the surface of B cells exist, with some increasing and others decreasing B cell receptor (BCR) signals. Of these, the positive B cell regulator, CD19, is the most established in SSc disease research. CD19 is an important regulatory molecule expressed by B cells. CD19+ B cells increase in SSc, with expression of CD19 on the surface of B cells significantly higher in SSc patients compared to healthy controls 99. CD19‐deficient mice have decreased sera levels of several autoantibodies 100 suggesting that B cells could be responsible for the autoantibodies detected in SSc patients. In agreement, a transgenic mouse model, with an elevation in CD19 expression similar to SSc human patients, shows an increase in the levels of autoantibodies 101, 102. It is also worth noting that CD19 over‐expression has not been observed in the Tsk mouse model, suggesting that a role for CD19 in B cell activation in SSc is not straightforward or that the animal models can only replicate the human disease phenotypes to a degree. However, the apparent lack of CD19 over‐expression may be explained partly through constitutive activation of CD19 and the downstream signalling pathway via up‐regulated CD19 tyrosine phosphorylation, which could negate the need for over‐expression 102. Autoantibody production is prevalent, and can be used diagnostically in SSc. Furthermore, autoantibodies against platelet‐derived growth factor receptor (PDGFR) were found in SSc patients, and caused collagen I‐increased expression and transition of normal human primary fibroblasts to a myofibroblast phenotype through activation of an intracellular loop that involves Ha‐Ras, ERK1/2 and reactive oxygen species (ROS) 103. However, it is still possible that B cell activation is the cause of both autoantibody production and fibrosis, as the two may be linked. Interestingly, B cell activation via CD19 specifically may also be a cause of other immune cell type infiltration in SSc. CD19‐deficient mice showed less infiltration of mast cells, macrophages, T cells and B cells after bleomycin treatment compared to wild‐type cells exposed to bleomycin 104. In the same study, it was discovered that B cells, via hyaluronan‐induced TLR‐4 activation, produced various cytokines which were dramatically reduced in CD19‐deficient cells. Therefore, B cells have the potential to contribute to fibrosis directly as well as indirectly through recruitment and activation of other immune cells to promote a cycle of cytokine and fibrogenic compound release. Mast cells Mast cell infiltration was detected from lip biopsy in very early stages of SSc and preceded the onset of skin changes 105 and more recently cutaneous mastocytosis was found to precede the onset of SSc in a 36‐year‐old woman 106 suggesting that mast cells may play an early role in the onset of SSc. Mast cell infiltration has also been detected late in the development of SSc 107 and in a subset of SSc patients with localized scleroderma‐like lesions 108. An increase in mast cell numbers has also been detected in SSc skin 109. Mast cells are able to produce TGF‐β and are found localized to fibroblasts in the skin of SSc patients 110. Interestingly, mast cells are not only a source of TGF‐β; they can also directly transfer TGF‐β to fibroblasts mediated by transgranulation via cell–cell contacts 111, which has also been observed in the dermis of SSc patients 112. The triggers of mast infiltration in SSc or other fibrotic diseases are not known, but a very recent study has identified Snail‐dependent production of plasminogen activator inhibitor‐1 (PAI1) in keratinocytes as a chemoattractant of mast cells, a mediator of mast cell–fibroblast adhesion and a promoter of fibrogenesis 113. Interestingly, PAI1 up‐regulated tenascin‐C (TENC) expression, which is the main activator of TLR‐4 to promote fibrosis and found to be elevated in SSc 114. Therefore, the role of PAI1 in SSc could involve mast cell recruitment and activation of fibroblasts to promote an inflammatory environment. Dendritic cells Two major types of dendritic cell are known: conventional (cDC) and plasmacytoid (pDC). pDC are a specialized cell type that when activated produce large amounts of interferon (IFN). A very recent study observed that pDCs infiltrate the skin of SSc patients and are chronically activated, producing IFN‐α and chemokine (C‐X‐C motif) ligand 4 (CXCL4). Fibrosis was reverted in a mouse model of SSc after pDCs depletion 115. In the same study, TLR‐8 signalling was found to be important for CXCL4 production and recruitment of pDCs to fibrotic skin. TLR involvement has also been found to be important for mediating the increased cytokine production in DCs in SSc, which has been comprehensively reviewed 116. pDCs isolated from SSc patients show up‐regulation of CXCL4 115, 117, which can also be detected at elevated levels and correlates with disease severity in SSc patient plasma 118 and has been suggested as a biomarker in SSc. In another recent study, pDC depletion in a bleomycin mouse model improved the clinical score, lung histopathology score, skin thickness and collagen content. The expression of genes involved in chemotaxis, dendritic cell differentiation, inflammation and fibrosis in the lungs of pDC‐depleted mice was also significantly reduced. Alongside this, B and T cells were also found to be reduced in the lungs, suggesting an important role for ongoing immune abnormalities induced by DCs 119. In another bleomycin‐induced pulmonary fibrosis mouse model, DC accumulation in the lung was reduced through blocking of TGF‐β with the use of inhibitor SB431542 120. TGF‐β was also found to be important for the recruitment of pDCs (and T cells) to the skin in an SSc mouse model 30 suggesting an important role for TGF‐β in DC location and activation. An important role for microRNAs in the pathogenesis SSc is emerging 121. Recently, microRNA expression profiling has identified miRNA‐618 (miR‐618) as being up‐regulated in pDCs from SSc patients, while over‐expression in healthy pDCs resulted in an SSc‐like pDC 122. Thus, microRNAs are disturbed, leading to altered functionality of immune cells. Alterations of microRNAs by restoration using microRNA therapeutics may be one way to reset dendritic cells to a ‘tolerogenic’ phenotype. Anti‐nuclear antibodies, which are a subset of autoantibodies, are found to be elevated in SSc patients 123. DNA topoisomerase I (TopoI) is an intracellular target of anti‐nuclear antibody anti‐TopoI. The presence of anti‐TopoI antibodies has been clinically associated with a more severe form of SSc 124. Immunization of mice with TopoI peptide‐loaded DCs induces anti‐TopoI autoantibody response and long‐term fibrosis of skin and lung, which is preceded by inflammation with increased IL‐17A and CXCL4 expression 125. TopoI peptide‐loaded DCs also induce proliferation of SSc and healthy‐derived T cells, but activation of T cells requires a fragmented form of TopoI and activation of full‐length TopoI is IL‐2‐dependent 126. Interestingly, antigen‐presenting cells within PBMCs were able to activate T cells more efficiently than dendritic cells, and even processed TopoI peptides differently, suggesting that there is a complex regulation of T cells by dendritic cells and other antigen‐presenting cells with regard to anti‐nuclear antibodies. Overall, experimental manipulation of DCS can mimic some major events in the pathogenesis of SSc, and therefore raises the intriguing prospect that DCs may be capable of initiating SSc. A broken loop that may perpetuate inflammation with cytokine‐mediated up‐regulation of co‐stimulatory molecules may also exist in SSc. Other immune cells Dysregulation and activation of immune cells is clearly a major hallmark of SSc involving many cell types. This complex network of signalling between different immune cells is only now beginning to become unravelled, with new evidence emerging regularly to provide new players in SSc immunopathogenesis. For example, only a few studies have highlighted the potential for platelets 127-129, neutrophils 130, 131, natural killer cells 132, 133 and innate lymphoid cells 134, 135 to be dysregulated and contribute to the pathogenesis of SSc. Type 2 innate lymphoid cells are found in higher numbers in SSc and correlate strongly with the Rodnan skin score and also the presence of lung fibrosis. Although not considered to be innate immune cells, fibroblasts play a crucial role in the fibrotic phenotype of SSc, but they also express TLRs and are therefore capable of responding to DAMPs. Expression of TLR‐2 was found to be increased in fibroblasts from SSc skin 136. Recently, fibroblasts exposed to TGF‐β and IL‐17A responded with a 100‐fold increase in the production of IL‐6 137, a known profibrotic mediator. Conclusion Various cell types of the immune system appear to be involved to some degree in the immunopathogenesis of SSc through promoting other immune cell activation, fibrosis or vascular damage. Very recent studies have highlighted the importance of this plethora of immune cell types in SSc (Table 1). However, research to date provides evidence for macrophages, T cells and B cells having the most important role in SSc. Whether this accurately represents their importance in SSc or is a result of research interests combined with the practicality of investigating specific cell types remains to be seen. Nevertheless, immune cell activation is a recurring observation in SSc research and is leading to the development and testing of therapeutic interventions. Although the over‐production of cytokines is a well‐accepted symptom of SSc, TGF‐β, IL‐6 and IL‐4 specifically seem to be integral to many of the immune abnormalities recorded. Thoroughly understanding how these and other cytokines fully regulate, and are regulated by, all the different immune cells and their subcategories in SSc will be a difficult task, but every study into immune cell activation, regardless of cell type, brings us closer to achieving it and as a result developing therapeutic interventions. Current trials such as the Fassinate trial in SSc blocking IL‐6 seem promising, with the Phase II trial positive, although the primary end‐point was not reached. Phosphodiesterase type 4 (PDE4) inhibitors appear to regulate macrophages leading to reduced fibroblast activation. There is an ongoing trial concerning morphea. Immune cell Recent findings Reference T cell Angiogenic T cells were elevated in SSc patients displaying digital ulcers, which is a severe peripheral vascular complication 59 Macrophage The soluble form of the M2 macrophage marker CD163 is elevated in the serum of patients with SSc, highlighting it as a potential biomarker 66 B cell Used a mouse model of SSc to demonstrate the importance of B cell homeostasis. Depletion of IL‐6‐producing B effector cells reduced fibrosis while depleting of IL‐10‐producing B regulatory cells had the opposite effect 97 Mast cell A subset of SSc patients with localized scleroderma‐like lesions were found to have an inflammatory phenotype leading to the activation of mast cells in the dermis of mechanically stressed skin 108 Dendritic cell After depletion of pDCs fibrosis was reverted in mice with established SSc‐like disease. pDC depletion prior to induction of disease also prevented fibrosis 115 Platelets Activated platelets induced the production of the profibrotic mediator thymic stromal lymphopoietin (TSLP) in human dermal endothelial cells 128 Neutrophils Neutrophil activation was induced by SSc microparticles. Microparticles were derived from platelets and expressed the damage‐associated molecular pattern HMGB1. An inhibitor of HMGB1 attenuated neutrophil activation 131 Natural killer A peculiar natural killer cell phenotype in SSc patients was identified characterized by decreased chemokine and activation receptors expression. These SSc‐derived natural killer cells were potent inducers of endothelial microparticle release suggesting that there may be a role for natural killer cells in the activation of endothelial cells in SSc 133 Innate lymphoid Type 2 innate lymphoid (ILC2) cells are elevated in patients with SSc. ILC2 counts correlated with skin fibrosis. This study highlights that there may be a profibrotic role for ILC2 cells in SSc 134 Fibroblast Although not an immune cell type, fibroblasts exposed to TGF‐β and IL‐17a responded with a 100‐fold increase in the production of IL‐6 137 DCs = dendritic cells; IL = interleukin; TGF = transforming growth factor; HMGB1 = high mobility group box 1. Disclosures None. References
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Gilbert C FAURE
December 15, 2018 11:34 AM
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Methods Mol Biol. 2019;1901:191-196. doi: 10.1007/978-1-4939-8949-2_15.
Antibodies are vital components of the adaptive immune system for the recognition and response to foreign antigens. However, some antibodies recognize self-antigens in healthy individuals
Via Krishan Maggon
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Gilbert C FAURE
December 13, 2018 11:35 AM
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Case study of 3 month old with bloody urine - investigation, diagnosis and treatment of Neonatal lupus Erythematosus plus the immunology of the disease.
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Gilbert C FAURE
December 11, 2018 9:08 AM
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Editorial Antibodies Against M-Type Phospholipase Receptor and Prediction of Outcome in Membranous Nephropathy: We are Not There Yet Wetzels J.F.M. Author affiliations Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands Corresponding Author Prof. Dr. Jack F.M. Wetzels Department of Nephrology Radboud University Medical Centre, 464 PO Box 9101, NL–6500 HB, Nijmegen (The Netherlands) E-Mail jack.wetzels@radboudumc.nl Related Articles for "" Am J Nephrol 2018;48:434–437 First-Page Preview Related Articles: References Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361: 11–21. De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC: A proposal for a serology-based approach to membranous nephropathy. J Am Soc Nephrol 2017; 28: 421–430. Hofstra JM, Debiec H, Short CD, Pellé T, Kleta R, Mathieson PW, Ronco P, Brenchley PE, Wetzels JF: Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy. J Am Soc Nephrol 2012; 23: 1735–1743. Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, Suardi F, Gagliardini E, Orisio S, Benigni A, Ronco P, Remuzzi G: Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol. 2015; 26: 2545–2558. Qu Z, Zhang M, Cui Z, Wang J, Wang M, Zhang Y, Wang F, Wang X, Meng L, Cheng X, Liu G, Zhao M: Antibodies against M-type phospholipase A2 receptor may predict treatment response and outcome in membranous nephropathy. Am J Nephrol 2018; 48: 438–446. Tampoia M, Migliucci F, Villani C, Abbracciavento L, Rossini M, Fumarulo R, Gesualdo L, Montinaro V: Definition of a new cut-off for the anti-phospholipase A2 receptor (PLA2R) autoantibody immunoassay in patients affected by idiopathic membranous nephropathy. J Nephrol 2018, Epub ahead of print. Rood IM, Merchant ML, Wilkey DW, Zhang T, Zabrouskov V, van der Vlag J, Dijkman HB, Willemsen BK, Wetzels JF, Klein JB, Deegens JK: Increased expression of lysosome membrane protein 2 in glomeruli of patients with idiopathic membranous nephropathy. Proteomics 2015; 15: 3722–3730. Van de Logt AE, Dahan K, Rousseau A, van der Molen R, Debiec H, Ronco P, Wetzels J: Immunological remission in PLA2R-antibody-associated membranous nephropathy: cyclophosphamide versus rituximab. Kidney Int 2018; 93: 1016–1017. Zhang XD, Cui Z, Zhang MF, Wang J, Zhang YM, Qu Z, Wang X, Huang J, Wang F, Meng LQ, Cheng XY, Wang SX, Liu G, Zhao MH: Clinical implications of pathological features of primary membranous nephropathy. BMC Nephrol 2018; 19: 215. Van de Logt AE, Hofstra JM, Wetzels JF: Serum anti-PLA2R antibodies can be initially absent in idiopathic membranous nephropathy: seroconversion after prolonged follow-up. Kidney Int 2015; 87: 1263–1264. Article / Publication Details Received: October 15, 2018 Accepted: October 16, 2018 Published online: November 23, 2018 Issue release date: Published online first Number of Print Pages: 4 Number of Figures: 0 Number of Tables: 0 ISSN: 0250-8095 (Print) eISSN: 1421-9670 (Online) For additional information: https://www.karger.com/AJN Open Access License / Drug Dosage / Disclaimer This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
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Gilbert C FAURE
December 8, 2018 1:43 PM
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Autoantibodies are implicated in autoimmunity, but may also be present in healthy individuals. Here the authors find that the autoantibody specificity signatures against various G protein-coupled receptors are associated with multiple parameters, including disease states, to imply a physiological...
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Gilbert C FAURE
December 7, 2018 2:44 PM
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Scooped by
Gilbert C FAURE
December 7, 2018 12:41 PM
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Loss or dysfunction of β-cells is a characteristic of insulin-dependent diabetes mellitus. Regeneration of β-cells might stop or reverse the progression of the disease. This Review discusses the different modelling systems and technologies currently used to study β-cell biology in health and disease.
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Gilbert C FAURE
December 4, 2018 4:00 PM
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Objectives No simple or standardized assay is available to quantify interferon‐α (IFNα) in routine clinical practice. Single‐molecule–array (Simoa) digital enzyme‐linked immunosorbent assay (ELISA) technology enables direct IFNα quantification at fg/mL concentrations. This study was undertaken to assess IFNα digital ELISA diagnostic performances to monitor systemic lupus erythematosus (SLE) activity. Methods IFNα concentrations in serum samples from 150 consecutive SLE patients in a cross‐sectional study were determined with digital ELISA and a functional biological activity assay (bioassay). According to their SELENA–SLEDAI flare composite, patients were divided into groups with inactive (SLEDAI <4 or clinical SLEDAI =0) or active SLE (SLEDAI ≥4 or clinical SLEDAI >0), and into groups with no flare or mild/moderate flare or severe flare. Results Based on healthy blood donors, the abnormal serum‐IFNα level threshold value was 136 fg/mL. Next, using receiver operating characteristics curves for an SLE‐patient series, widely heterogeneous for disease activity and organ involvement, the threshold IFNα value associated with active disease was determined to be 266 fg/mL. The digital ELISA‐assessed serum‐IFNα level was a better biomarker of disease activity than the Farr test: its specificity, likelihood ratio for positive results and positive‐predictive value better discerned active SLE or flare from inactive patients. The digital ELISA was more sensitive than the bioassay to detect low‐abnormal serum‐IFNα concentrations and patients with low disease activity. Conclusion Direct serum‐IFNα determination with a highly sensitive assay might improve monitoring of clinical SLE activity and selection of the best candidates for anti‐IFNα treatment. This article is protected by copyright. All rights reserved.
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