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ID PMID Title PublicationDate abstract
27448590 Extensive Citrullination Promotes Immunogenicity of HSP90 through Protein Unfolding and Ex 2016 Sep 1 Post-translational protein modifications such as citrullination have been linked to the breach of immune tolerance and clinical autoimmunity. Previous studies from our laboratory support this concept, demonstrating that autoantibodies targeting citrullinated isoforms of heat shock protein 90 (HSP90) are associated with rheumatoid arthritis complicated by interstitial lung disease. To further explore the relationship between citrullination and structural determinants of HSP90 immunogenicity, we employed a combination of ELISA-based epitope profiling, computational modeling, and mass-spectrometric sequencing of peptidylarginine deiminase (PAD)-modified protein. Remarkably, ELISAs involving selected citrullinated HSP90β/α peptides identified a key epitope corresponding to an internal Arg residue (R502 [HSP90β]/R510 [HSP90α]) that is normally buried within the crystal structure of native/unmodified HSP90. In vitro time/dose-response experiments reveal an ordered pattern of PAD-mediated deimination events culminating in citrullination of R502/R510. Conventional as well as scaled molecular dynamics simulations further demonstrate that citrullination of selected Arg residues leads to progressive disruption of HSP90 tertiary structure, promoting exposure of R502/R510 to PAD modification and subsequent autoantibody binding. Consistent with this process, ELISAs incorporating variably deiminated HSP90 as substrate Ag indicate a direct relationship between the degree of citrullination and the level of ex vivo Ab recognition. Overall, these data support a novel structural paradigm whereby citrullination-induced shifts in protein structure generate cryptic epitopes capable of bypassing B cell tolerance in the appropriate genetic context.
26257191 Vascular remodeling underlies rebleeding in hemophilic arthropathy. 2015 Nov Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.
26173397 β-Lapachone suppresses neuroinflammation by modulating the expression of cytokines and ma 2015 Jul 16 BACKGROUND: β-Lapachone (β-LAP) is a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia sp.), and it has been used for treatment of rheumatoid arthritis, infection, and cancer. In the present study, we investigated whether β-LAP has anti-inflammatory effects under in vitro and in vivo neuroinflammatory conditions. METHODS: The effects of β-LAP on the expression of inducible nitric oxide synthase (iNOS), cytokines, and matrix metalloproteinases (MMPs) were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and rat primary microglia by ELISA, reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis. Microglial activation and the expression levels of proinflammatory molecules were measured in the LPS-injected mouse brain by immunohistochemistry and RT-PCR analysis. The detailed molecular mechanism underlying the anti-inflammatory effects of β-LAP was analyzed by electrophoretic mobility shift assay, reporter gene assay, Western blot, and RT-PCR analysis. RESULTS: β-LAP inhibited the expression of iNOS, proinflammatory cytokines, and MMPs (MMP-3, MMP-8, MMP-9) at mRNA and protein levels in LPS-stimulated microglia. On the other hand, β-LAP upregulated the expressions of anti-inflammatory molecules such as IL-10, heme oxygenase-1 (HO-1), and the tissue inhibitor of metalloproteinase-2 (TIMP-2). The anti-inflammatory effect of β-LAP was confirmed in an LPS-induced systemic inflammation mouse model. Thus, β-LAP inhibited microglial activation and the expressions of iNOS, proinflammatory cytokines, and MMPs in the LPS-injected mouse brain. Further mechanistic studies revealed that β-LAP exerts anti-inflammatory effects by inhibiting MAPKs, PI3K/AKT, and NF-κB/AP-1 signaling pathways in LPS-stimulated microglia. β-LAP also inhibited reactive oxygen species (ROS) production by suppressing the expression and/or phosphorylation of NADPH oxidase subunit proteins, such as p47(phox) and gp91(phox). The anti-oxidant effects of β-LAP appeared to be related with the increase of HO-1 and NQO1 via the Nrf2/anti-oxidant response element (ARE) pathway and/or the PKA pathway. CONCLUSIONS: The strong anti-inflammatory/anti-oxidant effects of β-LAP may provide preventive therapeutic potential for various neuroinflammatory disorders.
26344475 Differential effects of anti-TNF-α and anti-IL-12/23 agents on human leukocyte-endothelia 2015 Oct 15 Enhanced leukocyte recruitment is an inflammatory process that occurs during early phases of the vascular dysfunction that characterises atherosclerosis. We evaluated the impact of anti-TNF-α (adalimumab, infliximab and etanercept) and anti-IL-12/23 (ustekinumab) on interactions between human leukocytes and endothelial cells in a flow chamber that reproduced in vivo conditions. Clinical concentrations of anti-TNF-α were evaluated on the leukocyte recruitment induced by a variety of endothelial (TNF-α, interleukin-1β, lymphotoxin-α and angiotensin-II) and leukocyte (PAF, IL-12 and IL-23) stimuli related to inflammation and atherosclerosis. Treatment with anti-TNF-α, even before or after establishing the inflammatory situation induced by TNF-α, diminished leukocyte-endothelial cell interactions induced by this stimuli. Our results also implicated adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in the actions of anti-TNF-α in terms of leukocyte adhesion to endothelium. However, anti-TNF-α drugs did not influence the actions of interleukin-1β, but prevented those of lymphotoxin-α and angiotensin-II. However, once established, inflammatory response elicited by the latter three stimuli could not be reversed. Pre-treatment with anti-TNF-α, also prevented leukocyte actions induced by IL-23 on PBMC rolling flux and rolling velocity and by IL-12 on PMN adhesion. Ustekinumab exhibited a more discreet profile, having no effect on leukocyte recruitment induced by any of the endothelial stimuli, while blocking the effects of IL-23 on leukocyte activation and those of IL-12 on PMN adhesion and PAF on PBMC rolling velocity. These findings endorse the idea that biological anti-inflammatory drugs, in particular anti-TNF-α, have the capacity to influence cardiovascular risk accompanying psoriasis and rheumatoid arthritis by ameliorating vascular inflammation.
27814471 Reference data of the European Organisation for Research and Treatment of Cancer (EORTC) Q 2016 Dec OBJECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side-effect of chemotherapy. However, CIPN symptoms are also reported by patients not receiving chemotherapy. Normative data could help interpret CIPN among cancer patients. Our aim was to generate normative data for the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 Questionnaire designed to assess CIPN from the patients' perspective. The normative CIPN data have also been generated for stratified subgroups formed on the basis of sex, age and comorbidity. METHODS: The QLQ-CIPN20 and the Self-administered Comorbidity Questionnaire were administered to a representative panel of the Dutch-speaking population in the Netherlands. RESULTS: Two thousand one hundred and two (78%) of those invited completed the questionnaires. The majority reported no CIPN symptoms (83-97%). Cronbach's alpha coefficients for the sum score, and sensory, motor and autonomic subscales were 0.87, 0.76, 0.82 and 0.49, respectively. Compared with men, women scored significantly worse on the sum score (men, 3.0 versus women, 4.3; p < 0.001), motor scale (2.7 versus 5.1; p < 0.001) and autonomic scale (3.8 versus 5.2; p < 0.01), but this difference was not clinically relevant. CIPN symptoms increased significantly with age among both men (for the sum score and all scales) and women (for the sum score, sensory and motor scale). Those with self-reported comorbidities reported significantly more CIPN symptoms, both statistically and clinically, than those without. For instance, they had a lower mean sum score (1.5) compared to those with asthma/chronic obstructive pulmonary disease (COPD; 6.9), diabetes (5.9), heart disease (8.0), hypertension (6.2), osteoarthritis (9.6) and rheumatoid arthritis (13.8). CONCLUSIONS: A low prevalence of neuropathy was observed in the normative population without cancer, although neuropathy did increase with age and the presence of comorbidities. These data (which is freely available) can aid in the interpretation of QLQ-CIPN20 scores and can help increase our understanding of the influence of age, sex and comorbid conditions on CIPN among cancer patients.
27489109 Chaperonin-containing T-complex Protein 1 Subunit ζ Serves as an Autoantigen Recognized b 2016 Sep 16 Human γδ T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of γδ T cells in autoimmune diseases is not clear. Few autoimmune disease-related antigens recognized by T cell receptor (TCR) γδ have been defined. In this study, we compared Vδ2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors. We found no difference in the frequency of Jδ gene fragment usage between these two groups. According to the dominant CDR3δ sequences in SLE patients, synthesized SL2 peptides specifically bound to human renal proximal tubular epithelial cell line HK-2; SL2-Vm, a mutant V sequence of SL2, did not bind. We identified the putative protein ligand chaperonin-containing T-complex protein 1 subunit ζ (CCT6A) using SL2 as a probe in HK-2 cell protein extracts by affinity chromatography and liquid chromatography-electrospray ionization-tandem mass spectrometry analysis. We found CCT6A expression on the surface of HK-2 cells. Cytotoxicity of only Vδ2 γδ T cells to HK-2 cells was blocked by anti-CCT6A antibody. Finally, we note that CCT6A concentration was significantly increased in plasma of SLE and rheumatoid arthritis patients. These data suggest that CCT6A is a novel autoantigen recognized by Vδ2 γδ T cells, which deepens our understanding of mechanisms in autoimmune diseases.
26522794 Trends in Opioid Prescriptions Among Part D Medicare Recipients From 2007 to 2012. 2016 Feb BACKGROUND: There is growing concern about potential overuse of, and toxicity from, opioid analgesics. No nationally representative study has examined inter-state variations in opioid use and impact of policy on opioid use among older adults. METHODS: We used national Medicare data from 2007-2012 to assess temporal and geographic trends in rates of opioid prescription and relationship to opioid toxicity and different state regulations in Part D Medicare recipients. We excluded those with a cancer diagnosis. Multilevel, multivariable regression analyses evaluated rates of prolonged prescriptions for schedule II, schedule III, and combination II/III opioid for each state, adjusting for patient characteristics. RESULTS: The percent of Part D recipients receiving prescriptions for combined schedule II/III opioid more than 90 days in a year increased from 4.62% in 2007 to 7.35% in 2012. Large variations existed among states in rates of opioid prescriptions: from 2.84% in New York to 10.93% in Utah, in 2012 data. The state variation was larger for schedule III than schedule II. Individual characteristics independently associated with prolonged use included older age, female gender, white race, low income, living in a lower-education area, and comorbidity of drug abuse, rheumatoid arthritis, and depression. Only state law regulating pain clinic was associated with reduction of schedule II opioid prescriptions. Prolonged opioid prescription use increased the odds of opioid overdose-related emergency room visits or hospitalization by 60%. CONCLUSIONS: Analyses of Medicare Part D data demonstrated a substantial growth in opioid prescriptions from 2007 to 2011 and large variation in opioid prescriptions across states.
25950682 Ashkenazi Jewish origin protects against formation of antibodies to infliximab and therapy 2015 May Infliximab is an anti-tumor necrosis factor (TNF) used for treatment of inflammatory bowel disease (IBD) as well as rheumatoid arthritis, psoriasis, and other inflammatory conditions. Antibodies to infliximab (ATI) develop in approximately 45% of infliximab-treated IBD patients and are correlated with loss of clinical response. Scarce data exist as to factors which predict infliximab immunogenicity.To investigate factors that may predict formation of antibodies to infliximab (ATI) and infliximab therapy failure an observational study of consecutive IBD patients treated with infliximab between 2009 and 2013 was performed. Trough levels of ATI were measured. Patients were monitored for disease activity using clinical activity indexes and were classified according to ATI formation and clinical response. All clinical and demographic parameters were analyzed for association with the designated outcomes.One hundred fifty-nine patients were included and 1505 sera were tested. On multivariate analysis, Jewish Ashkenazi ethnicity was protective against both development of ATI (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.17-0.7, P = 0.005) and treatment failure (OR 0.29, 95% CI 0.13-0.66, P = 0.003). Concomitant immunomodulator therapy was also negatively associated with immunogenicity and infliximab therapy failure (OR 0.31, 95% CI 0.15-0.65, P = 0.002; OR 0.42 95% CI 0.18-0.99, p = 0.04, respectively), whereas episodic therapy was positively associated with both outcomes (OR 4.2 95% CI 1.07-16.1, p = 0.04, OR 4.45 95% CI 1.2-16.6, p = 0.026 respectively). All other variables, including IBD type, gender, weight, age, smoking status and disease duration, were not predictive of ATI formation or clinical failure. However, among Crohn's disease patients, a non-stricturing non-penetrating phenotype was protective against ATI formation (OR 0.4, 95% CI 0.14-0.96, p = 0.04). P = 0.04, respectively), whereas episodic/interrupted therapy was positively associated with both outcomes (OR 4.2, 95% CI 1.07-16.1, P = 0.04; OR 4.45, 95% CI 1.2-16.6, P = 0.026, respectively). All other variables, including IBD type, sex, weight, age, smoking status, and disease duration, were not predictive of ATI formation or clinical failure. However, among Crohn disease patients, a nonstricturing nonpenetrating phenotype was protective against ATI formation (OR 0.4, 95% CI 0.14-0.96, P = 0.04).Jewish Ashkenazi ethnicity is protective of ATI formation and infliximab therapy failure. These findings suggest a role for ethnicity, and implicitly for genetic predisposition, in modulating the risk of anti-TNF immunogenicity and treatment unresponsiveness.
25733579 β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndr 2015 Apr 30 Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. β2-glycoprotein I (β2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact β2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize β2GPI/HLA class II complexes in the absence of phospholipids. In situ association between β2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against β2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that β2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis.
25498590 The chemokine receptor CCR5 plays a role in post-traumatic cartilage loss in mice, but doe 2015 Mar OBJECTIVE: C-C chemokine receptor type 5 (CCR5) has been implicated in rheumatoid arthritis and several inflammatory diseases, where its blockade resulted in reduced joint destruction. However, its role in modulating cartilage and bone changes in post-traumatic osteoarthritis (OA) has not yet been investigated. In this study, we investigated changes in articular cartilage, synovium and bone in a post-traumatic OA model using CCR5-deficient (CCR5(-/-)) mice. METHOD: Destabilization of the medial meniscus (DMM) was performed on the right knee of 10-week old CCR5(-/-) and C57BL/6J wild-type (WT) mice to induce post-traumatic OA. The contralateral left knee served as sham-operated control. Knee joints were analyzed at 4-, 8- and 12-weeks after surgery to evaluate cartilage degeneration and synovitis by histology, and bone changes via micro-CT. RESULTS: Our findings showed that CCR5(-/-) mice exhibited significantly less cartilage degeneration than WT mice at 8- and 12-weeks post-surgery. CCR5(-/-) mice showed some altered bone parameters 18- and 22-weeks of age, but body size and weight were not affected. The effect of CCR5-ablation was insignificant at all time points post-surgery for synovitis and for bone parameters such as bone volume/total volume, connectivity density index (CDI), structure model index (SMI), subchondral bone plate thickness, and trabecular bone number, thickness and spacing. CONCLUSION: These findings suggest that CCR5(-/-) mice developed less cartilage degeneration, which may indicate a potential protective role of CCR5-ablation in cartilage homeostasis. There were no differences in bone or synovial response to surgery suggesting that CCR5 functions primarily in cartilage during the development of post-traumatic OA.
27766695 Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α 2017 Apr Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFα) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid-refractory graft-vs-host disease and other immune-mediated conditions. Currently, five anti-TNFα agents are approved by the European Medicines Agency (EMA), including the monoclonal anti-TNF antibodies infliximab, adalimumab, golimumab and certolizumab pegol along with etanercept, a TNFα-receptor/IgG-Fc fusion protein. Theoretical considerations related to their mode of action and clinical observations suggest that opportunistic infectious complications should be seriously considered as possible adverse events of macromolecular immunosuppressants. The purpose of this review is to critically analyze the literature on invasive fungal infections (IFIs) occurring in association with TNFα inhibitors alone or in combination with other immunosuppressive agents, with a focus on pediatric patients, and to provide a framework of evaluating the risk for IFIs in this population.
27643385 RORγt antagonist suppresses M3 muscarinic acetylcholine receptor-induced Sjögren's syndr 2017 Feb We showed recently that M3 muscarinic acetylcholine receptor (M3R)-reactive CD3(+) T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid-related orphan receptor-gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R(-/-) ) mice immunized with murine M3R peptide mixture were inoculated into recombination-activating gene 1 knockout (Rag-1(-/-) ) mice (M3R(-/-) →Rag-1(-/-) ) with MIS. Immunized M3R(-/-) mice (pretransfer treatment) and M3R(-/-) →Rag-1(-/-) mice (post-transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide-stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme-linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4(+) T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)-γ and interleukin (IL)-17 production significantly compared with phosphate-buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4(+) T cells rather than CD11c(+) cells. Post-transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN-γ and IL-17 production (P < 0·05). In vitro, A213 suppressed IFN-γ and IL-17 production from M3R-stimulated splenocytes and CD4(+) T cells of immunized M3R(-/-) mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL-17 production from Th17 differentiated CD4(+) T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS-like sialadenitis through suppression of IL-17 and IFN-γ production by M3R-specific T cells.
26330346 Silicone implants and lymphoma: The role of inflammation. 2015 Dec The risk of hematological malignancies is mainly determined by genetic background, age, sex, race and ethnicity, geographic location, exposure to certain chemicals and radiation; along with the more recently proposed immune factors such as chronic inflammation, immunodeficiencies, autoimmunity, and infections. Paradigmatic examples include the development of lymphoma in Sjögren's syndrome and Hashimoto thyroiditis, gastric MALT lymphoma in Helicobacter pylori infection, or lymphomas associated with infections by Epstein-Barr virus, human herpes virus 8 (HHV 8) and leukemia/lymphoma virus 1 (HTLV-1). A growing number of reports indicates an increased risk of lymphoma, particularly of the anaplastic large cell (ALCL) type. The implants, specifically those used in the past, elicit chronic stimulation of the immune system against the prosthetic material. This is particularly the case in genetically susceptible hosts. We suggest that polyclonal activation may result in monoclonality in those at risk hosts, ultimately leading to lymphoma. We suggest that patients with an inflammatory response against silicone implants be monitored carefully.
27388111 Conjunctival lymphoma in right eye: Case report. 2017 Feb CASE REPORT: A 43-year-old woman presented with a salmon-coloured patch of 0.7mm diameter in the right eye that extended into the lower fornix in the bulbar and tarsal conjunctiva, with irregular edges, and highly vascularised. Incisional biopsy was performed, showing it to be a low-grade conjunctival non-Hodgkin B cell lymphoma (or a mucosa associated lymphoid tissue [MALT] lymphoma). DISCUSSION: The lesion remained stable for 24 months of follow-up, when a relapse of the condition occurred, producing an enlargement of the initial lesion. The definitive diagnosis is made by biopsy of the affected tissue and histopathologic study.
26518171 Comorbid autoimmune diseases in patients with vitiligo: A cross-sectional study. 2016 Feb BACKGROUND: Few large-scale studies have quantified the burden of comorbid autoimmune diseases in patients with vitiligo. OBJECTIVE: We sought to determine the prevalence of comorbid autoimmune diseases in patients with vitiligo. METHODS: We conducted a manual chart review on a cohort of 1873 patients with vitiligo seen between January 2002 and October 2012 at the Henry Ford Health System in Detroit, MI. Patients were excluded if they had fewer than 2 dermatology notes (N = 595) or if they were never given a diagnosis of vitiligo by a dermatologist (N = 180). RESULTS: Of 1098 patients with vitiligo, nearly 20% had at least 1 comorbid autoimmune disease. Compared with the general US population, we found a higher prevalence of thyroid disease (12.9%, P < .001), alopecia areata (3.8%, P < .001), inflammatory bowel disease (0.9%, P = .046), pernicious anemia (0.5%, P = .007), systemic lupus erythematosus (0.3%, P = .048), Guillain-Barre syndrome (0.3%, P < .001), discoid lupus (0.2%, P = .003), linear morphea (0.2%, P < .001), myasthenia gravis (0.2%, P = .002), and Sjögren syndrome (0.2%, P = .011). LIMITATIONS: The study lacked a control group. This was a single-institution study with possible selection bias, and thus the findings may not be representative of the overall population of patients with vitiligo. CONCLUSIONS: We observed a high prevalence of comorbid autoimmune diseases in patients with vitiligo and report several new associations.
27431346 Genetics in Sjögren Syndrome. 2016 Aug The genes associated with Sjögren syndrome (SS) can be assigned to the NF-kB pathway, the IFN signaling pathway, lymphocyte signaling, and antigen presentation. The frequencies of risk variants show they are common with modest genetic effects. The strongest genetic association outside the human leukocyte antigen region is in IRF5, a gene relevant in the IFN signaling pathway and for B cell differentiation. Although no association has been found with the NF-kB gene itself, associations in TNFAIP3 and TNIP1 (both genome-wide significant), VCAM1 and IRAK1BP (both suggestive), point to genetic explanations for dysregulation of the NF-kB pathway in SS.
25784251 Effect of Antimuscarinic Autoantibodies in Primary Sjögren's Syndrome. 2015 May The presence of functional autoantibodies against the muscarinic type 3 receptor (M3R) has been reported in primary Sjögren's syndrome (pSS). However, the pathogenic role of these autoantibodies in pSS development remains to be elucidated. In this experiment, we investigated a pathologic role of pSS autoantibodies (pSS IgG) associated with downregulation of the major histocompatibility complex I (MHC I) molecule with M3R through internalization. Anti-M3R autoantibodies in purified control and pSS IgG were detected using 4 synthesized cyclic M3R peptides by enzyme-linked immunosorbent assay. The binding reactivity of pSS IgG to M3R in situ was analyzed by a dual immunostaining method. Surface expression, interaction, and internalization of M3R with MHC I were analyzed by immunofluorescence confocal microscopy and biochemical assays. Synthetic cyclic peptides M3RP(205-221) and M3RP(520-527) showed significantly high reactivity with pSS IgG compared to the control IgG or the other 3 peptides (P < 0.05). Significantly high reactivity of pSS IgG to M3R in situ was observed. PSS IgG increased the interaction of membrane M3R with MHC I and induced their internalization in primary human submandibular gland cells. The pSS IgG-induced internalization of M3R with MHC I was significantly inhibited by the cholesterol-sequestering drug filipin. Our novel finding-namely, strong downregulation of the membrane MHC I with M3R through internalization of the cholesterol-rich microdomain associating with anti-M3R autoantibodies-could be an important mechanism contributing to the impaired salivation seen in pSS and linking secretory hypofunction to autoimmune pathogenesis.
25781195 High prevalence of gluten sensitivity in a cohort of patients with undifferentiated connec 2015 Mar OBJECTIVES: The aim of this study was to investigate if co-morbid conditions as hepatitis C virus infection and celiac disease may be associated to undifferentiated connective tissue disease. METHODS: We studied retrospectively and prospectively 52 patients with diagnosis of undifferentiated connective tissue disease, subdivided, according to Vaz criteria, in systemic lupus erythematosus, systemic sclerosis and Sjögren's syndrome-like subgroups. Serological markers of celiac disease as anti-gliadin, anti-endomysium and anti-tissue transglutaminase antibodies were investigated. An esophagogastroduodenoscopy with duodenal biopsy and histological examination was proposed to patients with positive celiac disease serology. In addition antibodies directed to hepatitis C virus and total IgA-antibodies were investigated. RESULTS: Six patients (11,5%) were positive for celiac disease serological tests although two of them were asymptomatic. Four patients underwent an esophagogastroduodenoscopy, showing total or subtotal villous atrophy at duodenal biopsies. Hepatitis C virus serology was negative in all patients and none had IgA deficiency. 83% of celiac patients showed a scleroderma-like phenotype. We observed a statistically higher incidence of autoimmune symptoms in patients with gluten sensitivity. Fatigue and myalgia regressed early after the beginning of gluten-free diet. CONCLUSIONS: In our cohort of patients the prevalence of celiac disease was higher than that reported in the general population. We believe that all patients with diagnosis of undifferentiated connective tissue disease, especially those with a systemic sclerosis-like presentation, should be investigated for celiac disease, even in absence of gastrointestinal symptoms. Gluten-free diet should be early recommended to all patients having undifferentiated connective tissue disease and gluten sensitivity.
25620976 Lupus risk variants in the PXK locus alter B-cell receptor internalization. 2014 Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3' UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10(-10), OR 0.81 (0.75-0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
31149462 Remitting seronegative symmetrical synovitis with pitting edema syndrome complicated with 2017 Jan Remitting seronegative symmetrical synovitis with pitting edema syndrome has been reported to be associated with malignant tumors. However, few cases occurring with lung cancer have been reported. We here report a case of remitting seronegative symmetrical synovitis with pitting edema syndrome complicated with lung cancer. A 77-year-old man presented with poly arthritis (both shoulders, knees, and hands), swelling of the hands, and an elevated C-reactive protein level. As the patient's rheumatoid factor was negative, he was diagnosed with remitting seronegative symmetrical synovitis with pitting edema syndrome. At the same time, computed tomography revealed a nodule suspicious of lung carcinoma in the right lower lobe. Right lower lobe lobectomy was performed, and the nodule was diagnosed as adenocarcinoma. Pathologically, pleural invasion and visceral pleural dissemination were detected, and the tumor was diagnosed as a primary lung carcinoma, p-T2aN0M1a, stage IV. During the preoperative interval, the remitting seronegative symmetrical synovitis with pitting edema syndrome had been successfully treated with prednisolone 20 mg/day, which was later reduced to 6 mg/day. Eighteen months after surgery, the patient's carcinoembryonic antigen levels increased, and the same symptoms recurred, this time more severely. We performed cranial magnetic resonance imaging and whole body positron emission tomography, but we did not detect any cancer recurrence. To treat the recurred remitting seronegative symmetrical synovitis with pitting edema syndrome, the patient has required not only prednisolone, but also azathioprine; however, the symptoms have not been controlled effectively. In our case, matrix metalloproteinase-3 levels were elevated, as shown in the tumor cells by immunohistochemistry. If higher matrix metalloproteinase-3 levels cause the symptoms, in our case, then remitting seronegative symmetrical synovitis syndrome might be considered a paraneoplastic syndrome. However, we could not conclusively determine if the subsequent reduction in matrix metalloproteinase-3 levels was the result of the surgery or the prednisolone treatment. Furthermore, based on the patient's progress following surgery, it is still not clear if the remitting seronegative symmetrical synovitis with pitting edema syndrome complicated with primary lung cancer in this case may be a paraneoplastic syndrome.