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ID PMID Title PublicationDate abstract
26509064 The incidence of tuberculosis in patients treated with certolizumab pegol across indicatio 2015 OBJECTIVES: We report the incidence of tuberculosis (TB) across certolizumab pegol (CZP) clinical trials in rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), before and after the introduction of stricter TB screening. METHODS: TB incidence rates (IRs) were assessed and stratified according to screening guidelines used at the time of CZP trials. Before 2007 (original trials), purified protein derivative (PPD) tuberculin skin test positivity varied according to local standards (induration ≥5 up to ≥20 mm). Since 2007, all CZP trial protocols have been amended, including trials spanning (intermediate) and initiated after 2007 (current), mandating that any patient with PPD≥5 mm receives treatment for latent TB infection (LTBI). All cases of suspected TB or PPD≥5 mm, in pooled data from 5402 CZP patients across all CZP trials up to 2012, underwent blinded central review by independent experts. RESULTS: 44 TB cases were confirmed in pooled CZP RA trials (IR 0.47/100PY, patient-years) with no cases in Japanese RA trials (J-RAPID, HIKARI). Single TB cases were confirmed in psoriasis and axSpA trials (RAPID-axSpA), and no cases in the PsA trial (RAPID-PsA). IR of TB was 0.51/100PY across original or intermediate RA trials and 0.18/100PY in current trials. The majority of TB cases in RA occurred in Eastern (IR 1.02/100PY) and Central Europe (IR 0.58/100PY). Of 242/370 PPD≥5 mm patients who received 9 months isoniazid (INH) treatment for latent TB infection (LTBI), none developed TB, versus 7.8% of 128 untreated PPD≥5 mm patients. CONCLUSIONS: Implementation of more stringent LTBI screening, plus treatment for LTBI, reduced the IR of TB, even when INH was administered after starting CZP therapy.
26246128 Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell acti 2015 Nov OBJECTIVE: B lymphoid kinase (BLK) is associated with rheumatoid arthritis (RA) and several other B cell-associated autoimmune disorders. BLK risk variants are consistently associated with reduced BLK expression, but the mechanisms by which reduced expression alters human B cell function to confer autoimmune disease susceptibility are unknown. This study was undertaken to characterize the BLK risk haplotype and to determine associated B cell functional phenotypes involved in autoimmunity. METHODS: The BLK risk haplotype association with RA (determined using whole-genome sequencing data) was confirmed in 2,526 RA cases and 2,134 controls. Peripheral blood mononuclear cells (PBMCs) from RA patients, healthy adults, and umbilical cord blood were used to study B cell functional phenotypes associated with the BLK risk genotype. Association of the BLK haplotype with B cell phenotypes was analyzed using cell culture and flow cytometry. RESULTS: Two insertion/deletions were found on the RA risk haplotype in BLK, and the reduction in BLK expression associated with the risk haplotype was confirmed in primary B lymphocytes. Carriers of the RA-associated haplotype had evidence of lower basal B cell receptor (BCR) signaling activity, yet their B cells were hyperactivatable, with enhanced up-regulation of CD86 after BCR crosslinking and greater T cell stimulatory capacity. The number of isotype-switched memory B cells was also significantly increased in subjects carrying the risk haplotype. CONCLUSION: A major mechanism underlying the BLK association with autoimmune disease involves lowered thresholds for BCR signaling, enhanced B cell-T cell interactions, and altered patterns of isotype switching.
29787158 IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases. 2015 A series of studies have revealed that IL-6 has pleiotropic activity in various cells and that its deregulated expression is responsible for the development of multiple autoimmune inflammatory diseases. A humanized antibody against the IL-6 receptor, tocilizumab, has exhibited outstanding therapeutic efficacy against rheumatoid arthritis, juvenile idiopathic arthritis, Castleman’s disease, and other autoimmune inflammatory diseases, leading to its clinical use for treatment of several diseases. These findings indicate that overproduction of IL-6 is responsible for the pathogenesis of autoimmune inflammatory diseases, in which an imbalance between Th17 cells and regulatory T cells and autoantibodies play central roles. Recent studies have suggested that IL-6 blockade therapy can rectify these underlying immunological abnormalities in autoimmunity. However, the causes of deregulated IL-6 production in these diseases remain unknown. A novel IL-6-regulating molecule, Arid5a, specifically stabilizes IL-6 mRNA and sustains its overproduction; thus, Arid5a plays an important role in promoting inflammation and autoimmune diseases. Indeed, in Arid5a-knockout mice, experimental autoimmune encephalomyelitis does not develop, and lipopolysaccharide stimulation does not induce elevated expression of IL-6. Arid5a can counteract the destabilizing effect of a regulatory RNase, Regnase-1, on IL-6 mRNA; Regnase-1 knockout mice spontaneously develop various fatal autoimmune diseases. Further analyses of these RNA-binding proteins as well as other regulatory molecules for IL-6 expression are expected to elucidate the molecular mechanisms underlying deregulated synthesis of IL-6, and facilitate investigations of the pathogenesis of specific diseases.
27861567 Age-Related Cataract Is Associated with Elevated Serum Immunoglobulin E Levels in the Sout 2016 BACKGROUND: Previous research has suggested that immunoglobulin E (IgE)-mediated events lead to several chronic diseases. We investigated the association between allergic conditions and age-related cataracts in the South Korean adult population. METHODS: A cross-sectional study was performed using data obtained from 1,170 participants aged 40 years or older who were enrolled in the Korean National Health and Nutrition Examination Survey 2010. Multivariable logistic regression was used to examine the relationship between age-related cataracts and allergic conditions, including total serum IgE and allergen-specific serum IgE levels, after adjustment for potential confounders (age, sex, alcohol consumption, smoking, sun exposure, blood pressure, plasma glucose and cholesterol levels, as well as histories of asthma, atopic dermatitis, and rheumatoid arthritis). RESULTS: After adjusting for potential confounders, the odds ratio (OR) for age-related cataract was greater in participants with higher total serum IgE levels (OR = 1.37; P = 0.044). In particular, increased IgE levels were significantly associated with nuclear cataract (OR = 1.42; P = 0.032). However, allergen-specific serum IgE levels did not differ significantly between groups. In the trend analysis, no significant relationship was observed between serum IgE and any type of age-related cataract. CONCLUSION: Increased total serum IgE level is independently associated with age-related cataracts after adjustment for confounding factors.
26606383 Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chroni 2015 Dec This review provides the reader with the up-to-date evidence-based basis for prescribing exercise as medicine in the treatment of 26 different diseases: psychiatric diseases (depression, anxiety, stress, schizophrenia); neurological diseases (dementia, Parkinson's disease, multiple sclerosis); metabolic diseases (obesity, hyperlipidemia, metabolic syndrome, polycystic ovarian syndrome, type 2 diabetes, type 1 diabetes); cardiovascular diseases (hypertension, coronary heart disease, heart failure, cerebral apoplexy, and claudication intermittent); pulmonary diseases (chronic obstructive pulmonary disease, asthma, cystic fibrosis); musculo-skeletal disorders (osteoarthritis, osteoporosis, back pain, rheumatoid arthritis); and cancer. The effect of exercise therapy on disease pathogenesis and symptoms are given and the possible mechanisms of action are discussed. We have interpreted the scientific literature and for each disease, we provide the reader with our best advice regarding the optimal type and dose for prescription of exercise.
26559805 Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modu 2016 Jan INTRODUCTION: TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying antirheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis and/or psoriatic arthritis, and may be administered off-label to treat disseminated granuloma annulare systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. AREAS COVERED: infliximab and adalimumab can induce the development of anti-infliximab (anti-IFX) and anti-adalimumab (anti-ADA) monoclonal antibodies (mAbs). In this review, we discuss the impact of anti-IFX and anti-ADA mAbs upon efficacy and safety of these biological agents. EXPERT OPINION: IgG/IgE neutralizing antibodies against infliximab and adalimumab decrease the possibility of achieving a minimal disease activity state or clinical remission, decrease drug survival, increase the need for doctors to prescribe a higher drug dosage and, finally, favor the occurrence of adverse events. Concomitant administration of DMARDs such as methotrexate or leflunomide prevents the development of neutralizing Abs against infliximab and adalimumab.
26135958 Roles of A20 in autoimmune diseases. 2016 Apr A20 (TNFAIP3), known to inhibit NF-κB function by deubiquitinating-specific NF-κB signaling molecules, has been found in many cell types of the immune system. Recent findings suggest that A20 is essential for the development and functional performance of dendritic cell, B cell, T cell and macrophage. A number of studies further demonstrate that these cells are crucial in the pathogenesis of autoimmune diseases, such as type 1 diabetes, systemic lupus erythematosus, inflammatory bowel disease, ankylosing arthritis, Sjögren's syndrome and rheumatoid arthritis. In this article, we focus on the recent advances on the roles of A20 in autoimmune diseases and discuss the therapeutic significance of these new findings.
25613732 Modeling EBV infection and pathogenesis in new-generation humanized mice. 2015 Jan 23 The development of highly immunodeficient mouse strains has allowed the reconstitution of functional human immune system components in mice. New-generation humanized mice generated in this manner have been extensively used for modeling viral infections that are exclusively human tropic. Epstein-Barr virus (EBV)-infected humanized mice reproduce cardinal features of EBV-associated B-cell lymphoproliferative disease and EBV-associated hemophagocytic lymphohistiocytosis (HLH). Erosive arthritis morphologically resembling rheumatoid arthritis (RA) has also been recapitulated in these mice. Low-dose EBV infection of humanized mice results in asymptomatic, persistent infection. Innate immune responses involving natural killer cells, EBV-specific adaptive T-cell responses restricted by human major histocompatibility and EBV-specific antibody responses are also elicited in humanized mice. EBV-associated T-/natural killer cell lymphoproliferative disease, by contrast, can be reproduced in a distinct mouse xenograft model. In this review, recent findings on the recapitulation of human EBV infection and pathogenesis in these mouse models, as well as their application to preclinical studies of experimental anti-EBV therapies, are described.
25488380 Sparing effect of hemiplegia on skin fibrosis and microvascular involvement: reports of tw 2015 Apr OBJECTIVES: The sparing effect of hemiplegia in rheumatic diseases has been described, but reports on systemic sclerosis (SSc)-spectrum disorders are unusual. SSc-spectrum disorders are complex diseases of unknown origin characterized by multisystem involvement, skin and organ fibrosis, microvascular alterations, and immunologic abnormalities. We describe two cases of patients with hemiplegia who developed Raynaud׳s phenomenon and skin fibrosis of the non-paretic limb. METHODS: Clinical, laboratory, and investigation findings of two cases with hemiplegia who developed scleroderma spectrum disorders of the non-paretic limb are presented. A review of the medical literature was performed in PubMed for all articles in English. RESULTS: A total of 46 reports from 1935 to 2012 were identified, especially on osteoarthritis and rheumatoid arthritis. Only two case reports on patients with SSc describe asymmetric SSc skin involvement and unilateral acro-osteolysis on x-ray images of the non-paretic limb. By contrast, we report the first description of capillaroscopic microvascular changes in patients with hemiplegia and asymmetric SSc skin involvement. CONCLUSIONS: Our cases point out the potential role of a "cross-talk" between the nervous system and the skin in SSc-spectrum disorders and suggest future directions for research in studies of pathogenesis.
25354654 Risk factors for fracture among current, persistent users of bisphosphonates. 2015 Feb SUMMARY: Bisphosphonate therapy reduces fracture risk but does not eliminate fracture occurrence. We determined the fracture incidence and risk factors for fractures among 14,674 bisphosphonate users in a community setting. Bisphosphonate users remained at risk of fracture, and additional measures to prevent fractures in these patients would be beneficial. INTRODUCTION: Bisphosphonate therapy reduces but does not eliminate fracture occurrence. The incidence of fracture and risk factors for fractures among persistent, current users of bisphosphonates in a community setting have not been well studied. METHODS: We conducted a retrospective cohort study of 14,674 bisphosphonate users in a health maintenance organization. Patients were followed until a 3-month gap in therapy, creating a pool of highly compliant [mean medication possession ratio (MPR) of 94%] current users. We used Cox proportional hazards models to identify risk factors for fractures among these persistent, current users. RESULTS: There were 867 fractures over the period of observation or 3.7 fractures per 100 users per year. Older patients who take multiple medications, have lower bone mineral density, have a history of prior fracture, and suffer from particular comorbidities (i.e., dementia, chronic kidney disease, and rheumatoid arthritis) are at higher risk of fracture while taking bisphosphonates. CONCLUSION: Persistent, current bisphosphonate users remain at risk of fracture, and additional measures to prevent fractures in these patients would be of benefit.
24807846 Sacroiliac joint involvement in systemic sclerosis. 2015 Jan AIM: One of the major problems for systemic sclerosis (SSc) patients is suggested to be articular involvement. Mostly involved joints in SSc were reported as wrist, carpometacarpal-interphalangeal, foot, knee, hip and shoulder; however, there has been little knowledge on the sacroiliac joint. Our aim was to evaluate sacroiliac joint involvement in SSc. METHODS: Fifty-seven SSc patients, 54 rheumatoid arthritis patients and 64 healthy subjects were included. Anteroposterior pelvic radiographs were obtained and graded twice by three blinded rheumatologists. One competent radiologist has re-evaluated the X-ray results. The ASAS (Assessment of Spondylo Arthritis International Society) scoring method was applied for grading sacroiliac involvement. Inflammatory back pain was also evaluated. Other clinical and laboratory data were collected as proposed by the European Study Group. RESULTS: In the SSc group sacroiliitis was found in 13 patients (23%) and was significantly different from RA patients (two patients, 4%), P = 0.003; and the healthy control group (one participant, 2%), P < 0.001. The frequency of inflammatory back pain in SSc patients with sacroiliitis (8/13 patients, 62%) was significantly higher in SSc patients without sacroiliitis (4/44 patients, 9%), P < 0.001. The SSc patients with sacroiliitis and with inflammatory back pain (8/57 patients, 14%) were regarded as axial spondyloarthritis overlap. Male gender, diffuse subtype, inflammatory back pain and high C-reactive protein levels (odds ratio: 1.069, 1.059, 1.059 and 3.698, respectively) were found to be the significant risk factors for sacroiliitis. CONCLUSION: We suggest that, sacroiliitis may be a concern to be considered in SSc practice.
26814615 Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by 2016 Jun Compelling evidence suggests that interleukin (IL)-17 and IL-17-producing cells play a pivotal role in the pathogenesis of primary Sjögren's syndrome (pSS). We investigated phenotypical and functional effects of the anti-CD20 antibody rituximab (RTX) on circulating and glandular IL-17-producing T cells in pSS. RTX is able to deplete glandular IL-17(+) CD3(+) CD4(-) CD8(-) double-negative (DN) and CD4(+) Th17 cells as well as circulating IL-17(+) DN T cells. A fraction of glandular and circulating IL-17(+) DN cells and CD4(+) T helper type 17 (Th17) cells co-expresses CD20 on the cell surface explaining, at least in part, such depletive capacity of RTX. The exposure to RTX does not rescue the in-vitro corticosteroid resistance of IL-17(+) DN T cells. Our results support further the therapeutic role in pSS of RTX that, despite its B cell specificity, appears able to also hamper IL-17-producing T cells in this disease.
26828975 Mobilization of lymphatic endothelial precursor cells and lymphatic neovascularization in 2016 Apr Although lymphatic neovascularization may be a key feature of chronic inflammation, it is almost unexplored in primary Sjögren's syndrome (pSS). A recent study revealed a pro-lymphangiogenic function of interleukin (IL)-17, a leading player in pSS pathogenesis. The aims of the study were to investigate lymphangiogenic mediators and lymphatic vasculature in pSS, as well as their possible association with IL-17. Circulating lymphatic endothelial precursor cells (LEPCs) and Th17 cells were enumerated in pSS patients and healthy donors. VEGF-C and IL-17 levels were assessed in paired serum samples. Lymphatic vasculature, VEGF-C/VEGF receptor (VEGFR)-3 and IL-17 were evaluated in pSS minor salivary glands (MSGs) and compared with normal and non-specific chronic sialadenitis (NSCS) MSGs. Circulating LEPCs were expanded in pSS and correlated with circulating Th17 cells, IL-17 and VEGF-C. In pSS MSGs, a newly formed lymphatic capillary network was found within periductal inflammatory infiltrates and the number of interlobular lymphatic vessels was significantly increased compared with normal and NSCS MSGs. Strong VEGF-C expression was detected in pSS ductal epithelial cells and periductal inflammatory cells. Numerous VEGFR-3(+) infiltrating mononuclear cells were exclusively observed in pSS MSGs. VEGFR-3 expression was strongly increased in lymphatic capillaries of pSS MSGs. IL-17(+) inflammatory cells were preferentially observed around lymphatic vessels in pSS MSGs. This study supports the notion that lymphvasculogenesis and lymphangiogenesis are active in pSS, thereby unmasking a novel aspect of disease pathogenesis. In addition, our results suggest another possible pathogenic role of IL-17 in pSS, further supporting its therapeutic targeting in this disease.
27880731 Smad4 in T cells plays a protective role in the development of autoimmune Sjögren's syndr 2016 Dec 6 We investigated the role of Smad4, a signaling molecule of the TGF-beta pathway, in T cells on the pathology of Sjögren's syndrome (SS) in nonobese diabetic (NOD) mice, an animal model of SS. T cell-specific Smad4-deleted (Smad4fl/fl,CD4-Cre; Smad4 tKO) NOD mice had accelerated development of SS compared with wild-type (Smad4+/+,CD4-Cre; WT) NOD mice, including increased lymphocyte infiltration into exocrine glands, decreased tear and saliva production, and increased levels of autoantibodies at 12 weeks of age. Activated/memory T cells and cytokine (IFN-γ, IL-17)-producing T cells were increased in Smad4 tKO NOD mice, however the proportion and function of regulatory T (Treg) cells were not different between Smad4 tKO and WT NOD mice. Effector T (Teff) cells from Smad4 tKO NOD mice were less sensitive than WT Teff cells to suppression by Treg cells. Th17 differentiation capability of Teff cells was similar between Smad4 tKO and WT NOD mice, but IL-17 expression was increased under inducible Treg skewing conditions in T cells from Smad4 tKO NOD mice. Our results demonstrate that disruption of the Smad4 pathway in T cells of NOD mice increases Teff cell activation resulting in upregulation of Th17 cells, indicating that Smad4 in T cells has a protective role in the development of SS in NOD mice.
26463157 Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical applicat 2016 Feb Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues - cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p < 0.001, respectively). This improved corneal barrier integrity upon adhesion molecule blockade was consistent with significantly reduced corneal expression of pro-inflammatory IL-1β compared to vehicle treated groups (p < 0.05 for both treatments). Significant improvement in goblet cell density was also noted in mice treated with 0.1% dexamethasone and GW559090 (p < 0.05 for both). We conclude that similar to topical dexamethasone, topically administered GW559090 successfully improved corneal barrier integrity and inflammation in an established ocular surface disease associated with Sjögren's syndrome.
27734292 Refractory necrotizing scleritis successfully treated with adalimumab. 2016 Dec Necrotizing scleritis is the most severe and destructive form of scleritis with vision-threatening sequelae. It is divided into with inflammation and without inflammation (scleromalacia perforans). Adalimumab is a tumour necrosis factor (TNF)-inhibiting anti-inflammatory medication licensed for the treatment of rheumatoid and psoriatic arthritis, ankylosing spondylitis and inflammatory bowel disease (in the USA). We report two cases of necrotizing scleritis successfully treated with adalimumab.
25488989 Ig gene analysis reveals altered selective pressures on Ig-producing cells in parotid glan 2015 Jan 15 In this study, we sought to understand the selective pressures shaping the Ig-producing cell repertoire in the parotid glands of primary Sjögren's syndrome (pSS) patients before and after rituximab treatment (RTX). In particular, we evaluated the role of potential N-glycosylation motifs acquired by somatic hypermutation (ac-Nglycs) within Ig H chain V region (IGHV) genes as alternative selective pressures for B cells in pSS. Five pSS patients received RTX. Sequential parotid salivary gland biopsies were taken before RTX, at 12 wk and at 36-52 wk after treatment. Parotid biopsies from four non-pSS patients served as controls. Sequence analysis was carried out on the IgA and IgG RNA transcripts expressing IGHV3 genes in all parotid biopsies. Both IgG and IgA sequences from pSS patients exhibited no evidence for positive Ag-driven selection pressure in their CDRs in contrast to non-pSS controls. The prevalence of IgG sequences with ac-Nglycs was significantly higher in pSS patients than in non-pSS controls. Selection pressures shaping the IgG and IgA repertoire within pSS patients' parotid glands are distinct from those in non-pSS controls, with very little evidence for positive (auto)antigen selection. The higher prevalence of ac-Nglycs on pSS-IgG compared with non-pSS IgG indicates that ac-Nglycs could be an alternative form of selection pressure. We speculate that B cell hyperproliferation within parotid glands of pSS patients may result from Ag-independent interactions such as that between glycosylated B cell receptors and lectins within the microenvironment rather than (auto)antigen-specific stimulation. Our study brings a new perspective into research on pSS.
25726719 Action of anti-M₃muscarinic acetylcholine receptor IgG of primary Sjögren's syndrome on 2015 Nov BACKGROUND: We demonstrate that serum immunoglobulin G (IgG) directed against glandular M3 muscarinic acetylcholine receptors (M₃mAChR) and pilocarpine triggers the increment of superoxide dismutase (SOD) and catalase (CAT) and the production of nitric oxide (NO) and prostaglandin E₂(PGE₂). METHODS: Enzyme-linked immunosorbent assay (ELISA) was performed in the presence of the human M₂mAChR synthetic peptide as antigen to detect in serum of pSS patients the autoantibodies. Further, SOD and CAT specific activity and NO were determined chemically in the presence of anti-M₃mAChR IgG and pilocarpine. The level of PGE₂generation in the presence of autoantibody and pilocarpine was determined by ELISA. RESULTS: An association between anti-M₂mAChR autoantibodies and pilocarpine given the increment of the specific activity of SOD and CAT in the serum of pSS patients and in the rat submandibular gland was observed. As a result of this action, M₃synthetic peptide and atropine abrogated the stimulatory action. The L-type calcium channel, calcium/calmodulin complex and COX-2 inhibitors selectively blocked the increment of the specific activity of SOD and CAT in the rat submandibular gland. An increased production of NO and PGE₂by the cholinergic autoantibody and pilocarpine was also detected. CONCLUSION: On the basis of these results, the increment of the specific activity of SOD and CAT in pSS patients as compared to control healthy individuals may be seen as a defensive reaction to the increment of the amount of ROS, which becoming uncontrollable, leads to irreversible cellular and tissue damage.
25889621 A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoade 2015 Feb 21 BACKGROUND: IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease, is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in glandular tissues. Recently, several studies reported both malignant lymphoma developed on the background of IgG4-associated conditions and IgG4-producing malignant lymphoma (non-IgG4-related disease). CASE PRESENTATION: We report on the case of a 70-year-old man who was strongly suspected IgG4-DS because of high serum IgG4 concentration (215 mg/dl) and bilateral swelling of parotid and submandibular glands. Biopsies of cervical lymph node and a portion of submandibular gland were performed. These histopathological findings subsequently confirmed a diagnosis of marginal zone B cell lymphoma. CONCLUSION: Differential diagnosis of IgG4-DS is necessary from other disorders, including Sjögren's syndrome, sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, and cancer. We suggest that biopsy of swollen lesions is important for a definitive diagnosis of IgG4-DS and discuss the mechanism of development in this case.
25845745 Endoplasmic reticulum stress causes autophagy and apoptosis leading to cellular redistribu 2015 Aug The aim of this study was to examine the levels of endoplasmic reticulum (ER) stress in minor salivary glands, to investigate the interplay between ER stress-induced autophagy and apoptosis in human salivary gland (HSG) cells and to test the effect of ER stress-induced apoptosis on the cellular redistribution of the two major Sjögren's syndrome (SS) autoantigens Ro/Sjögren's syndrome-related antigen A (SSA) and La/Sjögren's syndrome-related antigen B (SSB). Minor salivary gland biopsies from SS patients and sicca controls were examined by immunohistochemistry for the expression of 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/BiP) as an indicator of unfolded protein response (UPR). HSG cells were treated with thapsigargin (TG) and cell viability, autophagy and apoptosis were assessed. Immunoblot was applied to detect the conversion of LC3I to LC3II and the protein levels of GRP78/BiP and X-box binding protein-1 (XBP-1). Apoptosis was evaluated by a single-stranded DNA enzyme-linked immunosorbent assay (ELISA). Ro/SSA and La/SSB localization was visualized using immunofluorescence. GRP78/BiP was expressed by acinar and ductal epithelial cells in salivary glands of patients and sicca controls. TG treatment induced autophagy, as indicated by enhanced protein expression of LC3II. The protein levels of UPR marker XBP-1 were increased after TG treatment, while GRP78/BiP levels were decreased. TG treatment resulted in induction of HSG apoptosis. Ro/SSA and La/SSB autoantigens were localized predominantly to the cytoplasm in resting cells, while they were redistributed to cell membrane and blebs in the apoptotic cells. In conclusion, ER stress is activated in minor salivary gland epithelial cells from SS patients and controls. ER stress-induced apoptosis in HSG cells leads to cell surface and apoptotic blebs relocalization of Ro/SSA and La/SSB autoantigens.