Onset Of Autoimmune Diseases Research Articles

Hypothyroidism incidence in and around pregnancy: a Danish nationwide study.

Immunological changes in and after a pregnancy may influence the onset of autoimmune diseases. An increased incidence of hyperthyroidism has been observed both in early pregnancy and postpartum, but it remains to be studied if the incidence of hypothyroidism varies in a similar way. Population-based cohort study using Danish nationwide registers. All women who gave birth to a singleton live-born child in Denmark from 1999 to 2008 (n = 403 958) were identified, and data on hospital diagnosis of hypothyroidism and redeemed prescriptions of thyroid hormone were extracted. The overall incidence rate (IR) of hypothyroidism during 1997-2010 and the IR in three-month intervals before, during and after the woman's first pregnancy in the study period were calculated and compared with the IR of hyperthyroidism. Altogether 5220 women were identified with onset of hypothyroidism from 1997 to 2010 (overall IR 92.3/100 000/year) and 1572 women developed hypothyroidism in the period from 2 years before to 2 years after birth of the first child in the study period. The incidence of hypothyroidism decreased during the pregnancy (incidence rate ratio (IRR) vs overall IR in the rest of the study period: first trimester: 0.89 (95% CI: 0.66-1.19), second trimester: 0.71 (0.52-0.97), third trimester: 0.29 (0.19-0.45)) and increased after birth with the highest level at 4-6 months postpartum (IRR 3.62 (2.85-4.60)). These are the first population-based data on the incidence of hypothyroidism in and around pregnancy. The incidence declined during pregnancy followed by a sharp increase postpartum. Notably, hypothyroidism as opposed to hyperthyroidism showed no early pregnancy increase.

Complex relation of HLA-DRB1*1501 , age at menarche, and age at multiple sclerosis onset

Objective:To examine the relationship between 2 markers of early multiple sclerosis (MS) onset, 1 genetic (HLA-DRB1*1501) and 1 experiential (early menarche), in 2 cohorts.Methods:We included 540 white women with MS or clinically isolated syndrome (N = 156 with genetic data available) and 1,390 white women without MS but with a first-degree relative with MS (Genes and Environment in Multiple Sclerosis [GEMS]). Age at menarche, HLA-DRB1*1501 status, and age at MS onset were analyzed.Results:In both cohorts, participants with at least 1 HLA-DRB1*1501 allele had a later age at menarche than did participants with no risk alleles (MS: mean difference = 0.49, 95% confidence interval [CI] = [0.03–0.95], p = 0.036; GEMS: mean difference = 0.159, 95% CI = [0.012–0.305], p = 0.034). This association remained after we adjusted for body mass index at age 18 (available in GEMS) and for other MS risk alleles, as well as a single nucleotide polymorphism near the HLA-A region previously associated with age of menarche (available in MS cohort). Confirming previously reported associations, in our MS cohort, every year decrease in age at menarche was associated with a 0.65-year earlier MS onset (95% CI = [0.07–1.22], p = 0.027, N = 540). Earlier MS onset was also found in individuals with at least 1 HLA-DRB1*1501 risk allele (mean difference = −3.40 years, 95% CI = [−6.42 to −0.37], p = 0.028, N = 156).Conclusions:In 2 cohorts, a genetic marker for earlier MS onset (HLA-DRB1*1501) was inversely related to earlier menarche, an experiential marker for earlier symptom onset. This finding warrants broader investigations into the association between the HLA region and hormonal regulation in determining the onset of autoimmune disease.

Risk of new onset autoimmune disease in 9- to 25-year-old women exposed to human papillomavirus-16/18 AS04-adjuvanted vaccine in the United Kingdom

ABSTRACTTo assess the risk of autoimmune disease (AD) in 9–25 year-old women within 1 year after the first AS04-HPV-16/18vaccine dose, a retrospective, observational database cohort study was conducted using CPRD GOLD. From CPRD GOLD 4 cohorts (65,000 subjects each) were retrieved: 1 exposed female cohort (received ≥1 AS04-HPV-16/18 vaccine dose between Sep2008–Aug2010) and 3 unexposed cohorts: historical female (Sep2005–Aug2007), concurrent male, and historical male. Co-primary endpoints were confirmed neuroinflammatory/ophthalmic AD and other AD, secondary endpoints were confirmed individual AD. Risk of new onset of AD was compared between cohorts (reference: historical cohort) using Poisson regression. The main analysis using confirmed cases showed no neuroinflammatory/ophthalmic AD cases in the female exposed cohort. Incidence rate ratio (IRR) (95% CI) of other AD was 1.41 (0.86 to 2.31) in female and 1.77 (0.94 to 3.35) in male cohorts when compared to the female and male historical cohort, respectively. Secondary endpoints were evaluated for diseases with >10 cases, which were Crohn's disease (IRR: 1.21 [0.37 to 3.95] for female and 4.22 [0.47 to 38.02] for male cohorts), autoimmune thyroiditis (IRR: 3.75 [1.25 to 11.31] for female and no confirmed cases for male cohorts) and type 1 diabetes (IRR: 0.30 [0.11 to 0.83] for female and 2.46 [1.08 to 5.60] for male cohorts). Analysis using confirmed and non-confirmed cases showed similar results, except for autoimmune thyroiditis in females, IRR: 1.45 (0.79 to 2.64). There was no evidence of an increased risk of AD in women aged 9 to 25 years after AS04-HPV-16/18 vaccination.

What's LPS Got to Do with It? A Role for Gut LPS Variants in Driving Autoimmune and Allergic Disease.

The bacterial communities that live in and on our bodies have a profound influence on our health. In a new paper in Cell, Vatanen etal. (2016) report that the composition of the early-life gut microbiome, particularly those species producing lipopolysaccharide, influences the onset of autoimmune and allergic disease.

Pregnancy and autoimmune connective tissue diseases.

Autoimmune connective tissue diseases predominantly affect women and often occur during the reproductive years. Thus, specialized issues in pregnancy planning and management are commonly encountered in this patient population. This chapter provides a current overview of pregnancy as a risk factor for onset of autoimmune disease, considerations related to the course of pregnancy in several autoimmune connective tissue diseases, and disease management and medication issues before pregnancy, during pregnancy, and in the postpartum period. A major theme that has emerged across these inflammatory diseases is that active maternal disease during pregnancy is associated with adverse pregnancy outcomes, and that maternal and fetal health can be optimized when conception is planned during times of inactive disease and through maintaining treatment regimens compatible with pregnancy.

Immunomodulation By Subchronic Low Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Experimental Autoimmune Encephalomyelitis in the Absence of Pertussis Toxin.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder, characterized by demyelination of neurons in the central nervous system. To investigate the pathogenicity of various T cell types in MS, especially IFN-γ- or IL-17-producing CD4(+ )cells (TH1 or TH17 cells, respectively), the mouse model, experimental autoimmune encephalomyelitis (EAE), is commonly used. One method by which EAE is induced is immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (MOG35-55) followed by subsequent injections of pertussis toxin (PTX) as an adjuvant. We have an interest in the mechanisms by which EAE occurs in the absence of PTX because it induces a milder disease state more consistent with autoimmune disease onset and PTX inactivates Gi/o protein-coupled receptors, many of which contribute to immune homeostasis. Another receptor that plays a role in immune homeostasis is the aryl hydrocarbon receptor (AHR). In fact, the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to attenuate EAE pathogenesis by affecting CD4(+ )T and regulatory T (Treg) cells in an AHR-dependent manner. However, many of these studies have been conducted with an acute high dose TCDD. Thus, the goal of this work was to investigate the modulation of MOG-specific immune responses with subchronic low dose TCDD (0.1-1.0 μg/kg/d for 12 days) in EAE without PTX. The results demonstrate that subchronic, low dose exposure of TCDD attenuates the immune responses in EAE development in the absence of PTX, which is due in part to suppression of MOG-specific IL-17A and IFN-γ responses.

New-Onset Sarcoidosis After Remission of Cushing's Syndrome.

Exposure to high levels of endogenous or exogenous glucocorticoids suppresses the inflammatory response genes. Excessive endogenous hypercortisolism may mask the active inflammatory diseases. Rebound immune modulation may occur after Cushing's syndrome (CS) remission, leading to the new onset of autoimmune diseases. Here, we report a 27-year-old female patient who was recently diagnosed with sarcoidosis after remission of CS. Normal thorax imaging showed that the patient was free of disease during the course of CS and without any symptoms of sarcoidosis. After complete remission of CS, she was diagnosed with sarcoidosis based on clinical and radiological evidence. Excessive hypercortisolism may suppress the active inflammatory stage of sarcoidosis. However, the disease became apparent after the reduction of cortisol levels following the treatment of CS.

Rheumatic manifestations of hepatitis C virus chronic infection: Indications for a correct diagnosis.

Hepatitis C virus (HCV) is a hepato- and lymphotropic agent that is able to induce several autoimmune rheumatic disorders: vasculitis, sicca syndrome, arthralgias/arthritis and fibromyalgia. The severity of clinical manifestations is variable and sometimes life-threatening. HCV infection can mimic many primitive rheumatic diseases, therefore, it is mandatory to distinguish HCV-related manifestations from primitive ones because the prognosis and therapeutic strategies can be fairly dissimilar. The new direct-acting antivirals drugs can help to avoid the well-known risks of worsening or new onset of autoimmune diseases during the traditional interferon-based therapies.

The Role of Regulatory T-cells in Antitumor Immune Response

Regulatory T-lymphocytes (Treg) are essential for regulation of immune homeostasis and prevention of autoimmune disease development. Regulatory T-cells prevent the onset of autoimmune diseases; they keep immune homeostasis and modulate immune response during infection. Their activity is precisely controlled. Regulatory T-cells belong to one group of immune cells, which can support tumor survival and growth. They realize their function through inhibition of effector T-cells and by regulation of tumor microenvironment through production of various soluble factors. Many publications have proven that the amount of Treg cells is elevated in both solid tumors and in hematologic malignancies. Nevertheless, little is known about mechanisms, which allow increase and maintenance of elevated Treg cells in cancer patients. In this review, we will focus, among others, on the description of function and phenotype of Treg cells, their modulation of humoral immune response and interaction with cancer stem cells. Current development of modern tumor immunotherapy allows new possibilities of influencing Treg cells function.

Récidive de sarcoïdose cutanée lors du syndrome de restauration immunitaire chez une patiente infectée par le VIH

Association of sarcoidosis and HIV can occur in the context of immune reconstitution syndrome (IRS) after initiation of antiretroviral therapy (ART). Herein we report a case of cutaneous sarcoidosis in remission in an HIV-infected patient but relapsing during IRS associated with initiation of ART. A 33-year-old female HIV-infected patient from Cameroon was treated with triple therapy with good efficacy. The patient previously had a small nodular lesion on her left cheek which disappeared spontaneously 2 months before the diagnosis of HIV infection. Three months after initiation of triple ART, the patient consulted again for recurrence of the lesion, which had gradually increased in size. Clinical examination revealed a purplish-red nodular plaque of lupoid appearance under vitropression, located between the inner corner of the eye, the nasal wing and the left cheek. A skin biopsy revealed giant-cell epithelioid dermal granulomas without caseous necrosis. Blood angiotensin-converting enzyme levels were elevated and intradermal reaction to tuberculin was negative. A diagnosis was made of cutaneous sarcoidosis. The patient was treated with chloroquine 200mg/day for 3 months, resulting in total subsidence of the lesions. No recurrence was observed at 1 year. Introduction of ART has changed the dermatological aspect of HIV infection. In addition to specific dermatological signs specific to HIV and to immunosuppression, there are the cutaneous adverse effects of antiretroviral drugs and skin disorders indicating reconstituted immunity during IRS. Schematically, three forms of IRS may be distinguished: the paradoxical form, the infectious form, and the inflammatory form. The latter corresponds to the onset or exacerbation of inflammatory conditions or autoimmune diseases after the start of ART. Thirty cases of association between sarcoidosis and HIV have been described, of which two-thirds occurred during IRS. The central role of CD4 in sarcoidosis explains its occurrence in HIV patients during reconstitution of the CD4 count. In HIV-infected patients treated with anti-retroviral treatment, certain skin diseases such as sarcoidosis may be related to IRS.

Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CDGEMM) Study Design: Approach to the Future of Personalized Prevention of Celiac Disease.

In the past it was believed that genetic predisposition and exposure to gluten were necessary and sufficient to develop celiac disease (CD). Recent studies however suggest that loss of gluten tolerance can occur at any time in life as a consequence of other environmental stimuli. Many environmental factors known to influence the composition of the intestinal microbiota are also suggested to play a role in the development of CD. These include birthing delivery mode, infant feeding, and antibiotic use. To date no large-scale longitudinal studies have defined if and how gut microbiota composition and metabolomic profiles may influence the loss of gluten tolerance and subsequent onset of CD in genetically-susceptible individuals. Here we describe a prospective, multicenter, longitudinal study of infants at risk for CD which will employ a blend of basic and applied studies to yield fundamental insights into the role of the gut microbiome as an additional factor that may play a key role in early steps involved in the onset of autoimmune disease.

Autoimmune rheumatic disease and sleep: a review.

Sleep has an important role to play in the human immune system and it is critical in the restoration and maintenance of homeostasis. Sleep deprivation and disorders may have a profound impact on health, well being and the ability to resist infection. Autoimmune rheumatic diseases are multisystem disorders that involve complicated hormonal and immunological pathophysiology. Previous studies have suggested that sleep deprivation may lead to immunological disturbance in experimental mouse models. Sleep disorders may trigger immune system abnormalities inducing autoantibody production, possibly leading to the development of autoimmune disease such as systemic lupus erythematosus, scleroderma or rheumatoid arthritis. Indeed, in experimental models, it has been suggested that sleep deprivation may induce the onset of autoimmune disease. Chronic deprivation of sleep is common in modern society and has been seen in various autoimmune inflammatory rheumatic diseases. We have reviewed various aspects of sleep deprivation and sleep apnoea syndrome, and their effects on the immune system and their relevance to autoimmune diseases. We hope that these data will encourage greater awareness of the role that improved sleep hygiene may play in the management of these rheumatic diseases.

Genetic sharing and heritability of paediatric age of onset autoimmune diseases.

Autoimmune diseases (AIDs) are polygenic diseases affecting 7–10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h2). SNP-h2 estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h2 in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Central sympathetic inhibition ameliorates joint pathology and shifts cytokines profiles in spleen but not joint draining lymph nodes in a model of rheumatoid arthritis

In 80% of patients, major life stressors precede onset of autoimmune diseases, including rheumatoid arthritis (RA) linking stress pathway activation to disease onset. We examined the contribution of high sympathetic nervous system activity to RA onset using the adjuvant-induced (AA) arthritis model in Lewis rats. Rats were immunized with complete Freund’s adjuvant to induce AA. From day (D)12 (disease onset) through D28, rats were treated with vehicle or 2 mg/kg/day moxonidine, an imidazoline receptor-1 agonist that acts centrally to reduce SNS tone. Disease outcome was assessed using dorsoplantar widths and X-ray analysis. Cytokines critical for inflammation and CD4+ Th cell development (interleukin (IL)-1 β , IL-10, tumor necrosis factor (TNF)- α , IL-6, IL-2, IL-4, IFN- γ , and tumor growth factor (TGF)- β ) were assessed in spleen, draining lymph node (DLN) and peripheral blood mononuclear cells (PBMCs) by enzyme-linked immunoassays. Treatment with moxonidine dramatically prevented hind foot inflammation and joint destruction in AA compared with vehicle treatment. In DLN cells, moxonidine treatment had no effect on cytokine production. In contrast, moxonidine treatment significantly reduced IL-1 β , IL-2, IL-4 and IFN- γ in PBMCs. Drug treatment decreased splenocyte production of TGF- β and IFN- γ by ∼ 50% and ∼ 30%, respectively. Lowering SNS tone effectively reduced clinical signs of disease and altered production of cytokines involved in inflammation and shifting the balance between auto-reactive CD4+Th cells and T regulatory cells in directions expected to limit disease activity.

Foxo1 Is a T Cell-Intrinsic Inhibitor of the RORγt-Th17 Program.

An uncontrolled exaggerated Th17 response can drive the onset of autoimmune and inflammatory diseases. In this study, we show that, in T cells, Foxo1 is a negative regulator of the Th17 program. Using mixed bone marrow chimeras and Foxo1-deficient mice, we demonstrate that this control is effective in vivo, as well as in vitro during differentiation assays of naive T cells with specific inhibitor of Foxo1 or inhibitors of the PI3K/Akt pathway acting upstream of Foxo1. Consistently, expressing this transcription factor in T cells strongly decreases Th17 generation in vitro as well as transcription of both IL-17A and IL-23R RORγt-target genes. Finally, at the molecular level, we demonstrate that Foxo1 forms a complex with RORγt via its DNA binding domain to inhibit RORγt activity. We conclude that Foxo1 is a direct antagonist of the RORγt-Th17 program acting in a T cell-intrinsic manner.

The microbiome and autoimmune disease: Report from a Noel R. Rose Colloquium

Although the mechanisms by which the human microbiome influences the onset and progression of autoimmune diseases remain to be determined, established animal models of autoimmune diseases indicate that local and systemic bidirectional interactions with the microbiome play a signaling or promoting role through the immune system. Whether alterations in the microbiome are a pathogenic cause or simply an effect of inflammation and autoimmune disease remains an essential question to be addressed in disease-specific research, as well as whether particular conditions of the microbiome promote health or promote disease. Future research in this area needs to account for sex differences in microbiome composition because autoimmune diseases disproportionately affect women. Probiotic and other treatments that manipulate assemblage of the microbiome may offer methods of preventing or mitigating the effects of autoimmune disease.

Intolerant bodies: a short history of autoimmunity

Autoimmune diseases, which affect 5 to 10 percent of the population, are as unpredictable in their course as they are paradoxical in their cause. They produce persistent suffering as they follow a drawn-out, often lifelong, pattern of remission and recurrence. Multiple sclerosis, lupus, rheumatoid arthritis, and type 1 diabetes - the diseases considered in this book - are but a handful of the conditions that can develop when the immune system goes awry. Intolerant Bodies is a unique collaboration between Ian Mackay, one of the prominent founders of clinical immunology, and Warwick Anderson, a leading historian of twentieth-century biomedical science. The authors narrate the changing scientific understanding of the cause of autoimmunity and explore the significance of having a disease in which one's body turns on itself. The book unfolds as a biography of a relatively new concept of pathogenesis, one that was accepted only in the 1950s. In their description of the onset, symptoms, and course of autoimmune diseases, Anderson and Mackay quote from the writings of Charles Dickens, Edgar Allan Poe, Joseph Heller, Flannery O'Connor, and other famous people who commented on or grappled with autoimmune disease. The authors also assess the work of the dedicated researchers and physicians who have struggled to understand the mysteries of autoimmunity. Connecting laboratory research, clinical medicine, social theory, and lived experience, Intolerant Bodies reveals how doctors and patients have come to terms, often reluctantly, with this novel and puzzling mechanism of disease causation.

Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways.

Innate immunity, which is the first line of host defense against invading microbial pathogens in multicellular organisms, occurs through germline-encoded pattern-recognition receptors. The Toll-like receptor/Interleukin (IL)-1 receptor (TLR/IL-1R) superfamily comprises proteins that contain the phylogenetically conserved Toll/IL-1 receptor (TIR) domain, which is responsible for the propagation of downstream signaling through recruitment of TIR domain containing cytosolic adaptor proteins such as MyD88, TIRAP/MAL, TRIF, TRAM and SARM. These interactions activate transcription factors that regulate the expression of various proinflammatory cytokines (IL-1, IL-6, IL-8 and TNF-α) and chemokines. Activation of the TLR/IL-1R signaling pathway promotes the onset of inflammatory diseases, autoimmune diseases and cancer; therefore, this pathway can be used for the development of therapeutic strategies against these types of pathogenesis. In this review paper, we illustrate the role of the TIR-TIR domain interaction with the TLR/IL-1R signaling pathway in inflammation and apoptosis and recent therapeutic drugs targeted to inhibit the downstream signaling cascade for treatment of inflammatory diseases and cancer.

Vitiligo and Associated Autoimmune Diseases in Zagazig University Hospitlas, Sharkia Governate, Egypt

Although the pathogenesis of vitiligo is not yet fully understood, the autoimmune hypothesis is the most commonly accepted. The aim of this study was to study the frequency of autoimmune diseases in a group of Egyptian patients with vitiligo compared with control. This study involved 50 Egyptian patients with vitiligo and 50 healthy subjects as control group. Patients should be made aware of signs and symptoms that suggest the onset of thyroid dysfunction, diabetes, or other autoimmune disease. If signs or symptoms occur, appropriate tests were performed. Screenings for thyroid disease were through evaluation of thyroid antibodies (anti-thyroidperoxidase, anti-thyroglobulin antibody), serum thyrotropin (TSH), free tri-iodothyronine (T3) and free thyroxine (T4). Screening for diabetes was done with fasting blood glucose or glycosylated hemoglobin testing. A complete blood count with indices helped rule out anemia. Antinuclear antibody screening was also done. Screening for celiac disease, IgA anti-glutaminase antibody was measured. The frequencies of autoimmune disorders were significantly elevated in vitiligo patients: vitiligo itself, autoimmune thyroid disease (particularly hypothyroidism), alopecia areata, pernicious anaemia, adult-onset type 1 diabetes mellitus, psoriasis and probably inflammatory bowel disease. These associations indicate that vitiligo shares common genetic aetiologic links with these other autoimmune disorders.

Myasthenia Gravis and Its Comorbidities

Background: Myasthenia gravis (MG) is an unpredicted neurologic disorder that may cause death; previous reports have failed to find a prognostic marker for the disease. Aim: To determine the impact of comorbidities in patients with Myasthenia gravis. Material and Methods: From January of 2002 to February of 2008 a database was created for patients with Myasthenia gravis (MG). The following variables were studied: age at onset of MG, gender, diabetes mellitus, dyslipidemia, arterial hypertension, dysthyroidism, autoimmune disease, thymectomy procedure and histopathologic result, myasthenic crisis, emergency room visits due to weakness, use and maximum dose of pyridostigmine, prednisone and azathioprine. Results: In a total of 253 patients, we found comorbidities in 73%. The most frequent associated disorders were dyslipidemia, thyroid disease, diabetes, hypertension and other autoimmune conditions. Patients with MG and thymoma, diabetes, dyslipidemia, dysthyroidism and/or hypertension had higher rates of ER visits, myasthenic crises, and required higher doses of drugs. Conclusions: This study demonstrates that comorbidities are frequent in patients with MG (73%) and that they might worsen the prognosis of MG.