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Phosphodiesterase inhibitor pentoxifylline: An antiinflammatory/immunomodulatory drug potentially useful in some rheumatic diseases
Phosphodiesterase inhibitor pentoxifylline: an antiinflammatory/immunomodulatory drug potentially useful in some rheumatic diseases: Adjuvants, Immunologic/therapeutic use, Animals, Anti-Inflammatory Agents, Non-Steroidal/therapeutic use, Arthritis, Rheumatoid/drug therapy in Humans
Primary immunodeficiency and autoimmunity: A comprehensive review
The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented. © 2019 Elsevier Ltd
Autoimmunity co-signaling system: Regulatory T cells, CTLA-4 and FOXP3
Co-signaling molecules can act as co-stimulators or co-inhibitors, depending on whether they promote or suppress T-cell activation, respectively. At the specific time and location, co-signaling molecules positively and negatively control antigen presentation, growth, differentiation and function of T-cells. An important cellular group implicated in the regulation of co-stimulation is known as regulatory T cells (Treg). These cells can be used clinically in treatments ranging from cellular transfer in transplant patients to autoimmune diseases and suppression in cancer patients. Treg act through CTLA-4 molecules, which have the ability to suppress the co-stimulation signals and to stop the T cell response. Recently, CTLA-4Ig fusion molecules have been developed, which can block the presentation of auto-antigens. FOXP3 transcription factor is a specific molecule present in Treg that inhibits the production of IL-2 by CD4+ activated cells. Currently, FOXP3 functions are being extensively studied in order to develop new therapeutic targets. This article reviews co-signaling and its mechanism in Treg (CTLA-4, FOXP3), as well as its role in the physiopathology of autoimmune diseases.
La résilience chez les patientes atteintes de maladies auto-immunes
Objectif Évaluer le lien entre résilience et évolution clinique chez des patientes atteintes de maladies auto-immunes. Méthodes Les données de 188 femmes atteintes de maladies auto-immunes, incluant la polyarthrite rhumatoïde (n = 51), le lupus érythémateux systémique (n = 70), la sclérodermie systémique (n = 35) et le syndrome de Sjögren (n= 32), ont été collectées lors de groupes de discussion, d’entretiens individuels et de l’examen des dossiers médicaux. Les variables démographiques, cliniques et biologiques ont été analysées incluant l’activité de la maladie perçue par le patient. Pour mesurer la résilience, nous avons eu recours à la brève échelle de résilience. La régression linéaire multiple et bivariée et les arbres de classification et de régression ont été utilisés pour l’analyse des données.
The putative protective role of hepatitis B virus (HBV) infection from autoimmune disorders
Background: The etiology of autoimmune diseases is not fully clarified and the mechanisms underlying their initiation and progression are still obscure. It is becoming clear that in a genetic susceptible individual an environmental trigger such as infectious agent in general and viruses in particular could initiate the development of an autoimmune disease. Hepatitis B virus (HBV) is notorious in its association with diverse autoimmune diseases. Therefore, we aimed to determine the presence of hepatitis B core antibody (HBcAb), a seromarker for past or present infection with HBV, in a large number of sera collected from patients with different autoimmune diseases. Methods: A cohort of 675 sera samples of 5 different autoimmune diseases and healthy donors were screened for evidence of a prior infection with HBV. All samples were tested for hepatitis B core antibody (IgG) using the Monolisa anti-HBc PLUS commercial kit (Bio-Rad, Hercules, San Francisco, USA). Results: Lower percentage of HBcAb was found in sera of the autoimmune diseases when compared to normal controls. Fifteen (10.7%) from 140 normal controls were found positive for the presence of HBcAb. Two (2%) out of 98 multiple sclerosis (MS) sera were positive for the presence of HBcAb (OR: 0.17, 95%CI: 0.03-0.77, p = 0.01), 3 (2.5%) out of 117 systemic lupus erythematosus (SLE) sera (OR: 0.2, 95%CI: 0.06-0.77, p = 0.01), 4 (4.5%) out of 89 type 1 diabetes (T1D), 5 (6.1%) from 82 Sjogren's syndrome (SS) sera and 12 (8%) from 149 rheumatoid arthritis (RA) sera were positive for the presence of HBcAb. Conclusions: Our data divulge an unexpected low percentage of antibodies to HBcAg in patients with SLE, MS and T1D in comparison to healthy matched donors. This finding may raise a protective role to HBV in some autoimmune diseases i.e. hygiene theory. © 2008 Elsevier B.V. All rights reserved.
Depresión y familia en pacientes con artritis reumatoide
Objective: To evaluate the prevalence of depression and the characteristics of family behaviour in patients with rheumatoid arthritis (RA). Methods: This was a cross-sectional study. The Zung test was applied to evaluate depression. The health status and the family support in patients were evaluated by specific questionnaires. Results: 107 patients with RA were included. We found a high incidence of depression (58%), a low satisfaction attitude towards the working conditions (40%) and the country’s socio-political situation (7%). The relation with the family group was good in most of the patients leading to an important percentage of satisfaction (60%). Among the family group, the couple (53%) and the offspring (63%) were the most important support givers. This support was perceived by the patients mostly when family listen to them. Conclusion: There was a higher rate of depression in patients with RA, although the family support was still adequate in spite of an unsatisfactory sociopolitical environment. The adequate and supporting family environment may play a buffering effect in quality of life of patients with RA.
Expansion of gut associated immunoglobulin A secreting lymphocytes in rheumatoid arthritis correlates with high levels of serum IgA
We report the emergence of polyclonal expansion of gut lymphocyte associated tissues producing IgA in a patient with rheumatoid arthritis associated with a high serum IgA concentration. The role of IgA in rheumatoid arthritis is reviewed.
Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome
Background: Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. Methods: The DNA of eight patients affected by MAS [all of whom presenting with Sjögren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic-deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity. Results: Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti-inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very well known autoimmunity genes. Conclusions: Novel and rare exonic mutations that may account for autoimmunity were identified. Among those, the LRP1/STAT6 novel mutation has the strongest case for being categorised as potentially causative of MAS given the presence of intriguing patterns of functional interaction with other major genes shaping autoimmunity. © Johar et al.
STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians
The aim of this study was to determine the influence of STAT4 (rs7574865) and TRAF1/C5 (rs10818488 and rs2900180) gene polymorphisms on the risk of developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Colombian population. This was a case-control study in which 839 individuals with RA (N = 274) and SLE (N = 144) and matched healthy controls (N = 421) were included. Genotyping was performed by using a polymerase chain reaction system with pre-developed TaqMan allelic discrimination assay. STAT4 rs7574865T allele disclosed a significant influence on the risk of developing SLE (P = 0.0005; OR 1.62, 95% CI 1.22-2.16) and RA (P = 0.008; OR 1.36; 95% CI 1.08-1.71), whereas no effect on these autoimmune diseases was observed for the TRAF1/C5 polymorphisms examined. Our data strengthen STAT4 rs7574865 polymorphism as a susceptibility factor for RA and SLE and provide further evidence for a common origin of autoimmune diseases.
Latent Autoimmune Thyroid Disease
Objective To determine the prevalence of thyroid autoantibodies and the associated factors in euthyroid subjects. Methods 300 euthyroid subjects, chosen by stratified sampling from an inception cohort of 1335 individuals, were included. Thyroid function was evaluated by measuring the serum levels of TSH (0.3–4.5 ?IU/mL) and FT4 (5.2–12.7?g/dL). Anti-peroxidase (TPOAbs), anti-thyroglobulin (TgAbs), and anti-TSH receptor (TrAbs) antibodies were evaluated with 23 additional autoantibodies as well as vitamin D (VitD) levels. The analysis included sociodemographic, clinical, and environmental characteristics. Data were analyzed by bivariate and multivariate tests. Results Thyroid autoimmunity was observed in 15.3% of the subjects (TPOAbs 11.3% and TgAbs 2.0%). In six individuals, both autoantibodies were positive. TrAbs were not detected in any individual. Familial thyroid disease (? ?= ?3.4, 95% CI: 1.2–9.5, P ?= ?0.021), the presence of other autoimmune diseases (? ?= ?10.8, 95% CI: 1.6–72.9, P ?= ?0.014) VitD insufficiency (P ?= ?0.030), never smoke (? ?= ?6.9, 95% CI: 1.6–30.4, P ?= ?0.010), drinking more than 4 cups of coffee (? ?= ?3.8, 95% CI: 1.1–13.1, P ?= ?0.036), and a higher number of years exposed to wood smoke (P ?= ?0.04) were associated with thyroid autoimmunity. In the case of TPOAbs, familial thyroid disease (? ?= ?4.9, 95% CI: 1.7–14.0, P ?= ?0.003), never smoke (? ?= ?5.7, 95% CI: 1.4–21.0, P ?= ?0.002), and drinking more than 4 cups of coffee (? ?= ?3.6, 95% CI: 1.1–13.1, P ?= ?0.047) were associated with their positivity. In addition, the presence of anti–SS–A/Ro52 (? ?= ?36.7, 95% CI: 2.5–549.9, P ?= ?0.009) and anti-Ku antibodies (? ?= ?10.2, 95% CI: 1.1–100.7, P ?= ?0.046) was also associated with TPOAbs. The presence of African ancestry (? ?= ?10.5, 95% CI: 1.7–63.2, P ?= ?0.01), anti–SS–A/Ro52 (? ?= ?15.8, 95% CI: 1.2–198.6, P ?= ?0.03), and anti-CENP-B antibodies (? ?= ?31.2, 95% CI: 1.8–565.9 ?P ?= ?0.02) were associated with TgAbs. Conclusion Latent thyroid autoimmunity is not rare. Environmental, genetic, and immunological factors as well as ancestry are associated risk factors. These results would facilitate the implementation of screening strategies in order to provide timely diagnosis and treatment.
