Carlos A. Cañas

Confirmation of an association between rs6822844 at the IL2-IL21 region and multiple autoimmune diseases: Evidence of a general susceptibility locus

OBJECTIVE Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2-IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in non-European populations, and to perform disease-specific and overall meta-analyses using data from previously published studies. METHODS We evaluated case-control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögrens syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçets disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies. RESULTS We detected significant associations of rs6822844 with SLE (P = 0.008), type 1 DM (P = 0.014), RA (P = 0.019), and primary SS (P = 0.033) but not with BD (P = 0.34) or CD (P = 0.98). We identified little evidence of population differentiation (F(ST) = 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (P(meta) = 3.61 x 10(-6)), inflammatory bowel disease (IBD; Crohns disease and ulcerative colitis) (P(meta) = 3.48 x 10(-12)), type 1 DM (P(meta) = 5.33 x 10(-5)), and CD (P(meta) = 5.30 x 10(-3)). Overall meta-analysis across all autoimmune diseases reinforced association with rs6822844 (23 data sets; P(meta) = 2.61 x 10(-25), odds ratio 0.73 [95% confidence interval 0.69-0.78]). CONCLUSION Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.

Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases

OBJECTIVES Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations. METHODS To replicate this association in non-European populations, we evaluated case-control association between rs763361 and coeliac disease (CED) samples from Argentina; SLE, RA, type-1 diabetes (T1D) and primary SS (pSS) from Colombia; and SLE samples from China and Japan. We genotyped rs763361 and evaluated its genetic association with multiple ADs, using chi(2)-test. For each association, odds ratio (OR) and 95% CI were calculated. RESULTS We show that rs763361 is significantly associated with Argentinean CED (P = 0.0009, OR = 1.60). We also observed a trend of possible association with Chinese SLE (P = 0.01, OR = 1.19), RA (P = 0.047, OR = 1.25), SLE (P = 0.0899, OR = 1.24) and pSS (P = 0.09, OR = 1.33) in Colombians. Meta-analyses for SLE (using our three populations) and T1D (our population and three published populations) yielded significant association with rs763361, P = 0.009 (OR = 1.16) and P = 1.1.46 x 10(-9) (OR = 1.14), respectively. CONCLUSIONS Our results demonstrate that the coding variant rs763361 in CD226 gene is associated with multiple ADs in non-European populations.

Are autoimmune diseases predictable

Autoimmune diseases are complex diseases resulting of the interaction between both genetics and environmental factors over time. Different phases in the development of autoimmune diseases are characterized by the detection of serum autoantibodies several months or years before the onset of clinical manifestations and subsequent diagnosis. In addition to serum antibodies, genetic susceptibility factors may predict the future development of the disease. Currently, prediction in type 1 diabetes is the most accurate, with the analysis of genetic susceptibility factors in first-degree relatives of patients and several autoantibody tests. In the future, multiple antibodies test, in combination with the analysis of genetics, epigenetics and immunological anomalies in fine models may allow the precise prediction in autoimmune diseases. Prevention measures might thus be introduced as an attempt to avoid or delay the disease.

B Lymphocytes: Development, Tolerance, and Their Role in Autoimmunity—Focus on Systemic Lupus Erythematosus

B lymphocytes are the effectors of humoral immunity, providing defense against pathogens through different functions including antibody production. B cells constitute approximately 15% of peripheral blood leukocytes and arise from hemopoietic stem cells in the bone marrow. It is here that their antigen receptors (surface immunoglobulin) are assembled. In the context of autoimmune diseases defined by B and/or T cell autoreactive that upon activation lead to chronic tissue inflammation and often irreversible structural and functional damage, B lymphocytes play an essential role by not only producing autoantibodies but also functioning as antigen-presenting cells (APC) and as a source of cytokines. In this paper, we describe B lymphocyte functions in autoimmunity and autoimmune diseases with a special focus on their abnormalities in systemic lupus erythematosus.

Direct oral anticoagulants in antiphospholipid syndrome: a real life case series

Aim The aim of this study was to describe a case series of patients with primary or secondary antiphospholipid syndrome (APS) treated with direct oral anticoagulants (DOACs). Patients and methods Clinical charts of eight patients with thrombotic primary or secondary APS treated with direct oral anticoagulants (DOACs) between January 2012 and May 2015 were reviewed. Results The mean age was 45 ± 14.36 (range 27–69 years). Four patients had secondary APS (50%). All patients were initially treated with warfarin by a mean time of 70.87 ± 57.32 months (range 17–153 months). Changes in anticoagulation were defined by recurring thrombosis in five patients (62.5%) and life-threatening bleeding in the other three cases. Seven patients (87.5%) received rivaroxaban treatment and one patient (12.5%) apixaban. The mean follow-up period with DOACs was 19 ± 10.06 months (range 2–36 months). There was no recurrence of thrombosis by the time of data collection. Conclusions Despite not being the standard treatment in APS, we propose DOACs as a rational alternative for the management of patients with this diagnosis. Further interventional clinical studies are necessary for possible standardization of this therapy in APS patients.

Lupus Nephritis in Colombians: Contrasts and Comparisons with Other Populations

Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) since it is the major predictor of poor prognosis. The purpose of this study was to examine the clinical and immunological characteristics associated with LN development during the course of SLE in Colombians. Therefore, patients with SLE followed at five different referral centers in Medellin, Bogota, and Cali were included in this cross-sectional and multicenter study. Factors influencing LN were assessed by conditional logistic regression analysis, adjusting by gender, age at onset, duration of disease, and city of origin. The entire sample population included 467 patients, of whom 51% presented with LN. The presence of anti-dsDNA antibodies (adjusted odds ratio (AOR), 2.06; 95% confidence interval (CI), 1.16–3.65), pleuritis (AOR, 3.82; 95% CI, 1.38–10.54), and hypertension (AOR, 2.63; 95% CI, 1.23–5.62) were positively associated with LN, whereas the presence of anti-La antibodies was a protective factor against LN development (AOR, 0.4; 95% CI, 0.19–0.85). A review of literature on LN in different populations is made. The identified clinical- and laboratory-associated factors would assist earlier diagnosis and guide decisions on therapeutic interventions on this critical and frequent complication of SLE.

Epigenetics changes associated to environmental triggers in autoimmunity.

Abstract Autoimmune diseases (AIDs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens and represent a heterogeneous group of disorders that affect specific target organs or multiple organs in different systems. While the pathogenesis of AID remains unclear, its aetiology is multifunctional and includes a combination of genetic, epigenetic, immunological and environmental factors. In AIDs, several epigenetic mechanisms are defective including DNA demethylation, abnormal chromatin positioning associated with autoantibody production and abnormalities in the expression of RNA interference (RNAi). It is known that environmental factors may interfere with DNA methylation and histone modifications, however, little is known about epigenetic changes derived of regulation of RNAi. An approach to the known environmental factors and the mechanisms that alter the epigenetic regulation in AIDs (with emphasis in systemic lupus erythematosus, the prototype of systemic AID) are showed in this review.

Efficacy and Safety of Anti–interleukin 6 Receptor Monoclonal Antibody (tocilizumab) in Colombian Patients With Takayasu Arteritis

Purpose The aim of this study was to describe the efficacy and safety of anti–interleukin 6 receptor antibody (tocilizumab [TCZ]) in patients with severe or refractory Takayasu arteritis (TA). Methods We describe 8 Colombian patients with severe and/or refractory TA treated with TCZ during a period of at least 9 months. Clinical, radiological, biological, and associated treatments were evaluated before, during, and after TCZ infusions. Results The median age at evaluation was 31 years (12–43 years). All patients were female and experienced clinical and biological improvement, in addition to a corticosteroid-sparing effect from a median dose of 50 mg/d at baseline (30–60 mg/d) to 6.25 mg/d (2.5–10 mg/d) at 9 months. In 4 cases, in which imaging studies were available, an improvement was observed. The median duration of TCZ infusions was 18 months (9–36 months). Major adverse effects related to TCZ were not evidenced during a period of at least 9 months of treatment. One relapse was observed. Tocilizumab was continued in all cases until the last follow-up. Conclusions This study shows a clinical, biological, and radiological response in patients with refractory TA treated with TCZ.

Linear IgA bullous dermatosis associated with systemic lupus erythematosus: a case report

We describe a patient with linear IgA bullous dermatosis, who developed characteristics of systemic lupus erythematosus (SLE). This association is rare and might be considered in the spectrum of the nonspecific bullous lesions associated to SLE.

Calcio, canales, señalización intracelular y autoinmunidad

Calcium (Ca²⁺) is an important cation able to function as a second messenger in different cells of the immune system, particularly in B and T lymphocytes, macrophages and mastocytes, among others. Recent discoveries related to the entry of Ca²⁺ through the store-operated calcium entry (SOCE) has opened a new investigation area about the cell destiny regulated by Ca²⁺ especially in B and T lymphocytes. SOCE acts through calcium-release-activated calcium (CRAC) channels. The function of CRAC depends of two recently discovered regulators: the Ca²⁺ sensor in the endoplasmic reticulum or stromal interaction molecule (STIM-1) and one subunit of CRAC channels called Orai1. This review focuses on the role of Ca²⁺ signals in B and T lymphocytes functions, the signalling pathways leading to Ca²⁺ influx, and the relationship between Ca²⁺ signals and autoimmune diseases.