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MicroRNA (miRNA) are approximately 22 nucleotide single-stranded RNA that regulate the stability of target messenger RNA by selective binding to specific sites at the 3'-untranslated regions (UTR). This triggers repression in translation and mRNA degradation. It has been estimated that approximately 60% of all mRNA are under the control of miRNA. Among the known hundreds of miRNA, some are considered master regulators controlling either a single or multiple cellular pathways. Some miRNA are known to affect development and cell differentiation, while others are implicated in immunity and autoimmune diseases. A very interesting example is miR-146a, which has been reported to be downregulated in systemic lupus erythematosus and upregulated in rheumatoid arthritis (RA). Several groups have recently focused their attention on miRNA in the pathogenesis of RA. Interestingly, the expression of miR-146a is upregulated in different cell types and tissues in RA patients. miRNA in RA could also be considered as possible future targets for new therapeutic approaches. This discussion will focus on the current understanding in the function of miR-146a in endotoxin tolerance and cross-tolerance, and how it may contribute to modulate the overproduction of known pathogenic cytokines, such as tumour necrosis factor α.

The role of microRNAs (miRNAs) in the regulation of many physiological and pathological processes has been intensely studied in recent years. Some miRNAs, such as miR-146a and miR-182, play a dominant role in the regulation of the innate and adaptive immune responses, respectively. Many miRNAs are reportedly deregulated in autoimmune diseases, but miR-146a in particular seems to be consistently altered. The overexpression or underexpression of miRNAs can influence specific targets and pathways, leading to autoimmune disease phenotypes, and this is supported also by some in vivo studies. Targeting miRNAs could represent a valid future therapeutic option for autoimmune diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Anti-mitochondrial antibodies (AMA) are found in >90% of primary biliary cholangitis patients. Anti-rods/rings antibodies (anti-RR) are most commonly associated with interferon-a and ribavirin treatment in hepatitis C patients. Clinical laboratories routinely screen for AMA and anti-RR using indirect immunofluorescence on HEp-2 cells (HEp-2-IFA). Therefore, we sought to establish reference materials for use in AMA and anti-RR testing. Methods: AMA-positive and anti-RR-positive human plasma samples (AMA-REF and RR-REF), identified as potential reference materials based on preliminary data, were further validated by multiple laboratories using HEp-2-IFA, immunoprecipitation (IP), western blotting, IP-western, line immunoassay (LIA), addressable laser bead immunoassay (ALBIA) and enzyme-linked immunosorbent assay (ELISA). Results: AMA-REF showed a strong positive cytoplasmic reticular/AMA staining pattern by HEp-2-IFA to =1:1280 dilution and positive signal on rodent kidney/stomach/liver tissue. AMA-REF reacted with E2/E3, E3BP, E1a and E1ß subunits of the pyruvate dehydrogenase complex by IP and western blotting and was positive for AMA antigens by LIA, ALBIA and ELISA. RR-REF showed a strong positive rods and rings staining pattern by HEp-2-IFA to =1:1280 dilution. RR-REF reacted with inosine monophosphate dehydrogenase by IP, IP-western and ALBIA. RR-REF also produced a nuclear homogenous staining pattern by HEp-2-IFA, immunoprecipitated proteins associated with anti-U1RNP antibody and reacted weakly with histones, nucleosomes, Sm and nRNP/Sm by LIA. Conclusions: AMA-REF and RR-REF are useful reference materials for academic or commercial clinical laboratories to calibrate and establish internal reference standards for immunodiagnostic assays. AMA-REF and RR-REF are now available for free distribution to qualified laboratories through Plasma Services Group. [ABSTRACT FROM AUTHOR]

Objective To describe a new immunoprecipitation pattern identified in Italian patients affected by systemic sclerosis (SSc), corresponding to the pyruvate dehydrogenase antigen complex recognized by anti-mitochondrial antibodies (AMA) in primary biliary cholangitis (PBC). Methods Autoantibodies in sera from 85 patients with SSc were tested by protein- and RNA-immunoprecipitation. Immunoprecipitation-Western blot was used to determine the identified proteins, and medical records re-evaluated for liver function tests and PBC. Results In 13/85 (15%) SSc sera, a unique set of 75-50-40-34 kD proteins that had not been previously reported, was noted. The four proteins were identified as the proteins X/E3BP, E1α, E1β, and E2/E3 of the pyruvate dehydrogenase antigen complex by immunoprecipitation-Western blot. From clinical record evaluation, 9/13 (69%) SSc patients with this new pattern were positive for AMA by routine indirect immunofluorescence, and 7/13 (54%) had a diagnosis of PBC, while 4/13 (31%) manifested no biochemical signs of cholestasis. Twelve of 13 patients with SSc and AMA by immunoprecipitation have a limited cutaneous form of SSc and anti-centromere antibodies. Conclusions We describe a pattern of 4 proteins in 15% of SSc patients, identified for the first time by protein-immunoprecipitation. This pattern corresponds to serum AMA against the pyruvate dehydrogenase antigen complex and it must be considered in the interpretation of protein-immunoprecipitation results. [ABSTRACT FROM AUTHOR]

The prevalence of ANA and anti-ENA in the general population is not well established, especially their clinical significance in healthy subjects. We herein determined the prevalence and predictive value of serum ANA and anti-ENA for connective tissue diseases (CTD), cancer, and mortality. We took advantage of a randomly selected sample of the 1998 general population (Isola I) consisting of 2828 subjects (53% women, age 43 ± 13 years) from a well-defined Northern Italian area. Serum ANA and anti-ENA were tested on the 2690 samples available in 2012 (Isola II, 50% women, age 58 ± 13 years). Administrative databases were searched for CTD, cancer diagnosis, and death cases occurring between enrollment and December 31, 2013. The hazard ratio (HR) was calculated for incident cases. Serum ANA is positive in 18.1% for any titer and 6.1% for titers ≥ 1:160, 23% in subjects over 50 years and 13.1% and 6.1% for any titer and titers ≥ 1:160, respectively, in women. The HR for CTD development was significantly high for all ANA titers, with the highest for ANA ≥ 1:160 (HR 14.19, 95% CI 3.07–65.68). ANA positivity was not associated with cancer (HR 1.03; 95% CI 0.75–1.43), or with mortality (HR adjusted for age and sex 1.40; 95% CI 0.94–2.09). Serum anti-ENA is positive in a minority of subjects with highest figures for anti-nucleosome (1.9%), -histone (1.6%) and -PM/Scl (1.5%). In conclusion, serum ANA prevalence in the general population is highest in senior subjects and in women, while the female predominance is significantly lower compared to overt CTD. Serum ANA is associated with an increased probability of CTD development over time, but does not influence survival or cancer risk. [ABSTRACT FROM AUTHOR]

Objectives: We retrospectively compared disease activity, treatment, clinical and laboratory features, and rate of mortality of 535 SLE patients with adult and late disease onset. Methods: patients were divided into two groups based on the onset of the disease before or after 50 years of age. Clinical data were collected from medical reports. Disease activity was measured by ECLAM score. Parameters were compared by χ2-test, Fisher's test, Student's t or the Mann-Whitney test. Results: Forty patients (7.5%) were included in the late SLE onset group (group A), while 495 (92.5%) in the adult SLE onset group (group B). Sicca symptoms were more frequent in group A ( p < 0.0008), while glomerulonephritis ( p < 0.0069), reduced C3 ( p < 0.0006) and low C3 ( p < 0.00002) and C4 levels ( p < 0.0006) were more prevalent in group B. Twenty-two deaths (4.3%) were recorded: 14 (2.8%) in group B and 8 (20%) in group A. Deaths were mainly due to infections in group B (28.5%) and cardiovascular events in group A (50%). A lower use of HCQ and LDA were recorded in deceased versus living patients ( p < 0.0001 and 0.0166, respectively), while a higher ECLAM score was measured at onset in dead versus living patients ( p < 0.048). Conclusions: Late onset SLE occurred in 7.5% of patients and it was associated with sicca symptoms. The use of HCQ and LDA is positively correlated with survival. Death in late onset SLE occurred more frequently for cardiovascular involvement. Higher disease activity at onset of the disease might represent a poor prognostic factor for death in adult onset. [ABSTRACT FROM AUTHOR]

Abstract: Rheumatoid arthritis (RA) is a chronic and severe autoimmune disease that affects joint tissues, bone, and cartilage. However, the pathogenesis of RA is still unclear. Autoantibodies such as rheumatoid factor and anti-cyclic citrullinated peptide are useful tools for early diagnosis, monitoring disease activity, and predicting prognosis. Recently, many groups have focused their attention on the role of microRNAs in the pathogenesis of RA, as well as a potential biomarker to monitor RA. In fact, the expression of some microRNAs, such as miR-146a, is upregulated in different cell types and tissues in RA patients. MicroRNAs in RA could also be considered as possible future targets for new therapeutic approaches. [Copyright &y& Elsevier]

Objectives. Primary anti-phospholipid syndrome (PAPS) is an autoimmune condition defined by anti-phospholipid antibodies (aPL) and thrombotic or obstetric events. Some PAPS can evolve into systemic lupus erythematosus (SLE) during follow-up. Few studies systematically examined lupus autoantibodies and their clinical significance in PAPS. The aim of our study is to analyze the clinical and laboratory correlations with lupus-related autoantibodies, detected by immunoprecipitation (IP), a technique not yet systematically applied to investigate autoantibodies in this condition. Methods. Sera from 52 PAPS patients were screened by indirect immunofluorescence (IIF) antinuclear antibodies (ANA), IP of 35S-labeled K562 cell extract, and ELISA [anti-Argonaute2 (Ago2, Su), 60kRo, 52kRo, La, dsDNA)]. Anti-Ago2/Su positive sera were also tested for anti-GW bodies (GWBs) by IIF double staining, using rabbit anti-Rck/p54 serum. Results. First, 56% of PAPS patients (29/52) were ANA positive, mainly with speckled pattern. Anti-Ago2/Su antibodies were found in 13% (7/52), anti-Ro/SSA in 10% (5/52), anti-La in one case. The clinical profile of patients did not seem to be related to the presence of these antibody specificities. However, levels of IgG anti-ββ2 glycoprotein I antibodies were lower in anti-Ago2/Su positive patients ( p  ==  0.02). None of anti-Ago2/Su or --Ro patients developed SLE during a 2-year follow-up. Ago2 is a key component of GWBs, however, only 1/7 anti-Ago2/Su serum showed a typical cytoplasmic GWBs staining. Conclusions. Anti-Ago2/Su and -Ro antibodies are the two autoantibodies detected by IP in our PAPS cohort. Clarifying why Ago2/Su and Ro are specific targets of autoimmunity may help to understand the mechanisms of autoantibody production. [ABSTRACT FROM AUTHOR]