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Most patients affected by celiac disease (CD) are asymptomatic or hyposymptomatic and undiagnosed, and are at risk of preventable complications. Therefore, early diagnosis is highly recommended. Multiple diagnostic antibodies are available; the most frequently used is IgA to tissue transglutaminase (IgA-tTg). It may yield false results and, alone, does not address IgA deficiency. Recently, a new generation of anti-neo-epitope tTg check (IgG + IgA) has become available. It is highly sensitive and specific, covers IgA-deficient patients with CD, reflects intestinal damage, and has predictive potential in the diagnosis of CD.

Objective Autoantibodies against CD74 (anti-CD74) are associated with ankylosing spondylitis (AS). The present multicenter study, the International Spondyloarthritis Autoantibody (InterSpA) trial, was undertaken to compare the sensitivity and specificity of anti-CD74 and HLA-B27 in identifying patients with nonradiographic axial spondyloarthritis (axSpA). Methods Patients ages 18-45 years with inflammatory back pain of ≤2 years' duration and a clinical suspicion of axSpA were recruited. HLA-B27 genotyping and magnetic resonance imaging of sacroiliac joints were performed in all patients. One hundred forty-nine patients with chronic inflammatory back pain (IBP) not caused by axSpA served as controls, and additional controls included 50 AS patients and 100 blood donors whose specimens were analyzed. Results One hundred patients with inflammatory back pain received a diagnosis of nonradiographic axSpA from the investigators and fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria. The mean age was 29 years, and the mean symptom duration was 12.5 months. The sensitivity of IgA anti-CD74 and IgG anti-CD74 for identifying the 100 axSpA patients was 47% and 17%, respectively. The specificity of both IgA anti-CD74 and IgG anti-CD74 was 95.3%. The sensitivity of HLA-B27 was 81%. The positive likelihood ratios were 10.0 (IgA anti-CD74), 3.6 (IgG anti-CD74), and 8.1 (HLA-B27). Assuming a 5% pretest probability of axSpA in chronic back pain patients, the posttest probability, after consideration of the respective positive test results, was 33.3% for IgA anti-CD74, 15.3% for IgG anti-CD74, and 28.8% for HLA-B27. A combination of IgA anti-CD74 and HLA-B27 results in a posttest probability of 80.2%. Conclusion IgA anti-CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test in daily practice requires further confirmation.

Genetic risk factors for autoimmune diseases are constantly discovered, however, environmental factors are laggingbehind and the precipitating events leading to development of autoimmune diseases remain enigmatic. Gluten is a well-established inducing nutrient in celiac disease and gluten withdrawal is the only current effective therapy. More and more studies have shown that non-celiac autoimmune diseases can partially respond to gluten free diet. The present editorial reviews those conditions and suggest multiple potential mechanisms that might operate in clinical amelioration of non-celiac autoimmune diseases.

Celiac disease is a multi-organ disorder which is highly variable in its clinical expression, presenting multiple enteric and extraintestinal manifestations. However, most of treating physicians and dieticians regard celiac disease as a chronic, gradually evolving, asymptomatic or hypo-symptomatic entity. The present mini-review aims to screen the literature for acute presentations of celiac disease and to increase the awareness of the medical communities, for such a possibility. It appears that the disease can present acutely in multiple symptomatic, phenotypic and laboratory pictures. The acute presentation involves mainly the gastrointestinal tract and adjacentorgans like liver and gallbladder, however, extraintestinal and remote organs presentations can occur.

OBJECTIVE The aim of this study is to analyse the influence of LILRA3 and the genetic leukocyte immunoglobulin-like receptor 3 (LILRA3) deletion on transmission and clinical course of HIV infection. DESIGN Case and control study. METHODS LILRA3 genotypes were determined by PCR. HIV patients were categorized into short-term progressors, normal progressors and long-term nonprogressors according to the clinical course. Functional studies were performed using real-time PCR, intracellular flow cytometry and ELISA. RESULTS The prevalence of the homozygous LILRA3 deletion was higher in HIV-positive individuals (n = 439) than in controls (n = 651) (P = 0.02). The disease progression was faster in homozygously deleted patients with more short-term progressors than in heterozygous (P = 0.03) and homozygously positive (P = 0.002) individuals. These results have been confirmed in a seroconverter cohort (n = 288). The frequency of the homozygous deletion in the confirmation cohort was higher than in controls (P = 0.04). Combining both cohorts, the proportion of homozygously LILRA3-deleted individuals was 6.2% in HIV-infected patients (n = 727) vs. 3.2% in controls (P = 0.01). Functional analysis revealed an upregulation of the LILRA3 gene in real-time PCR in treated patients when compared with untreated patients (P = 0.007) and controls (P = 0.02) resulting in a higher LILRA3 expression in CD4 (P = 0.008) and CD14 (P = 0.02) cells of untreated patients in intracellular flow cytometry. LILRA 3 concentrations in the sera were similar between the groups, in untreated patients a correlation between viral load and LILRA3 concentration was found. CONCLUSION The homozygous LILRA3 deletion is associated with a higher susceptibility for HIV disease and with a faster disease progression.

Microbial transglutaminase (mTg) is capable of cross-linking numerous molecules. It is a family member of human tissue transglutaminase (tTg), and is involved in CD. Despite declarations of the safety of mTg for industrial use, direct evidence for immunogenicity of the enzyme is lacking. The serological activity of mTg, tTg, gliadin complexed mTg (mTg neo-epitope) and gliadin complexed tTg (tTg neo-epitope) were studied in 95 pediatric celiac patients (CD), 99 normal children (NC), 79 normal adults (NA) and 45 children with nonspecific abdominal pain (AP). Sera were tested by ELISAs, detecting IgA, IgG or both IgA and IgG (check): AESKULISA® tTg (tTg), AESKULISA® tTg New Generation (tTg neo-epitope (tTg-neo)), microbial transglutaminase (mTg) and mTg neo-epitope (mTg-neo). Marsh criteria were used for the degree of intestinal injury. Parallel, mTg and tTg neo-epitopes were purified by asymmetric field flow fractionation, confirmed by multi-light-scattering and SDS-PAGE, and analyzed in adult CD and control groups by competition ELISAs. No sequence homology but active site similarity were detected on alignment of the 2 Tgs. Comparing pediatric CD patients with the 2 normal groups: mTg-neo IgA, IgG and IgA + IgG antibody activities exceed the comparable mTg ones (p tTg-neo IgA ≥ mTg-neo IgG > tTg-neo IgG > mTg-neo check > mTg-neo IgA. Taken together, tTg-neo check, tTg-neo IgA and mTg-neo IgG correlated best with intestinal pathology (r2 = 0.6454, r2 = 0.6165, r2 = 0.5633; p mTg is immunogenic in children with CD and, by complexing to gliadin, its immunogenicity is enhanced. Anti-mTg-neo-epitope IgG antibodies correlate with intestinal damage to a comparable degree as anti-tTg-neo IgA. mTg and tTg display a comparable immunopotent epitope. mTg-neo IgG is a new marker for CD. Further studies are needed to explore the pathogenic potential of anti-mTg antibodies in CD.

Wheat is the most important source of carbohydrate in the Western world with a constant increase in sales also in Eastern societies. Since gluten comprises 80% of the contemporary wheat proteins an...

The human gut is inhabited by overcrowded prokaryotic communities, a major component of which is the virome, comprised of viruses, bacteriophages, archaea, eukaryotes and bacteria. The virome is required for luminal homeostasis and, by their lytic or synergic capacities, they can regulate the microbial community structure and activity. Dysbiosis is associated with numerous chronic human diseases. Since the virome can impact microbial genetics and behavior, understanding its biology, composition, cellular cycle, regulation, mode of action and potential beneficial or hostile activities can change the present paradigm of the cross-talks in the luminal gut compartment. Celiac disease is a frequent autoimmune disease in which viruses can play a role in disease development. Based on the current knowledge on the enteric virome, in relation to celiac disease pathophysiological evolvement, the current review summarizes the potential interphases between the two. Exploring and understanding the role of the enteric virome in gluten-dependent enteropathy might bring new therapeutic strategies to change the luminal eco-event for the patient’s benefit.

Spondyloarthritis (SpA) is a chronic inflammatory disease of unknown aetiology. Previously, we identified autoantibodies against CD74 in sera of SpA patients. The aim of this study was to evaluate CD74 as a T cell antigen in SpA.Recombinant CD74 protein and a panel of selected peptides representing its amino acid residues were examined for their capability to stimulate peripheral blood mononuclear cells from patients with SpA. In particular, cytokine production by CD4+ T cells was evaluated with flow cytometric detection of intracellular TNF-α, IFNγ, TGFβ and IL-17A. Patients' sera were tested for antibodies against CD74 using ELISA. Samples from patients with rheumatoid arthritis and healthy blood donors were similarly tested as controls.Significantly more CD4+ T cells from SpA patients produced TNF-α, IFNγ and IL-17A in response to recombinant CD74 than patients with rheumatoid arthritis or healthy blood donors. Among evaluated epitopes, the most promiscuous one lies within the peptide of the amino acid residues 142-185, which appeared more immunogenic. Further, the proportion of cytokine producing CD4+ T cells was significantly higher among SpA patients with autoantibodies against CD74.CD74 is a T cell antigen in SpA, eliciting Th1 and Th17 responses, which may be relevant in disease pathogenesis. Recognition of the highly immunogenic amino acid residues of CD74 may contribute to our understanding of autoimmune responses of T helper cells in SpA.

Gluten is a major constituent in modern human food and its industrial applications are expanding constantly. Its increasing consumption, evolutionary increased content in wheat, and enhanced toxicity and immunogenicity make it a prime candidate as a modern environmental factor that might impact autoimmunogenesis. Its capacity to change the balance between microbiome and dysbiome, being a good substrate for PTMP, to disrupt tight junction functional integrity resulting in a leaky gut and its multiple side effects represent mode of actions that might drive autoimmune diseases' (ADs) initiation, maintenance, and progression. Its beneficial effects, when withdrawn in multiple ADs, further reinforce its place in impacting autoimmunity. Further exploration on its potential detrimental effects on human health may be beneficial for the autoimmune affected populations.

Detection of IgA-transglutaminase2 (TG2) autoantibodies has become the test of choice for the diagnosis and monitoring of celiac disease (CD), and is recommended as the serological ‘gold standard’ by most of the CD societies. Despite its wide acceptance and reasonable performance, several aspects are problematic and disputed. The normal range levels between positivity and negativity are modified, manufacturers’ cut-off levels are extremely variable, far from matching in house determinations, insufficient standardization, inadequate reference protocols and no reliable quality assessment of the ELISA antibody (AB) kits for CD diagnosis and follow-up of dietary adherence. Numerous limitations exist in its detection, diagnosis, and follow-up capacities, resulting in frequent clinical circumstances when professionals encounter false positive and negative situations. The present review updates and discusses these facets and aims to extend our knowledge and help CD associated professionals to use the IgA-TG2 antibodies appropriately. We hope that the content of the review will stimulate the scientific community to explore and better delineate the role and functions of the AB and the industrial manufacturers to improve clinical performance of their diagnostic tests.

The surge in incidence of celiac disease (CD) is due more to environmental than to genetic changes. It is paralleled by a food industry that is continuously introducing additives to processed products. Microbial transglutaminase (mTG) is an enzyme that deamidates/transamidates proteins, enabling cross-linkage of molecules and revolutionizing the properties of many food products. It belongs to the family of transaminases and tissue transglutaminase (tTG) has been identified as the autoantigen in CD. Both enzymes de/transamidate gluten, the nutritional environmental factor that induces CD. Although several studies have shown that mTG transamidation of wheat flour/gluten can detoxify gluten peptide in vitro, by inhibiting the response to intestinal gliadin, inducing T cells and reducing INFγ production without influencing their main technological properties, a word of caution is advised. The oral challenge of adult CD patients with mTG transamidated flour was found to be only partially effective, not fulfilling expectations, and there have been multiple recent observations that indicate that mTG transamidated flour/gluten could be dangerous to gluten sensitive populations: mTG cross-linking of gluten may be hazardous in CD since the enzyme can deamidate gluten, thus mimicking endogenous tTG, it can link an extensive repertoire of proteins and other macromolecules with immunogenic potential, mTG treated gluten peptides are immunogenic to celiac patients, inducing specific IgA antibodiesand are recognized by gluten-specific humanT cells. Their effect on CD intestinal permeability has not yet been studied. To better understand the actual processes and events, associated with the suggested mTG therapy, long-term ex vivo and in vitro studies are needed. Until then, it is best to respect the data but suspect the safety of the gluten sensitive populations.

Epidemiological data provide evidence of a steady rise in autoimmune disease throughout Westernized societies over the last decades. Multiple publications exist, describing past or actual incidences/prevalence of individual autoimmune diseases, however, long term studies on selected populations are scarce. Aims: to calculate the % increases per year of autoimmune diseases frequencies worldwide, analyze the differential increases per country and disease, and identify geoepidemiological trends. Methods: A systematic review was performed to identify incidence and prevalence of autoimmune diseases. 30 Studies from the last 30 years were identified using Medline, Google, and Cochrane Library databases. Only long-term regional or national follow-ups are reported. Results: The means ± s.d. of the net % increased /year incidence and prevalence of autoimmune diseases worldwide were 19.1±43.1 and 12.5±7.9, respectively. Rheumatic, endocrinological, gastrointestinal and neurological autoimmune diseases revealed the following annual % increases per year: 7.1, 6.3, 6.2, and 3.7, respectively. In all of these, differences between old vs new frequencies were highly significant (p< 0.0001). Comparing various autoimmune diseases, celiac disease increased the most and the highest increase in incidence, comparing old to new surveys is allocated to myasthenia gravis. Despite considerable variations between the countries, celiac, type 1 diabetes and myasthenia gravis frequencies increased the most in , and , respectively. Frequencies of the autoimmune diseases increased significantly in the West and North when compared to East and South, respectively. Conclusions: Despite multiple reports on autoimmune diseases frequencies, long-term longitudinal follow-ups are scarce. Incidences and prevalences have increased significantly over the last 30 years. Rheumatic, endocrinological and gastrointestinal autoimmune diseases in , , and increased the most. These observations point to a stronger influence of environmental factors as opposed to genetic factors on autoimmune disease development.

Background The incidence of infectious diseases in the RA ADAPTHERA study by ELISA antibody screening and the differences in infectious distribution in active or low active disease patients was explored. Methods Sera from 88 naive RA patients out of the ADAPTHERA study cohort, disease duration Results 82% RA patients were found to be positive for HSV1 +2 IgG (2% IgM positive), 8% for Adenovirus (IgA), 77% (IgG), and 1% (IgM). 99% for EBV-IgG (no IgM positive). 53% (IgG), and 26% (IgM) for CMV. 38% for HP-IgG and 15% for IgA and 79% for P-B19-IgG (3% IgM). 6% for Borrelia-IgM and 14% for IgG. A slightly increase was found for EBV sera positivity (99% IgG), compared to the normal population. Conclusions Limited evidence exists regarding the impact of the disease activity on the susceptibility for infections, possibly due to the close association of RA disease activity and therapy dependent dosage of immunosuppressive treatment. Still, some infections may present memory contact, presenting an epiphenomenon. On the contrary, they might play an active role in RA pathophysiology. Disclosure of Interest None declared

In light of the coincident surge in overall gluten intake and the incidence of autoimmune diseases, the possible biological adverse effects of gluten were explored. PubMed, MEDLINE, and the Cochrane Library databases were screened for reports published between 1964 and 2016 regarding the adverse effects of gluten as well as the effects of a gluten-free diet on autoimmune diseases. In vitro and in vivo studies describing gluten intake in animal models or cell lines and gluten-free diets in human autoimmune diseases were reviewed. Multiple detrimental aspects of gluten affect human health, including gluten-dependent digestive and extradigestive manifestations mediated by potentially immunological or toxic reactions that induce gastrointestinal inadequacy. Gluten affects the microbiome and increases intestinal permeability. It boosts oxidative stress and affects epigenetic behavior. It is also immunogenic, cytotoxic, and proinflammatory. Gluten intake increases apoptosis and decreases cell viability and differentiation. In certain nonceliac autoimmune diseases, gluten-free diets may help curtail the adverse effects of gluten. Additional in vivo studies are needed to unravel the puzzle of gluten effects in humans and to explore the potential beneficial effects of gluten-free diets in autoimmune diseases.

Many essential functions of the human body are dependent on the symbiotic microbiota, which is present at especially high numbers and diversity in the gut. This intricate host–microbe relationship is a result of the long-term coevolution between the two. While the inheritance of mutational changes in the host evolution is almost exclusively vertical, the main mechanism of bacterial evolution is horizontal gene exchange. The gut conditions, with stable temperature, continuous food supply, constant physicochemical conditions, extremely high concentration of microbial cells and phages, and plenty of opportunities for conjugation on the surfaces of food particles and host tissues, represent one of the most favorable ecological niches for horizontal gene exchange. Thus, the gut microbial system genetically is very dynamic and capable of rapid response, at the genetic level, to selection, for example, by antibiotics. There are many other factors to which the microbiota may dynamically respond including lifestyle, therapy, diet, refined food, food additives, consumption of pre- and probiotics, and many others. The impact of the changing selective pressures on gut microbiota, however, is poorly understood. Presumably, the gut microbiome responds to these changes by genetic restructuring of gut populations, driven mainly via horizontal gene exchange. Thus, our main goal is to reveal the role played by horizontal gene exchange in the changing landscape of the gastrointestinal microbiome and potential effect of these changes on human health in general and autoimmune diseases in particular.

The incidence of celiac disease is increasing worldwide, and human tissue transglutaminase has long been considered the autoantigen of celiac disease. Concomitantly, the food industry has introduced ingredients such as microbial transglutaminase, which acts as a food glue, thereby revolutionizing food qualities. Several observations have led to the hypothesis that microbial transglutaminase is a new environmental enhancer of celiac disease. First, microbial transglutaminase deamidates/transamidates glutens such as the endogenous human tissue transglutaminase. It is capable of crosslinking proteins and other macromolecules, thereby changing their antigenicity and resulting in an increased antigenic load presented to the immune system. Second, it increases the stability of protein against proteinases, thus diminishing foreign protein elimination. Infections and the crosslinked nutritional constituent gluten and microbial transglutaminase increase the permeability of the intestine, where microbial transglutaminases are necessary for bacterial survival. The resulting intestinal leakage allows more immunogenic foreign molecules to induce celiac disease. The increased use of microbial transglutaminase in food processing may promote celiac pathogenesis ex vivo, where deamidation/transamidation starts, possibly explaining the surge in incidence of celiac disease. If future research substantiates this hypothesis, the findings will affect food product labeling, food additive policies of the food industry, and consumer health education.

Transient anti transglutaminase2 and anti endomysial antibody elevation in systemic lupus erythematosus is fundamentally thought-provoking with respect to establishment of autoimmunity and its progression. Celiac disease and systemic lupus erythematosus are both relayed within the mosaic framework of autoimmunity. Transglutaminase2 is a multifunctional enzyme, involved in cell biology and survival and is one of the post translational modifiers of protein, enhancing autoimmunity. TG2 and its specific antibodies are heavily involved in celiac disease. TG2 is essential in clearance of apoptotic cells and experimentally participates in systemic lupus-like induction. However, the role of anti TG2 autoantibodies is far from being unraveled. Despite disappearance of these antibodies on gluten containing diet, in the present case, the boy is at risk of developing celiac disease in the future.

The links between microorganisms /viruses and autoimmunity are complex and multidirectional. A huge number of studies demonstrated the triggering impact of microbes and viruses as the major environmental factors on the autoimmune and inflammatory diseases. However, growing evidences suggest that infectious agents can also play a protective role or even abrogate these processes. This protective crosstalk between microbes/viruses and us might represent a mutual beneficial equilibrium relationship between two cohabiting ecosystems. The protective pathways might involve post-translational modification of proteins, decreased intestinal permeability, Th1 to Th2 immune shift, induction of apoptosis, auto-aggressive cells relocation from the target organ, immunosuppressive extracellular vesicles and down regulation of auto-reactive cells by the microbial derived proteins. Our analysis demonstrates that the interaction of the microorganisms /viruses and celiac disease (CD) is always a set of multidirectional processes. A deeper inquiry into the CD interplay with Herpes viruses and Helicobacter pylori demonstrates that the role of these infections, suggested to be potential CD protectors, is not as controversial as for the other infectious agents. The outcome of these interactions might be due to a balance between these multidirectional processes.

In view of the increasing importance of serological biomarkers for screening and diagnosing celiac disease (CD) and the lack of back-to-back comparison of their differential performance to their reliability to reflect the intestinal damage in children with CD, their performances were evaluated. 95 pediatric CD patients (mean age 8.3), 45 nonspecific abdominal pain children (AP) (mean age 7.3), 99 normal children (NC) (mean age 8.5) were tested with following ELISAs (detecting IgA, IgG or both, IgA and IgG (check)): AESKULISA® Gliadin (AGA), AESKULISA® DGP (DGP), AESKULISA® tTg “New Generation” (Neo-epitope tTg complexed to gliadin=tTg-neo), tTg (for in house research purpose only), AESKULISA® mTg neo-epitope and mTg (RUO). Anti-endomysial antibodies (EMA) were checked via immunofluorescence test. Results were compared to the degree of intestinal injury, using the revised Marsh criteria. Scatter diagrams and regression analysis comparing the 17 antibodies’ activities to the degree of the intestinal damage were performed. Most of the assays were able to discriminate patients with low and high degree of intestinal damage. Comparing the different correlations of CD associated IgA and IgG antibodies’ isotypes, the tTg-neo IgA (r2=0.6165, p

Both, celiac disease and IgA nephropathy are autoimmune diseases that are IgA mediated and share multiple clinical, pathophysiological, genetic, nutritional and immunological aspects. In view of recent observations and wider understanding of the central role played by the intestinal ecosystem in celiac disease and IgA nephropathy development, the present review highlights those shared aspects, concentrating on potential nutritional therapeutic strategies in IgA nephropathy.

Human beings assemble and maintain a diverse but host-specific gut microbial community along the longitudinal axis of the intestines. Helped by a functional tight junction, the default response to commensal microbes is tolerance, whereas the default response to pathogens is an intricately orchestrated immune response, resulting in pathogen clearance. Nutrients and industrial food additives were suggested to impact the intestinal ecosystem and to breach tight junction integrity. Taken together, certain nutritional components, increased intestinal permeability, disease specific dysbiotic pathobionts and their capacity of post translation modification of proteins, are luminal events that impact autoimmunogenesis. The present review expands on the multi gut originated axes and their relationship to remote organ autoimmune diseases. Brain, joint, bone, endocrine, liver, kidney, heart, lung and skin autoimmune diseases are connected to the intestinal luminal compartmental deregulated events to form the gut-systemic organs axes.

The neo-epitope tTg (tTg-neo) autoantibody, never challenged the anti-tissue transglutaminase (tTg) premiership, recommended by ESPGHAN, for celiac disease (CD) diagnosis.Pediatric CD (PCD), abdominal pains and normal children, normal adults, and rheumatoid arthritis patients, were tested using the following ELISAs detecting IgA, IgG or both IgA and IgG (check): AESKULISA® tTg (tTg; RUO) and AESKULISA® tTg-neo.Higher OD activity was detected for tTg-neo IgA, IgG and IgA+IgG than for tTg. tTg-neo IgA, IgG correlated better with intestinal damage than tTg. The tTg-neo combined IgA+IgG ELISA kit had higher sensitivity and a comparable specificity for the diagnosis of PCD. The drop in the % competition was much higher with the tTg-neo then the tTg antibodies. The false positivity of the tTg was significantly higher than the tTg-neo one.Serological diagnostic performances, reflection of intestinal damage, diverse epitopes and false positivity were better with the tTg-neo.

Celiac disease (CD) is one of the most common food intolerances in developed world. It affects genetically susceptible individuals and has severe consequences if it remains undiagnosed. A disease known for more than a century, it is still the focus for experts from various fields of research and development. Geneticists, pathologists, immunologists, food engineers and dieticians share their knowledge and expertise to improve the conditions of CD patients. With new insights in the pathomechanism of gluten processing and antigen presentation in CD, it was possible to improve the diagnostic antigen mimicking the primary epitope in CD. These celiac neo-epitopes are comprised of a complex of gliadin peptides crosslinked with transglutaminase (tTg). They are an early diagnostic marker for CD which occurs up to 6 months earlier than classical markers known to miss a certain amount of CD patients.

Leukocyte immunoglobulin-like receptors (LILR) are a family of at least 13 receptors mainly expressed on lymphoid and myelomonocytic cells. They are involved in the activation of the immune system. Inhibitory LILR (termed LILRB) signal through immunoreceptor tyrosine-based inhibitory motives in the cytoplasmic domain, whereas LILRA with short cytoplasmic domains are stimulatory receptors. Polymorphisms and deletions of leukocyte immunoglobulin-like receptors have been shown to be associated with autoimmune disorders, and some of the receptors are involved in the generation of regulatory T cells. Therefore, leukocyte immunoglobulin-like receptors may be central in the pathogenesis of autoimmunity. The data linking these receptors to autoimmune diseases is reviewed here.

Risk genes for multiple sclerosis (MS) are localized in the gene regions 6p21-11 and 19q13, the latter harboring the genes of the immunoglobulin-like transcripts (ILTs). ILTs are a family of activating and inhibitory receptors expressed on antigen-presenting cells (APCs) as well as on natural killer (NK) and T cells. Because of the inhibitory function of ILT2 and ILT4 and their binding to human leukocyte antigen (HLA)-G, they play a role in immune tolerance and may be important in pathogenesis of autoimmunity. ILT6 shows presence-absence variability and is produced by macrophages in a soluble form. ILT6 deletion is associated with MS. Furthermore, ILT6 activates T cell proliferation and is therefore a candidate gene for autoimmune disorders.

The significance of antibodies against alpha-fodrin compared to antibodies against Ro (SSA) as markers of Sjögren's syndrome has been controversially discussed. We therefore compared the association of alpha-fodrin and Ro antibodies with dry eyes and dry mouth in the general population. In 168 "normal" participants, the prevalence of IgA antibodies against alpha-fodrin was 5% and of IgG antibodies against alpha-fodrin was 3%. IgA antibodies against alpha-fodrin were present in 3 of 4 and IgG antibodies against alpha-fodrin in 2 of 4 participants with the combination of dry eyes and dry mouth (P = 0.0002 and 0.005). Only one participant had antibodies against Ro and had dry eyes but normal saliva production. Antibodies against alpha-fodrin are associated with sicca syndrome and may be valuable diagnostic markers in patients with Sjögren's syndrome lacking Ro antibodies.

Rheumatoid arthritis (RA) and celiac disease (CD) belong to the autoimmune disease family. Despite being separate entities they share multiple aspects. Epidemiologically they share comparable incidence environmental influences, associated antibodies and a recent incidental surge. They differ in their HLA pre-dispositions and specific predictive and diagnostic biomarkers. At the clinical level, celiac disease exhibits extra-intestinal rheumatic manifestations and RA gastrointestinal ones. Small bowel pathology exists in rheumatic patients. A trend towards responsiveness to a gluten free diet has been observed, ameliorating celiac rheumatic manifestations, whereas dietary interventions for rheumatoid arthritis remain controversial. Pathophysiologically, both diseases are mediated by endogenous enzymes in the target organs. The infectious, dysbiotic and increased intestinal permeability theories, as drivers of the autoimmune cascade, apply to both diseases. Contrary to their specific HLA pre-disposition, the diseases share multiple non-HLA loci. Those genes are crucial for activation and regulation of adaptive and innate immunity. Recently, light was shed on the interaction between host genetics and microbiota composition in relation to CD and RA susceptibility, connecting bugs and us and autoimmunity. A better understanding of the above mentioned similarities in the gut-joint inter-relationship, may elucidate additional facets in the mosaic of autoimmunity, relating CD to RA.

Transglutaminase2 is a pleiotropic enzyme expressed ubiquitously and abundantly. It has been implicated in a variety of physiological processes, such as growth, differentiation, migration, signaling, cytoprotection, cell death and survival, wound healing, angiogenesis, inflammation, apoptosis and autophagy. It operates intracellularly in multiple organelles, extracellularly and on cell surface. Apart from catalyzing post-translational modifications of proteins, by deamidation and cross-linking, it exercises G-protein, isomerase and kinase activities and non-enzymatic biological functions. Aberrant activation or deregulation of its functions is involved in numerous human disease. The most known one is celiac disease, but the present review will expand on extraintestinal entities. It plays a role in inflammatory, degenerative-age related, neurodegenerative, malignant, metabolic and hormonal, autoimmune and genetic conditions. Increased knowledge of its structure, functions and regulation in homeostatic phase, open the opportunity to design new therapeutic strategies to inhibit its malfunction in pathological situations.

Tissue transglutaminase is a multifunctional enzyme, exerting intra and extracellular, enzymatic and nonenzymatic, Ca2+ dependent and independent functions. Its specific autoantibody, the anti transglutaminase2 autoantibody is multifunctional, affecting many of the enzyme activities. Most of them are due to loss of function, the minority being gain of function of the enzyme. No beneficial protective effects, but only pathogenic ones, were assigned to those celiac disease associated anti TG2 autoantibodies. Taken together, celiac antibodies could collectively promote small bowel intestinal or extraintestinal damage. Yet, most of the transglutaminase2 autoantibody activities where explored in vitro and ex-vivo, very few in animal model but none in vivo, in human. The celiac disease serum contains numerous antibodies, IgA-transglutaminase2 is only one of them and up till now, its differential role in celiac disease induction and maintenance is far from being unraveled. Unraveling them might open some new therapeutic strategies for celiac disease.

Background Lupus nephritis is known to be associated with several antibodies including autoantibodies that target the DNA, C1q and histone, α-actinin, and the nucleosome. In addition, circulating anti-phosphoribosomal protein antibodies (anti-Ribos.P) were found to be associated with lupus nephritis. Study objective We have assessed the direct role of anti-Ribos.P in the development of glomerulonephritis in-vitro and in animal models. Study design NZBxW/F1 lupus prone mice were immunized with recombinant Ribos.P0 (rRibos.P). Evaluation of renal disease included mice evaluation for proteinuria and histologic analysis of the kidneys. Anti-Ribos.P monoclonal Ab was prepared from the rRibos.P immunized NZBxW/F1 mice by hybridoma technology. MAPKs expression was analyzed by MAPKs protein array and confirmed by real-time PCR and western blot. To elucidate whether anti-Ribos.P induce glomerulonephritis, naive C3H mice were immunized with recombinant rRibos.P and the glomerulonephritis was followed up as described above. Results The immunized NZBxW/F1 lupus prone mice developed anti-Ribos.P which was cross reactive with Sm and not dsDNA. The mice developed accelerated glomerulonephritis manifested by early proteinuria and immunoglobulin deposites in the mesangium of the kidneys. Anti-Ribos.P deposited in the glomerular mesangium were eluted from the kidney. The Ribos.P immunized naive C3H/Hen mice developed glomerulonephritis manifested by circulating autoantibodies directed to Ribos.P, dsDNA and Sm. The anti Ribos.P were cross reactive with Sm but not with dsDNA, and were deposited in the glomeruli. Interestingly these mice developed alopecia. In vitro. Primary mesangial cells exposed to mouse anti-Ribos.P mAb originated from the immunized lupus mice and to human anti-Ribos.P Abs, induced activation of mesangial cells via p38α, JNK, AKT and HSP27 MAPKs expression pathway. Conclusions Our data show for the first time that anti-Ribos.P are nephritogenic autoantibodies, as illustrated by in-vitro and in-vivo experiments: a) They accelerate the development of glomerulonephritis in lupus prone mice; b) They induce nephritis in naive mice. c) Anti-Ribos.P Abs trigger MAPKs expression in primary mesangial cells. These data contribute a direct mechanistic link between anti-Ribos.P and nephritis in lupus mice.

Background The deamidated gliadin peptides (DGP) cross linked to human tissue transglutaminase (tTg) comprises a novel neo-epitope structure (Neo-tTg) for serological screening of celiac disease (CD). Our aim is to verify anti-Neo-tTg IgA and IgG in adults with dermatitis herpetiformis (DH). Methods Multi-centric retrospective evaluation of the IgA/G autoantibodies in sera of DH patients on a regular diet (n = 40) and a gluten restricted diet (GRD, n = 53) and control adults with autoimmune skin diseases (n = 107) by ELISA. Results The sensitivities of Celicheck Neo IgA/G (76%, 95% CI 67–84%) and the Neo tTg-A (85%, 95% CI 70–97%) ELISA were significantly greater than that of tTg-A (56%, 95% CI 46–67%), eTg-A (62%, 95% CI 52–72%), DGP-A (55%, 95% CI 55–65%), DGP-G (61%, 95% CI 51–71%), Glia-A (55%, 95% CI 45–65%) and Glia-G (56%, 95% CI 46–66%) ELISA. The specificities of all 8 ELISA were in the range of 90–100%. The area under the curve (AUC) of receiver operator characteristic curve (ROC) for the two Neo-tTg ELISA (0.863 and 0.949) were higher than the AUCs for ROCs of tTg, DGP and eTG ELISA (range between 0.657 and 0.783). The autoantibody levels of DH patients on a normal diet were significantly higher than those on GRD in the Celicheck Neo IgA/IgG, NeotTg-A; tTg-A and the eTg-A; ELISA (p Conclusion Neo-epitope IgA autoantibodies represent a new and sensitive serological marker of DH.

Background Making the diagnosis of axial spondyloarthritis (axSpA) may be difficult. Antibodies against CD74 have been shown to be present in 2/3 of patients with long established axial SpA. Objectives InterSpA is an international multicenter study, conducted to compare the sensitivity and specificity of anti-CD74 and HLA-B27 in patients with axSpA of recent onset. Methods Patients between 18 and 45 years suffering from inflammatory back pain (IBP) for maximally 2 years were recruited. The presence of ankylosing spondylitis, additional inflammatory rheumatic disorders and biologic therapy were exclusion criteria. MRI of sacroiliac joint was performed in all patients; HLA-B27 was detected by genotyping and anti-CD74 using a CE certified kit of Aesku Diagnostics (Wendelsheim, Germany). The sensitivity of anti-CD74 and HLA-B27 were calculated in patients fulfilling the imaging arm of ASAS criteria, in all patients fulfilling ASAS criteria and in 100 blood donors. Both the MRI reading as well as the laboratory procedures were performed blinded. Results 205 patients suffering from IBP were recruited. There were 40 recruiting failures. The remaining 165 patients had a mean age of 29.4 years, a mean duration of IBP of 12.6 months, 50% of the patients were female. Sacroiliitis was diagnosed by the local and an independent expert reader in 71/123 (57.7%). So far complete data sets are available of 91 patients. Of these, 16 fulfilled the ASAS criteria of axSpA by a pathologic MRI only, 40 by both MRI and presence of HLA-B27 and 20 by HLA-B27 only. The sensitivities of IgA anti-CD74, IgG anti-CD74 and HLA-B27 were 71.4%, 26.8% and 75% in the 56 axSpA patients with a pathologic MRI, 73.7%, 23.7% and 81.6% in all 76 patients fulfilling ASAS criteria, and 3%, 5% and 8% in the blood donors. The likelihood ratios are 23.8 (IgA anti-CD74), 5.4 (IgG anti-CD74) and 9.4 (HLA-B27) when considering the patients with a pathologic MRI only, and 24.6 (IgA anti-CD74), 4.7 (IgG anti-CD74) and 10.2 (HLA-B27) when considering all patients fulfilling ASAS criteria. Conclusions Considering their specificity and sensitivity, IgA anti-CD74 is a useful addition to our diagnostic tools for axSpA. Acknowledgement This study is funded by AbbVie Deutschland GmbH & Co. KG. AbbVie contributes to study logistics and site management. The authors determined study design, conduct of the study and the content of the publication. No payments were made to the authors for writing this manuscript. Disclosure of Interest E. Riechers Grant/research support from: AbbVie GmbH, N. T. Baerlecken Grant/research support from: AbbVie GmbH, X. Baraliakos: None declared, K. Achilles-Mehr Bakhsh: None declared, P. M. Aries: None declared, B. Bannert: None declared, K. Becker: None declared, J. F. Brandt-Jurgens: None declared, J. Braun: None declared, B. Ehrenstein: None declared, H. Euler: None declared, M. Fleck: None declared, R. Hein: None declared, K. Karberg: None declared, L. Kohler: None declared, T. Matthias: None declared, R. Max: None declared, A. Melzer: None declared, D. Meyer-Olson: None declared, J. Rech: None declared, K. Rockwitz: None declared, M. Rudwaleit: None declared, E. Schweikhard Employee of: Aesku GmbH, J. Sieper: None declared, C. Stille: None declared, U. von Hinuber: None declared, P. Wagener: None declared, H. Weidemann: None declared, S. Zinke: None declared, T. Witte Grant/research support from: AbbVie GmbH

Background Spondyloarthritis (SpA) is a common debilitating inflammatory disorder. Pathogenesis of axial SpA (axSpA) including ankylosing spondylitis (AS) is still largely unclear. Objectives Diagnosis is difficult, since abnormalities in conventional X-rays develop with a latency of several years and only HLA-B27 is used as laboratory marker. The presence of radiographic sacroiliitis is essential for SpA diagnosis. To prevent destructive effects early diagnosis and intervention in SpA patients may be important. To evaluate antibodies to the human leukocyte antigen class II-associated invariant chain peptide (anti-CD74) as a diagnostic marker of SpA. Methods Sera of 117 patients with axial SpA and 38 non-SpA patients were analyzed for IgA and IgG antibodies against CD74 by ELISA. HLA-B27 status was available in 112 patients. All donors provided informed consent for the study approved by the local ethics committee (project number 4928). Results Anti-CD74 antibodies were detected in 85.1% of SpA patients but only in 5% of non-SpA patients (p≤0.0001). Detection of both IgG and IgA anti-CD74 antibodies for diagnosing SpA revealed a sensitivity of 77% and a specificity of 90%. Remarkably, IgA autoantibodies against CD74 alone had a sensitivity of 67% and a specificity of 95%. IgA anti-CD74 antibodies were even more frequent in SpA patients with short disease duration and significantly correlate with more advanced radiological sacroiliitis and reduced spinal mobility. Conclusions Anti-CD74 IgA antibodies were strongly associated with SpA. Antibodies against CD74 could provide an important additional tool for diagnosis of SpA. Disclosure of Interest None declared

The diagnosis of celiac disease (CD) remains a clinical challenge based on the incomplete specificity and sensitivity rates of current non-invasive tests. Furthermore, histological assessments fail to identify all overt cases and, in particular, do not manifest pathognomonic alterations in silent cases. Accordingly, the majority of CD cases are diagnosed with great delay. Recent research into the pathogenesis of CD, allowed us to identify a neo-antigen that appears to be the most promising serological tool for the detection of anti-tissue transglutaminase as well as anti-gliadin antibodies.

Venous or arterial thrombosis, abortion, and the presence of antiphospholipid antibodies (aPL) define the criteria for the antiphospholipid syndrome (APS). A heterogeneous group of antibodies against phospholipids and plasma proteins may influence several coagulation pathways and lead to thrombophilia. We investigated the presence of antibodies to thrombin (Thr) in patients with aPL and reviewed their clinical manifestations. IgG and IgM titers of aPL were measured by ELISA (Aesku.Diagnostics, Wendelsheim, Germany). Lupus anticoagulants (LA) were measured according to the criteria of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. One hundred twenty patients were identified with LA or anticardiolipin (aCL). Of the 120 patients, 98 (82%) had primary APS and 22 (18%) had secondary APS. Further, 76/120 (63%) were suffering from thromboembolic manifestations, mostly venous thrombosis. Anti-thrombin-IgG was detected in 20%, and anti-thrombin-IgM was detected in 23% of the patients. The presence of anti-thrombin antibodies was closely related to the presence of anti-beta(2)-glycoprotein-I (beta(2)-GP-I) (96%), aCL (97%), and LA (87%), and less well to the presence of anti-phosphatidylserine/prothrombin (Ser/Pro) antibodies (71%) or anti-prothrombin antibodies (Pro) (50%). Sixty-seven percent of the patients with anti-Thr-IgG suffered from thromboembolic complications, mostly arterial thrombosis. The rate of thrombosis was higher for these patients than for patients with anti-beta(2)-GP-I antibodies (37/60, 62%), LA (50/79, 63%), or anti-Ser/Pro antibodies (18/28, 64%). Anti-thrombin antibodies were found in 20% of patients with aPL; 67% of these patients were admitted with thrombotic manifestations of APS. The presence of anti-thrombin antibodies was closely associated with the presence of aCL and anti-beta(2)-GP-I antibodies. The sensitivity of the test for anti-thrombin antibodies for the diagnosis of APS was higher than the sensitivity of the anti-prothrombin assay and similar to the sensitivity of the anti-Ser/Pro assay.

Background The prevalence of serum autoantibodies in the general population is generally obtained from large datasets including blood donors or employees and are thus poorly representative. Similarly, it is challenging to determine the risk of developing an autoimmune disease in subjects found to be positive for serum autoantibodies in the absence of clinical suspicion. Objectives To determine the prevalence and predictive value of ANA, ENA, and ACPA antibodies in the general population participating in a 13-year longitudinal study. Methods The general population of a Northern Italian area was enrolled in 1998/1999 in a study to determine the prevalence of viral hepatitis infections. Resident subjects aged 18-75 were randomized 1:4 and 71% of subjects took part in the study (mean age 42, range 18-75, female/male 1.15). In 2011 serum samples (n=2690) were blindly tested for ANA, ENA, anti-CCP using commercially available indirect immunofluorescence and ELISA (Aesku.Diagnostics). For all subjects we sought for exemptions (i.e. the fiscal mechanism that allows subjects with a chronic condition to waive copayments for visits, medications, and blood tests) specific for autoimmune diseases (including connective tissue disease, CTD, and rheumatoid arthritis, RA) over the following 13 years. We should note that this approach does not account for 11% of the population which, for economic limits or advanced age, have a waiver overcoming the disease-specific exemptions. Administrative data were ultimately analyzed to determine the long-term predictive value of serum autoantibodies in terms of odd ratios (OR). Results Serum ANA were detected in 18.1% (for titers ≥1:80) and 5.7% (for titers ≥1:160) of tested samples and the observed pattern was speckled in 71% of cases. The prevalence of specific anti-ENA autoantibodies ranged between 0.1% (Jo-1) and 1.9% (anti-nucleosome) while ACPA were positive in 4.7% of subjects (0.9% considering only medium-to-high titers). In all cases, prevalence rates were higher in female individuals but the predominance was lower than classically reported for CTD and RA. The OR for developing any autoimmune disease for ANA positive individuals over 13 years was 2.77 (95% confidence interval -CI- 1.73-4.44). The OR of developing a CTD for individuals with high-titer ANA was 12.20 (95% CI 2.41-61.59) while the OR of developing RA with positive ACPA was 10.86 (95% CI 1.96-59.98). Conclusions We report that the prevalence of serum ANA, ENA, and ACPA may be higher than previously reported when a general unselected population is studied. Further, the serum positivity confers a significant risk of developing an autoimmune disease when subjects are observed for a sufficient period of time. Disclosure of Interest None Declared

It is often difficult to diagnose Sjogren syndrome (SS) with neurologic manifestations as frequently only the nervous system is affected and anti-Ro (SSA) and anti-La (SSB) antibodies are found in fewer than 50% of cases.1,2⇓ In a recent study, we demonstrated that primary progressive multiple sclerosis (PPMS) should be the principal differential diagnosis for SS with CNS manifestations.2 However, the question remains as to whether SS is secondary to MS or whether the two are separate entities.3,4⇓ It was recently reported that antibodies against α-fodrin are both a sensitive and a specific marker for SS.5,6⇓ α-Fodrin is a cytoskeletal protein that binds to the cytoplasmic domains of a variety of molecules expressed on the cell surface. It is abundantly expressed in salivary glands but also other tissues including synapses and is probably involved in exocytosis. α-Fodrin is cleaved by caspase 3 upon apoptosis into …

The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption.The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them.Glucose, salt, emulsifiers, organic solvents, gluten, microbial transglutaminase, and nanoparticles are extensively and increasingly used by the food industry, claim the manufacturers, to improve the qualities of food. However, all of the aforementioned additives increase intestinal permeability by breaching the integrity of tight junction paracellular transfer. In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part played by the tight junction in autoimmune diseases pathogenesis is extensively described. It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus, increasing intestinal permeability through the opened tight junction, resulting in entry of foreign immunogenic antigens and activation of the autoimmune cascade. Future research on food additives exposure-intestinal permeability–autoimmunity interplay will enhance our knowledge of the common mechanisms associated with autoimmune progression.

Infections can act as environmental triggers inducing or promoting autoimmune disease in genetically predisposed individuals. Identification of microbial peptides similar to self-tissues may by molecular mimicry, provide the inducing mechanism for an immune response. The aim of this study was to identify autoantibodies (autoAbs) in nonautoimmune individuals during acute bacterial, viral, or parasitic infections. Specific Abs or specific infections with an increased autoAb load may shed insight into the mechanisms of autoimmune disease. Sera from 88 patients with acute infections (41 bacterial, 23 viral, 17 parasitic, and 7 rickettsial) were tested by the ELISA method for antinuclear antibodies (ANA) 8 Pro, and Abs to thyroid peroxidase (TPO), thyroglobulin, phospholipids, annexin-V, laminin, anti-Saccharomyces cervisiae (ASCA), and prothrombin, along with 80 normal controls. Elevated titers of Abs to annexin-V and prothrombin were the most prevalent in viral, parasitic, and rickettsial infections and to laminin in viral and parasitic infections. Elevated titers of ASCA and ANA were found in viral and bacterial infections. Antiphospholipid Abs were found in parasitic and Q-fever infections. Thirty-four individuals harbored elevated titers of at least two Abs. An autoAb burden was detected in individuals with hepatitis A, hepatitis B, toxoplasma or Q-fever infections. In nonautoimmune individuals with various (bacterial, viral, parasitic, and rickettsial) infections, elevated titers of Abs to annexin-V, prothrombin, laminin, ASCA, ANA, and phospholipids were most frequently detected.