Wendelsheim, Germany
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Matthias T.,Aeskukipp Institute | Neidhofer S.,Aeskukipp Institute | Pfeiffer S.,AESKU.Diagnostics GmbH Co. KG | Prager K.,AESKU.Diagnostics GmbH Co. KG | And 2 more authors.
Cellular and Molecular Immunology | Year: 2011

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. © 2011 CSI and USTC. All rights reserved.


PubMed | Chaim Sheba Medical Center, Technion - Israel Institute of Technology, Shalvata Mental Health Care Center, Aeskukipp Institute and 2 more.
Type: | Journal: Digestive diseases and sciences | Year: 2016

Syndecan-1 (SDC1) is essential for maintaining normal epithelial barrier. Shedding of SDC1 ectodomain, reflected by serum soluble syndecan-1 (SSDC1) levels, is regulated by inflammation. Increased intestinal permeability plays a central role in celiac disease (CD). The association between SSDC1 levels and mucosal damage in CD has not been evaluated.To evaluate serum SSDC1 levels in children with CD and to determine its relationship with histological grading classified by modified Marsh criteria.This is a cross-sectional, pilot study, in which serum SSDC1 was analyzed by ELISA in a cohort of 49 untreated children with CD and 15 children with nonspecific abdominal pain (AP). CD was diagnosed based on positive celiac serology and small intestinal biopsy. SSDC1 levels at the time of biopsy were correlated with Marsh grading. Controls were defined by AP, negative celiac serology, normal upper endoscopy, and small intestinal biopsies.SSDC1 levels were significantly higher in CD patients compared to AP controls (116.2161 vs. 41.317.5ng/ml, respectively, p<0.01). SSDC1 levels were significantly higher in patients with Marsh 3c lesion compared to AP controls (170.6201 vs. 41.317.5ng/ml, respectively, p<0.05). SSDC1 concentrations displayed a significant correlation with mucosal damage defined by Marsh (r=0.39, p<0.05).This is the first study demonstrating elevated levels of serum SSDC1 in children with CD. Our results suggest that SSDC1 is a potentially novel marker of intestinal mucosal damage in patients with CD. Its applicability as a surrogate biomarker in CD remains to be determined.


Lerner A.,Technion - Israel Institute of Technology | Lerner A.,Aeskukipp Institute | Aminov R.,University of Aberdeen | Matthias T.,Aeskukipp Institute
Frontiers in Microbiology | Year: 2016

The gut ecosystem with myriads of microorganisms and the high concentration of immune system cells can be considered as a separate organ on its own. The balanced interaction between the host and microbial cells has been shaped during the long co-evolutionary process. In dysbiotic conditions, however, this balance is compromised and results in abnormal interaction between the host and microbiota. It is hypothesize here that the changed spectrum of microbial enzymes involved in post-translational modification of proteins (PTMP) may contribute to the aberrant modification of host proteins thus generating autoimmune responses by the host, resulting in autoimmune diseases. © 2016 Lerner, Aminov and Matthias.


PubMed | University College Dublin, Sagol Neuroscience Center, Tel Aviv University, Aeskukipp Institute and El Rosario University
Type: | Journal: Rheumatology (Oxford, England) | Year: 2016

Anti-ribosomal-phosphoprotein antibodies (anti-Ribos.P Abs) are detected in 10-45% of NPSLE patients. Intracerebroventricular administration of anti-ribosomal-P Abs induces depression-like behaviour in mice. We aimed to discern the mechanism by which anti-Ribos.P Abs induce behavioural changes in mice.Anti-Ribos.P Abs were exposed to human and rat neuronal cell cultures, as well as to human umbilical vein endothelial cell cultures for a control. The cellular localization of anti-Ribo.P Abs was found by an immunofluorescent technique using a confocal microscope. Identification of the target molecules was undertaken using a cDNA library. Immunohistochemistry and an inhibition assay were carried out to confirm the identity of the target molecules. Neuronal cell proliferation was measured by bromodeoxyuridine, and Akt and Erk expression by immunoblot.Human anti-Ribos.P Abs penetrated into human neuronal cells and rat hippocampal cell cultures in vitro, but not to endothelial cells as examined. Screening a high-content human cDNA-library with anti-Ribos.P Abs identified neuronal growth-associated protein (GAP43) as a target for anti-Ribos.P Abs. Ex vivo anti-Ribos.P Abs bind to mouse brain sections of hippocampus, dentate and amygdala. Anti-Ribos.P Abs brain-binding was prevented by GAP43 protein. Interestingly, GAP43 inhibited in a dose-dependent manner the anti-Ribos.P Abs binding to recombinant-ribosomal-P0, indicating mimicry between the ribosomal-P0 protein and GAP43. Furthermore, anti-Ribos.P Abs reduced neuronal cell proliferation activity in vitro (P < 0.001), whereas GAP43 decreased this inhibitory activity by a factor of 7.6. The last was related to Akt and Erk dephosphorylation.Anti-Ribos.P Abs penetrate neuronal cells in vitro by targeting GAP43. Anti -Ribos.P Abs inhibit neuronal-cell proliferation via inhibition of Akt and Erk. Our data contribute to deciphering the mechanism for anti-Ribos.P Abs pathogenic activity in NPSLE.


Baerlecken N.T.,Leibniz University of Hanover | Nothdorft S.,Leibniz University of Hanover | Stummvoll G.H.,Medical University of Vienna | Sieper J.,Charité - Medical University of Berlin | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Background Spondyloarthritis (SpA) is a common debilitating inflammatory disorder. Establishing the diagnosis is often difficult, since abnormalities in conventional X-ray develop with a latency of several years and only HLA-B27 is used as a laboratory marker. The goal of our study was to identify new autoantibodies as diagnostic markers of SpA. Methods: Protein array technology was used to screen for new autoantigens in ankylosing spondylitis. Then, the results were confirmed by ELISA using Class II-associated invariant chain peptide domain of CD74 as antigen. Sera for the ELISA were obtained from 216 patients with axial (n=156) and peripheral (n=60) SpA. Sera of patients with psoriatic arthritis without axial involvement as another subtype of peripheral SpA, rheumatoid arthritis, systemic lupus erythematosus, HIV infection and blood donors served as controls. All donors provided informed consent for the study which was approved by the local ethics committee ( project number 4928). Results: Using protein arrays, we detected IgG antibodies against CD74 in SpA sera. Using ELISA technology on sera that had previously been frozen for several years, IgG autoantibodies against CD74 were found in 67% of the SpA patients and were even more frequent in patients with a short disease duration. In the controls, the prevalence of the new autoantibodies was 18/40 (45%) in psoriatic arthritis without axial involvement, 9/80 (11%) in rheumatoid arthritis, 6/40 (15%) in systemic lupus erythematosus, 1/40 (2.5%) in HIV and 1/125 (0.8%) in blood donors. Conclusions: Antibodies against CD74 could provide an important additional tool for diagnosis of SpA.


Ben-Ami Shor D.,Tel Aviv University | Blank M.,Tel Aviv University | Reuter S.,Aeskukipp Institute | Matthias T.,Aeskukipp Institute | And 4 more authors.
Journal of Autoimmunity | Year: 2014

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, naïve 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 naïve 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 naïve 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. © 2014 Elsevier Ltd.


Lerner A.,Technion - Israel Institute of Technology | Matthias T.,Aeskukipp Institute
Autoimmunity Reviews | Year: 2015

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. © 2015.


Lerner A.,Technion - Israel Institute of Technology | Matthias T.,Aeskukipp Institute
Autoimmunity Reviews | Year: 2015

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. © 2015 Elsevier B.V.


PubMed | Aeskukipp Institute and Technion - Israel Institute of Technology
Type: Review | Journal: Autoimmunity reviews | Year: 2016

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<0.0001). All mTg-neo and tTg-neo levels were higher (p<0.001). tTg IgA and IgG+IgA were higher than mTg IgA and IgA+IgG (p<0.0001). The levels of tTg-neo IgA/IgG were higher than tTg IgA/IgG (p<0.0001). The sequential antibody activities best reflecting the increased intestinal damage were tTg-neo check>tTg-neo IgAmTg-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 (r


PubMed | Aeskukipp Institute and Technion - Israel Institute of Technology
Type: | Journal: Journal of immunological methods | Year: 2016

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.

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