The autoimmune targets in IPEX are dominated by gut epithelial proteins

Non peer reviewe

A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen

Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.Peer reviewe

A longitudinal follow-up of autoimmune polyendocrine syndrome type 1

Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971337/Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insuffi- ciency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse. Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator ( AIRE) mutations during extended follow-up (1996–2016). Patients: All known Norwegian patients with APS1. Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent compo- nents.Withage,mostpatientspresentedthreetofivediseasemanifestations,althoughsomehadmilderphenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceasedsiblingswithahighprobabilityofundisclosedAPS1.Allexceptthreehadinterferon- )autoantibodies,and allhadorgan-specificautoantibodies.Themostcommon AIRE mutationwasc.967_979del13,foundinhomozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879 1G A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes. Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon- ) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center

Biomarker Discovery in Tissue-specific Autoimmune Disease

Autoimmune diseases encompass a diverse group of disorders that collectively affect 5% of the population. Despite large clinical variability, autoimmune disorders share a common etiology in that they all develop from immune responses against self. T-cell receptors and antibodies recognize distinct self-molecules and direct destructive effector mechanisms to the target organs. Characterization of autoimmune targets can help in the understanding autoimmune disease features and is of additional importance for subsequent use in clinical diagnosis. Rare monogenic disorder can provide an access to the study and understanding of mechanisms underlying common and more complex diseases. Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the AIRE gene, and is a valuable model of tissue-specific autoimmune disease. APS1 patients develop multiple autoimmune disease manifestations and display autoantibodies against the affected tissues. Recent development in protein array technology has opened a novel avenue for explorative biomarker studies in autoimmune disorders. Present-day protein arrays contain many thousands of full-length human proteins and enable autoantibody screens at the proteome-scale. In the current work I have utilized proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Survey of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of 9000 proteins we further identified three novel, major autoantigens. Our findings revealed a marked enrichment for tissue-specific immune targets and further suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1. This work identifies prostatic transglutaminase 4 as novel male-specific autoantigen. In the mouse model of APS1 we could link TGM4 immunity with a tissue-destructive prostatitis, a compromised prostatic secretion of TGM4 and with defect in the establishment of central immune tolerance for TGM4. Our findings suggest prostate autoimmunity is a major manifestation in male APS1 patients with potential role in development of subfertility. In this doctoral work we also report on collecting duct autoantibodies in APS1 patients with interstitial nephritis and on the identification of aquaporin 2 as a collecting duct autoantigen. Collectively, the present investigations provide an overview-perspective on the autoimmune target repertoire in APS1 and identify novel autoimmune manifestations of the syndrome

Biomarker Discovery in Tissue-specific Autoimmune Disease

Autoimmune diseases encompass a diverse group of disorders that collectively affect 5% of the population. Despite large clinical variability, autoimmune disorders share a common etiology in that they all develop from immune responses against self. T-cell receptors and antibodies recognize distinct self-molecules and direct destructive effector mechanisms to the target organs. Characterization of autoimmune targets can help in the understanding autoimmune disease features and is of additional importance for subsequent use in clinical diagnosis. Rare monogenic disorder can provide an access to the study and understanding of mechanisms underlying common and more complex diseases. Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the AIRE gene, and is a valuable model of tissue-specific autoimmune disease. APS1 patients develop multiple autoimmune disease manifestations and display autoantibodies against the affected tissues. Recent development in protein array technology has opened a novel avenue for explorative biomarker studies in autoimmune disorders. Present-day protein arrays contain many thousands of full-length human proteins and enable autoantibody screens at the proteome-scale. In the current work I have utilized proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Survey of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of 9000 proteins we further identified three novel, major autoantigens. Our findings revealed a marked enrichment for tissue-specific immune targets and further suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1. This work identifies prostatic transglutaminase 4 as novel male-specific autoantigen. In the mouse model of APS1 we could link TGM4 immunity with a tissue-destructive prostatitis, a compromised prostatic secretion of TGM4 and with defect in the establishment of central immune tolerance for TGM4. Our findings suggest prostate autoimmunity is a major manifestation in male APS1 patients with potential role in development of subfertility. In this doctoral work we also report on collecting duct autoantibodies in APS1 patients with interstitial nephritis and on the identification of aquaporin 2 as a collecting duct autoantigen. Collectively, the present investigations provide an overview-perspective on the autoimmune target repertoire in APS1 and identify novel autoimmune manifestations of the syndrome

Screening for autoantibody targets in post-vaccination narcolepsy using proteome arrays

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a specific loss of hypocretin-producing neurons. The incidence of NT1 increased in Sweden, Finland and Norway following Pandemrix®-vaccination, initiated to prevent the 2009 influenza pandemic. The pathogenesis of NT1 is poorly understood, and causal links to vaccination are yet to be clarified. The strong association with Human leukocyte antigen (HLA) DQB1*06:02 suggests an autoimmune pathogenesis, but proposed autoantigens remain controversial. We used a two-step approach to identify autoantigens in patients that acquired NT1 after Pandemrix®-vaccination. Using arrays of more than 9000 full-length human proteins, we screened the sera of 10 patients and 24 healthy subjects for autoantibodies. Identified candidate antigens were expressed in vitro to enable validation studies with radiobinding assays (RBA). The validation cohort included NT1 patients (n = 39), their first-degree relatives (FDR) (n = 66), population controls (n = 188), and disease controls representing multiple sclerosis (n = 100) and FDR to type 1 diabetes patients (n = 41). Reactivity towards previously suggested NT1 autoantigen candidates including Tribbles homolog 2, Prostaglandin D2 receptor, Hypocretin receptor 2 and α-MSH/proopiomelanocortin was not replicated in the protein array screen. By comparing case to control signals, three novel candidate autoantigens were identified in the protein array screen; LOC401464, PARP3 and FAM63B. However, the RBA did not confirm elevated reactivity towards either of these proteins. In summary, three putative autoantigens in NT1 were identified by protein array screening. Autoantibodies against these candidates could not be verified with independent methods. Further studies are warranted to identify hypothetical autoantigens related to the pathogenesis of Pandemrix®-induced NT1

Monitoring drug–target interactions through target engagement-mediated amplification on arrays and in situ

Drugs are designed to bind their target proteins in physiologically relevant tissues and organs to modulate biological functions and elicit desirable clinical outcomes. Information about target engagement at cellular and subcellular resolution is therefore critical for guiding compound optimization in drug discovery, and for probing resistance mechanisms to targeted therapies in clinical samples. We describe a target engagement-mediated amplification (TEMA) technology, where oligonucleotide-conjugated drugs are used to visualize and measure target engagement in situ, amplified via rolling-circle replication of circularized oligonucleotide probes. We illustrate the TEMA technique using dasatinib and gefitinib, two kinase inhibitors with distinct selectivity profiles. In vitro binding by the dasatinib probe to arrays of displayed proteins accurately reproduced known selectivity profiles, while their differential binding to fixed adherent cells agreed with expectations from expression profiles of the cells. We also introduce a proximity ligation variant of TEMA to selectively investigate binding to specific target proteins of interest. This form of the assay serves to improve resolution of binding to on- and off-target proteins. In conclusion, TEMA has the potential to aid in drug development and clinical routine by conferring valuable insights in drug–target interactions at spatial resolution in protein arrays, cells and in tissues

Autoantibodies and infection with SARS-CoV2 infection: The spectrum from association to clinical implication:Report of the 15th Dresden Symposium on Autoantibodies

The relation between infections and autoimmune diseases has been extensively investigated. Multiple studies suggest a causal relation between these two entities with molecular mimicry, hyperstimulation and dysregulation of the immune system as plausible mechanisms. The recent pandemic with a new virus, i.e., SARS-CoV-2, has resulted in numerous studies addressing the potential of this virus to induce autoimmunity and, eventually, autoimmune disease. In addition, it has also revealed that pre-existing auto-immunity (auto-Abs neutralizing type I IFNs) could cause life-threatening disease. Therefore, the topic of the 15th Dresden Symposium on Autoantibodies was focused on autoimmunity in the SARS-CoV-2 era. This report is a collection and distillation of the topics presented at this meeting