Transcriptomic Segregation of Human Autoantigens Useful for the Diagnosis of Autoimmune Diseases

Abstract

The measurement of autoantibodies in the clinical care of autoimmune patients allows for diagnosis, monitoring, and even disease prediction. Despite their clinical utility, the functional significance of autoantibody target proteins in many autoimmune diseases remains unclear. Here we present a comprehensive review of 52 autoantigens commonly employed for the serological diagnosis of 24 autoimmune diseases. We discuss their function, whether they have extracellular-exposed epitopes, and whether antibodies to these proteins are known to be pathogenic. Transcriptomics (RNA-Seq) datasets were mined to display messenger RNA (mRNA) expression of the autoantigens across 32 tissues and organs. This analysis revealed that autoantigens cluster into one of three groups: expression in the tissue most strongly affected in the disease (Group I), ubiquitous expression with enrichment in immune tissues (Group II), or expression in other tissues not typically associated with the clinical presentation (Group III). Clustering demonstrated that the autoantigens within Group I were often proteins containing extracellular epitopes, many of which are targets of pathogenic autoantibodies. Group II autoantigens were targets for several rheumatological diseases, including Sjögren syndrome, systemic lupus erythematosus, myositis, and systemic sclerosis, and were ubiquitously expressed with enrichment in immune-rich tissues. This raises the possibility that immune cells in Group II disorders may be the source of autoimmunization and/or targets of immune cell responses. Since tissues showing enriched autoantigen gene expression may contribute to the development of autoantibodies and subsequent autoimmunity, the emergent patterns arising from the autoantigen transcriptomic profiles may provide a new heuristic framework to deconvolute these complex disorders.

Autoantibody Repertoire in APECED Patients Targets Two Distinct Subgroups of Proteins

“…Autoantibodies to these proteins emerge by actions of yet unknown mechanisms associated, for example, with apoptotic cell death or by dysfunctional B cell tolerance during differentiation in lymphoid tissues. Our findings are supported by RNA-seq analysis of autoantigen-encoding genes, which identified a subset of autoantigens, associated with autoimmune diseases, to be expressed ubiquitously but enriched in immune tissues ( 64 ). It should be noted that, in contrast to other immune tissues, the thymus was not available via Human Protein Atlas ( 20 ).…”

Trojans in Oral Environments: Evidence of Molecular Mimicry in Oral Immunity

“…Gastritis is a chronic inflammatory disease involving gastric body and fundus, with the progressive reduction and/or disappearance of gastric glands that are sometimes replaced by intestinal or pyloric epithelium [60]. Autoantigens for the autoimmune gastritis has been related as Gastric ATPase α subunit, Gastric ATPase β subunit and Gastric intrinsic factor [61]. Gastric ATPase α subunit have three epitopes in different position in the same protein with a 6 aa, 7aa and 15 aa similarity, to Ca2 + Àtransporting ATPase of Streptococcus pneumoniae ( Table 6).…”

“…Autoimmune hepatitis is a chronic and progressive inflammation of the liver from an unknown cause, whose pathology is explained by the failure of immune tolerance in a genetically susceptible individual leading to a reactive T-cell mediated inflammation caused by various environmental triggers including infections, medications, and toxins [62]. Autoantigens for autoimmune hepatitis have been related such as O-phosphoseryl-tRNA(Sec) selenium transferase (SLA), cytochrome P450 2D6 isoform 1 (CYP2D6) and formimidoyltransferasecyclodeaminase isoform C (FTCD) [61]. FTCD epitopes have similarities with glutamate Table 7).…”

“…Primary biliary cirrhosis is associated with highly specific autoantibody [64]. The anti-mitochondrial antibody is found in 85% of the cases, other antibodies associated with disease is an antinuclear antibody (ANA), anti-multiple nuclear dot antibody (anti-MND), anticentromere antibody, pyruvate dehydrogenase complex E2 (PDC-E2) and antinuclear envelop antibody [61,63] . PDC-E2, possess 7 aa with similarities to dihydrolipoyllysine-residue acetyltransferase of Enterococcus spp.…”

“…Although myositis is often treatable, these diseases are poorly understood and do not always completely respond to current medications [66]. Autoantigens has been related in the literature: histidine-tRNA ligase, cytoplasmic isoform 2, threonine-tRNA ligase, cytoplasmic isoform 1, exosome complex component RRP45 isoform 1, exosome component 10 isoform 1, chromodomain-helicase-DNA-binding protein 4 isoform 1, interferon-induced helicase C domain-containing protein 1, MORC family CW-type zinc finger protein 3 isoform 2, signal recognition particle 54 kDa protein isoform 2, E3 ubiquitin-protein ligase TRIM33 isoform alpha and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 1 [61]. Threonine-tRNA ligase, cytoplasmic isoform 1 autoantigen, possess many epitopes with high similarities with threonine-tRNA ligase of Aggregatibacter actinomycetemcomitans and threonine-tRNA ligase of Streptococcus spp.…”