Genetic background of tolerance breakdown in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a complex mutifactorial autoimmune disease. As anti-citrullinated peptide antibodies (ACPA) exhibit unique specificity for RA, breakdown of immunological tolerance to citrullinated self-proteins is considered to be a key feature of RA pathogenesis. While environmental factors such as smoking and viral infections have been implicated in the pathogenesis, recent genome-scans for RA have unraveled multiple genetic factors involved in RA. Some of these genetic factors may specifically contribute to the tolerance breakdown of RA. For instance, PADI4 gene encoding an enzyme that converts arginine residues to citrullines may enhance the production of auto-antigens. These citrullinated proteins are then presented to helper T-cells via HL-DR molecule on the antigen presenting cells, where specific HLA-DRB1 alleles encoding "shared-epitope" have significant relevance to RA. On the other hand, genes regulating the activity of lymphocytes such as PTPN22 and FCRL3 may influence auto-reactivity of individual lymphocytes. Taken together, combination of these genetic factors accelerates autoimmune response in RA.
Kochi
Yuta
Y
Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN.
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics*; D002956:Citrulline / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D006867:Hydrolases / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics*; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D020412:Multifactorial Inheritance / Q000235:genetics; D010455:Peptides / Q000276:immunology*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000502:physiology; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011971:Receptors, Immunologic / Q000502:physiology
D001323:Autoantibodies; C457775:FCRL3 protein, human; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010455:Peptides; D011971:Receptors, Immunologic; D002956:Citrulline; D001120:Arginine; D006867:Hydrolases; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; C552151:peptidylarginine deiminase 4, mouse