{"doi":"10.1016/j.xops.2021.100056","title":"EnRAPtured: Is Endoplasmic Reticulum Aminopeptidase a New Clue to the Pathogenesis and ThERAPy of Uveitis?","abstract":"Baruj Benacerraf and Hugh O. McDevitt are sometimes called the discoverers of immune response genes because their seminal research showed that the immune response was under genetic control. The primary genes identified by this pair are located in the major histocompatibility complex (MHC), known as HLA genes in humans. In 1972, the two wrote a prescient commentary that appeared in Science.1Benacerraf B. McDevitt H.O. Histocompatibility-linked immune response genes.Science. 1972; 175: 273-279Crossref PubMed Scopus (808) Google Scholar In essence, they argued that if genes control the immune response, and if some diseases are triggered by the immune response, then those same genes might influence who receives a diagnosis of diseases like rheumatoid arthritis, systemic lupus erythematosus, or Graves’ disease. Their prediction was validated approximately 1 year later2Brewerton D.A. Hart F.D. Nicholls A. et al.Ankylosing spondylitis and HL-A 27.Lancet. 1973; 1: 904-907Abstract PubMed Scopus (1396) Google Scholar and has been shown to hold true for more than 100 diseases.3Shiina T. Inoko H. Kulski J.K. An update of the HLA genomic region, locus information and disease associations: 2004.Tissue Antigens. 2004; 64: 631-649Crossref PubMed Scopus (269) Google Scholar For most genetically complex immune-mediated diseases, the HLA genes affect the likelihood of disease developing more than any other gene identified in genome-wide association studies. Although Benacerraf and McDevitt made an insightful deduction, their reasoning might have been incorrect. Fifty years ago, many immune-mediated diseases were labelled autoimmune. Rheumatoid arthritis, systemic lupus erythematosus, and Graves’ disease are characterized by autoantibodies, so it makes sense to believe that the immune system is attacking itself, and it is plausible that immune response genes of the major histocompatibility complex affect the magnitude of that response. But this logic has 2 flaws. First, many immune-mediated diseases like sarcoidosis, ankylosing spondylitis, or birdshot chorioretinopathy (BSCR) are not necessarily autoimmune diseases.4McGonagle D. McDermott M.F. A proposed classification of the immunological diseases.PLoS Med. 2006; 3: e297Crossref PubMed Scopus (508) Google Scholar Disease-causing autoantibodies are not characteristic of these diseases. Second and more importantly, even in diseases in which autoantibodies are detectable, rarely, if ever, has a study documented that the HLA genes affect the immune response to the putative autoantigen. In celiac disease, the HLA allele, DQ2.5, does impact the immune response to peptides derived from gluten,5Vader W. Stepniak D. Kooy Y. et al.The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses.Proc Natl Acad Sci U S A. 2003; 100: 12390-12395Crossref PubMed Scopus (290) Google Scholar which is present in diet. An immune response to gluten is causally related to celiac disease, although gluten itself is not an autoantigen. Nevertheless, celiac disease is arguably the disease that best connects disease predisposition to a genetically controlled immune response. The HLA system is the most polymorphic germline genetic system known. The major histocompatibility complex includes class I genes encoded by HLA A, B, and C loci and class II genes encoded by DR, DP, and DQ loci. HLA class I molecules present antigen to CD8 T cells (Fig 1), which perform killer and suppressor functions. HLA class II molecules present antigen to CD4 T cells, which are often labeled helper T cells. For most loci, hundreds of different alleles exist. Considering that an allele is inherited from each parent and some loci have hundreds of allotypes, there are many millions of combinations of different gene products. A teleologic argument is that this genetic diversity helps to protect a species from extinction during a pandemic. Class II genes are most likely to influence","journal":"Ophthalmology Science","year":2021,"id":197116,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":697090,"name":"Tejpal Gill","orcid":"0000-0002-9567-3827","position":1,"is_corresponding":false},{"id":293021,"name":"Tammy M. Martin","orcid":"0000-0002-4296-2422","position":2,"is_corresponding":false},{"id":293022,"name":"James T. Rosenbaum","orcid":"0000-0002-8452-2441","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-18T23:50:19.568641Z","pmid":"36247819","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}