Antigen processing and autoimmunity. Evaluation of mRNA abundance and function of HLA-linked genes.
Quantitative defects in the density of conformationally correct human lymphocyte antigen (HLA) class I complexes on the surface of lymphocytes are apparent in patients with diverse HLA-linked autoimmune diseases, including Type I diabetes and Sjögren's syndrome. First, HLA class I expression was investigated in individuals with two rare and genetically divergent polyglandular autoimmune diseases. Polyglandular failure patients whose disease showed HLA linkage, but not those whose disease was not HLA linked, exhibited decreased HLA class I expression on the surface of their lymphocytes as well as a reduced abundance of transcripts of the HLA-linked genes Tap1 and Tap2, both of which encode proteins that contribute to HLA class I processing. Second, lymphocytes from patients with insulin-dependent diabetes mellitus (IDDM), Sjögren's syndrome, Graves' disease, and Hashimoto's disease showed varying degrees of decreased abundance of mRNAs that encode Tap1, Tap2, Lmp2, or Lmp7 (the latter two proteins also contribute to HLA class I processing). Third, in twins discordant for IDDM, reduced transcript abundance was preferential to diabetic subjects. Fourth, functional assays of isolated diabetic proteasomes, the peptide cutting complex containing LMP2 and LMP7 proteins, revealed altered peptidase activity. These data suggest that defective transcription of HLA class I-processing genes could contribute to the quantitative defect in cell-surface expression in autoimmune lymphocytes of HLA-controlled disease.
Fu
Y
Y
Immunobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA.
Yan
G
G
Shi
L
L
Faustman
D
D
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology; D003546:Cysteine Endopeptidases; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005805:Genes, MHC Class I / Q000235:genetics*; D006111:Graves Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014427:Twins
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D006680:HLA Antigens; D009097:Multienzyme Complexes; D011506:Proteins; D012333:RNA, Messenger; C073119:TAP1 protein, human; C071313:LMP-2 protein; C071692:TAP2 protein, human; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex