Impaired processing and presentation by MHC class II proteins in human diabetic cells.
The biochemical processing of and Ag presentation by MHC class II molecules were examined in B cell lines derived from pairs of identical twins discordant for type 1 diabetes. MHC class II defects detected exclusively in cells derived from the twins with autoimmunity included increased rates of transport to and subsequent turnover at the cell surface, inadequate glycosylation, and a reduced display at the cell surface of antigenic peptides. These defects appeared to be secondary to a decreased abundance of the p35 isoform of the invariant chain (Ii), a human-specific chaperone protein for MHC class II normally generated by use of an alternative translation start site. Stable transfection of diabetic B cell lines with an Ii p35 expression vector corrected the defects in MHC class II processing and peptide presentation. A defect in the expression of Ii p35 may thus result in impairment of Ag presentation by MHC class II molecules and thereby contribute to the development of type 1 diabetes in at-risk genotypes.
Yan
Gang
G
Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Shi
Lijia
L
Penfornis
Alfred
A
Faustman
Denise L
DL
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004200:Diseases in Twins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology*; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D014162:Transfection; D014430:Twins, Monozygotic / Q000235:genetics
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D010455:Peptides; C045084:invariant chain