title: Immunodeficiency and autoimmunity in H2-O-deficient mice.
abstract: HLA-DO/H2-O is a highly conserved, nonpolymorphic MHC class II-like molecule expressed in association with H2-M in thymic epithelial cells, B lymphocytes, and primary dendritic cells. The physiological function of DO remains unknown. The finding of cell maturation-dependent DO expression in B lymphocytes and dendritic cells suggests the possibility that H2-O functions to promote the presentation of exogenous Ag by attenuating presentation of endogenous self-peptides. In the current study, we report that H2-O(-/-) mice spontaneously develop high titers of IgG2a/c antinuclear Abs (ANAs) with specificity for dsDNA, ssDNA, and histones. Reconstitution of RAG1(-)(/)(-) mice with T and B cells from H2-O(-)(/)(-) or wild-type mice demonstrated that production of ANAs requires participation of CD4(+) T cells from H2-O(-)(/)(-) mice. Bone marrow chimeras demonstrated that loss of H2-O expression in thymic epithelial cells did not induce ANAs, and that lack of H2-O expression in bone marrow-derived cells was sufficient to induce the autoimmune phenotype. Despite production of high titers of autoantibodies, H2-O(-/-) mice exhibit a delayed generation of humoral immunity to model Ags (OVA and keyhole limpet hemocyanin), affecting all major T-dependent Ig classes, including IgG2a/c. Ag presentation experiments demonstrated that presentation of exogenous Ag by H2-O(-/-) APC was inefficient as compared with wild-type APC. Thus, H2-O promotes immunity toward exogenous Ags while inhibiting autoimmunity. We suggest that H2-O, through spatially or temporally inhibiting H2-M, may enhance presentation of exogenous Ag by limiting newly generated MHC class II molecules from forming stable complexes with endogenous self-peptides.
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Yapeng
authors.initials: Y
authors.lastname: Gu
authors.forename: Peter E
authors.initials: PE
authors.lastname: Jensen
authors.forename: Xinjian
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control; D045744:Cell Line, Tumor; D006183:H-2 Antigens / Q000235:genetics* / Q000276:immunology*; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D001323:Autoantibodies; D006183:H-2 Antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; C046148:HLA-DO antigens