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.

Neutralizing Antibody Responses to Viral Infections Are Linked to the Non-classical MHC Class II Gene H2-Ob

“…Thus, it was predicted that H2-O has evolved to control humoral immunity to self. However, although some elements of autoimmunity were previously reported in aged mice from one colony of H2-O-deficient ( H2-Oa −/− ) mice (Gu et al, 2013) it was not supported by other studies (Liljedahl et al, 1998). These contradictory results may indicate that the Ab response observed by Gu et al .…”

“…Thus, we directly measured the impact of I/LnJ H2-Ob on MHC-II peptide presentation. Cells that lack H2-O have lower levels of MHC-II-CLIP complexes as H2-M function is enhanced in the absence of inhibition by H2-O (Gu et al, 2013) and MHC-II-CLIP levels on the cell surface can be used as a read-out to measure H2-M activity (Chen et al, 2002; Denzin et al, 1997; Glazier et al, 2002). Therefore, we used an Ab that specifically recognizes I-A b -CLIP complexes (Liljedahl et al, 1998) to measure H2-M activity in B cells from B6, B6.…”

The Other Function: Class II-Restricted Antigen Presentation by B Cells

“…Another non-classical class II molecule, HLA-DO (DO), also plays an essential role in antigen presentation in B cells (126–129), as knockout of the murine DO homolog, H2-O, leads to immunodeficiency and autoimmunity that are directly related to dysfunction of antigen presentation by bone marrow-derived cells (130). Although DO is structurally quite homologous to classical MHCII, there is no evidence that it can directly present peptides.…”

Fatal autoimmunity results from the conditional deletion of Snai2 and Snai3

“…Next, we analyzed the generation of IgG AA, an indicator of a break in T cell tolerance [27]. Our initial analysis of permeabilized cell reactivity showed that seven of eleven cDKO mice had circulating IgG AA (Fig.…”

“…WT plasma served as a negative control. Plasma from H2-O −/− deficient animals served as a positive control: these animals have been shown to develop IgG2a autoantibodies specific for nuclear antigens due to defects in MHC II presentation [27]. cDKO plasma samples demonstrated a diffuse pattern of IgM reactivity present in the cytoplasm with an apparent absence of nuclear staining (Fig.…”