Linda K. Myers

The Human Endoplasmic Reticulum Molecular Chaperone BiP Is an Autoantigen for Rheumatoid Arthritis and Prevents the Induction of Experimental Arthritis

Rheumatoid arthritis (RA) is the most common, crippling human autoimmune disease. Using Western blotting and tandem mass spectroscopy, we have identified the endoplasmic reticulum chaperone BiP, a 78-kDa glucose-regulated protein, as a possible autoantigen. It preferentially stimulated increased proliferation of synovial T cells from patients with RA but not from patients with other arthritides. Mice with established collagen- or pristane-induced arthritis developed IgG Abs to BiP. Although BiP injected in CFA failed to induce arthritis in several strains of rats and mice, including HLA-DR4+/−- and HLA-DR1+/+-transgenic animals, it completely inhibited the development of arthritis when given i.v. 1 wk before the injection of type II collagen arthritis. Preimmunization with BiP suppressed the development of adjuvant arthritis in Lewis rats in a similar manner. This is the first report of a mammalian chaperone that is an autoantigen in human RA and in experimental arthritis and that can also prevent the induction of experimental arthritis. These findings may stimulate the development of new immunotherapies for the treatment of RA.

Recognition of class II molecules by human T cells. I. Analysis of epitopes of DR and DQ molecules in a DRw11, DRw52, DQw3 haplotype.

The HLA-D region of individuals with the DRw11, w52, DQw3 haplotype encodes multiple molecular products of three distinct subregions, DR, DP, and DQ. Since each molecule can carry multiple stimulatory epitopes, the repertoire of allogeneic T-cell responses to determinants of this haplotype can be quite large. In the present experiments, alloreactive cloned T-cell lines recognized six distinct epitopes associated with DRw11, DRw52, DQw3 haplotypes. Panel studies established that three epitopes were DRwll-like and three were DRw52-like. Blocking with monoclonal antibodies showed that two DRw11-like epitopes were carried by DR-subregion products and one DRwll-like epitope was carried by DQ-subregion molecules. DRw52-like epitopes were detected on separate DR subregion-encoded molecules. One of them carried both DRwl1-and DRw52-like epitopes, the other carried two of the DRw52-like epitopes. These epitopes, which represent functional units that trigger T-cell responses, can be detected at the present time only with the methods used in this report. Conventional allogeneic T-cell responses represent the summation of responses to multiple epitopes encoded by different D-subregion genes.

Allostimulating cells in man. Quantitative variation in the expression of HLA-DR and HLA-DQ molecules influences T-cell activation

The adherent cells of the blood, which are powerful stimulators of the mixed lymphocyte reaction (MLR), contain subpopulations that differ in the quantity of class II major histocompatibility complex (MHC) antigens on their surface. Most of the adherent cells express HLA-DP and DR antigens, although in varying amounts (Nufiez et al. 1984). In contrast, detectable amounts of HLA-DQ products are found in less than half of the adherent cells (Gonwa et al. 1983, Nufiez et al. 1984, Chen et al. 1984). In the present report, experiments were performed to investigate the relationship between expression of class II MHC antigens on adherent cells and their ability to stimulate in the MLR.

Different specificities of an HLA-DRw6 haplotype detected by alloreactive T lymphocytes

DRw6 has been difficult to define serologically. In the present experiments we have developed T cell lines in order to characterize the components of a DRw6 haplotype. This was accomplished by priming T cells with allogeneic mononuclear cells mismatched for DRw6, Dw6, and MT2. Subsequently, three sublines with distinct reactivity patterns were derived by limiting dilution. The specificities detected by these sublines included: (a) a specificity found on a subset of cells positive for DRw6 which was inhibited by monoclonal antibodies against DS(DC), the human homologue of the murine IA-encoded molecules, (b) another DRw6-associated specificity blocked by an MT2-like antibody, and (c) an MT2-like specificity blocked by monoclonal antibodies reactive with a different MT2-associated determinant. These results show that more than one IE-like, as well as the DS/DC (IA-like) molecules, carry distinctive antigenic epitopes that can be recognized by allogeneic T cells. Primed T cell lines may be useful for a better definition of certain haplotypes which are at present difficult to characterize with serological reagents alone.

Expression of HLA-DQ Molecules on Human Monocytes: Identification of Two Phenotypically Different Monocyte Populations with Distinct Accessory Cell Function

Class II major histocompatibility antigens (MHC) play a fundamental role for both antigen presentation to T cells and stimulation in mixed lymphocyte reactions. Recent progress in the understanding of human class II MHC antigens has provided evidence for at least three types of Ia molecules:HLA-DR,DQ, and DP.

Serologic Detection of New Polymorphisms on DQ Molecules Distinct from the DQw1, 2, and 3 Specificities

Recent structural studies have suggested that DQ molecules are more polymorphic than presently defined by conventional serology [1–3]. We have analyzed 9W reagents for the presence of sera that might detect new polymorphisms on DQ molecules. To do this, we have utilized the following criteria: (1) expression on B cells but not on most monocytes; (2) specific inhibition of cytotoxicity by monoclonal anti-DQ but not by anti-DR antibodies; (3) panel distribution distinct from the known DQwl, 2, and 3 specificities.