Murine CD1d-restricted T cell recognition of cellular lipids.

NKT cells are associated with immunological control of autoimmune disease and cancer and can recognize cell surface mCD1d without addition of exogenous antigens. Cellular antigens presented by mCD1d have not been identified, although NKT cells can recognize a synthetic glycolipid, alpha-GalCer. Here we show that after addition of a lipid extract from a tumor cell line, plate-bound mCD1d molecules stimulated an NKT cell hybridoma. This hybridoma also responded strongly to three purified phospholipids, but failed to recognize alpha-GalCer. Seven of sixteen other mCD1d restricted hybridomas also showed a response to certain purified phospholipids. These findings suggest NKT cells can recognize cellular antigens distinct from alpha-GalCer and identify phospholipids as potential self-antigens presented by mCD1d.

Diverse TCRs recognize murine CD1.

Human and murine T cells that specifically recognize CD1d and produce IL-4 and IFN-gamma play a role in immunoregulation and tumor rejection. In the mouse, most CD1d1-reactive T cells described express an invariant Valpha14-Jalpha281 TCR associated with TCR beta-chains of limited diversity. Similarly, human CD1d-reactive T cells express a highly restricted TCR repertoire. Here we report the unexpected result that in mice immunized with CD1d1-bearing transfectant cells, a diverse repertoire of TCRs was expressed by CD1d1-reactive T cell clones isolated by limiting dilution without preselection for NK1 expression. Only 3 of 10 CD1d1-reactive T cell clones expressed the invariant Valpha14-Jalpha281 TCRalpha rearrangement. T cells expressing Valpha10, -11, -15, and -17, and having non-germline-encoded nucleotides resulting in diverse V-J junctions were identified. Like CD1d1-reactive T cells expressing the invariant Valpha14-Jalpha281 TCR alpha-chain, CD1d1-reactive clones with diverse TCRs produced both Type 1 (IFN-y) and Type 2 (IL-4, IL-10) cytokines. This establishes the existence of significant diversity in the TCRs directly reactive to the CD1d1 protein. Our findings reveal that CD1d interacts with a broad array of TCRs, suggesting substantial redundancy and flexibility of the immune system in providing T cells serving the role(s) mediated by CD1d reactivity.

Clinical correlates, serum autoantibodies and the role of the major histocompatibility complex in French Canadian and non-French Canadian Caucasians with SLE.

OBJECTIVE: To investigate the predisposing role of major histocompatibility complex (MHC) genes to autoantibody production and clinical manifestations comparing French Canadian and Non-French Canadian Caucasians with systemic lupus erythematosus (SLE) METHODS: Ninety-one Caucasian patients with SLE were studied. Clinical manifestations, autoantibody expression and HLA-A, B, (serology), DR, DQ and C4A gene deletion (restriction fragment length polymorphism [RFLP] typing) were determined. RESULTS: Photosensitivity was present in all SLE subjects with anti-Ro antibodies (P=0.001, RR=13.1, CI=1.8, 564). Photosensitivity was further associated with the HLA-A1, C4A gene deletion haplotype. More strikingly, C4A gene deletion was associated with anti-Ro (P=0.008, RR=4.6, CI=1.4, 16.2) and anti-La (P=0.02, RR=11.7, CI=1.4, 549) autoantibodies. This relationship was also significant for anti-Ro antibody in the French Canadian patients (P=0.01, RR=21.3, CI=1.7, 105.3). In contrast, anti-dsDNA autoantibodies were negatively associated with photosensitivity (P=0.02, RR=0.3, CI=0.07, 0.8) and correlated with HLA-DR15 (P=0.006, RR=4.2, CI=1.5, 12.8) and Dw2 (P=0.009, RR=3.9, CI=1.4, 11.9). CONCLUSION: C4A gene deletion has a previously unrecognized powerful association with anti-Ro and anti-La autoantibodies. These results support the concept of divergent MHC gene associations with autoantibody expression and emphasize the influence of ethnicity on the immunogenetic study of SLE.

A reader's guide to the evaluation of causation.

In this article, we review the criteria used to establish a causal association. A literature search strategy will be outlined. We present a clinical scenario that was formulated to examine the evidence for nonsteroidal anti-inflammatory drugs as a possible cause of gastrointestinal ulceration and bleeding. Several of the studies identified in the literature search were critically appraised and the criteria needed to confirm a causal link were then applied. These guidelines may be employed to not only demonstrate the aetiology of a disease but have wider applicability in terms of determining whether a medication may be causing certain adverse events.