Nature of T cell epitopes in lupus antigens and HLA-DR determines autoantibody initiation and diversification

Abstract

ObjectivesThe generation of systemic lupus erythematosus (SLE)-related autoantibodies have been shown to be T cell dependent and antigen driven with HLA-DR restriction. In this study, the initiating antigen(s) and the mechanism of autoantibody diversification were investigated.MethodsT cell epitopes (T-epitopes) of SmD1 (SmD) were mapped by T-T hybridomas generated from DR3+AE0 mice immunised with SmD and with SmD overlapping peptides. TCRs from the reactive hybridomas were sequenced. The core epitopes were determined. Bacterial mimics were identified by bioinformatics. Sera from DR3+AE0 mice immunised with SmD peptides and their mimics were analysed for their reactivity by ELISA and immunohistochemistry. Samples of blood donors were analysed for HLA-DR and autoantibody specificities.ResultsMultiple HLA-DR3 restricted T-epitopes within SmD were identified. Many T-T hybridomas reacted with more than one epitope. Some of them were cross-reactive with other snRNP peptides and with proteins in the Ro60/La/Ro52 complex. The reactive hybridomas used unique TCRs. Multiple T-epitope mimics were identified in commensal and environmental bacteria. Certain bacterial mimics shared both T and B cell epitopes with the related SmD peptide. Bacterial mimics induced autoantibodies to lupus-related antigens and to different tissues. HLA-DR3+ blood donors made significantly more SLE-related autoantibodies.ConclusionsThe unique antigenic structures of the lupus-related autoantigens provide the basis for being targeted and for T and B cell epitope spreading and autoantibody diversification with unique patterns. SLE-related autoantibodies are likely generated from responses to commensal and/or environmental microbes due to incomplete negative selection for autoreactive T cells. The production of SLE-related antibodies is inevitable in normal individuals. The findings in this investigation have significant implications in autoimmunity in general.

What structures are seen by a T cell in the immune response to a lupus autoantigen?

“…This finding extends the earlier study from Fu and colleagues that among transgenic mice with diverse HLA-DR and DQ alleles, those expressing HLA-DR3 make the greatest antibody responses to Ro60 and Sm 2. Moreover, in parallel Zhao et al 1 demonstrate that normal blood donors who have HLA-DR3 make significantly more anti-Sm and anti-Ro60 antibodies than those without this allele, indirectly supporting the thesis that the diversity of T cell recognition of different peptides with HLA-DR restriction is important in the generation of antibodies to these classic lupus autoantigens. These results suggest the property of HLA-DR3 to select a T cell repertoire enriched in clones with TCRs that recognise Sm peptides could be a direct molecular explanation for why both the susceptibility to develop SLE and the presence of antibodies to Sm and Ro60 are associated with the MHC.…”

“…This report by Zhao et al 1 did not address the important next question of whether this cross-reactivity is incidental to the vastness of microbial diversity or might play an important direct role in the initiation or in the progression of the autoimmune response. One can envision that the T cells in the repertoire of DR3 individuals responding to these cross-reacting microbial structures might be the starting point for the provision of help to autoantibody secreting B cells.…”

“…In this decade we have witnessed substantive progress in solving a number of the fundamental enigmas in systemic lupus erythematosus (SLE) that thwart progress towards achieving the goal of inducing disease remission in all patients with this challenging disease. This issue of the Annals of the Rheumatic Diseases contains a paper by Zhao et al 1 , ‘Nature of T cell epitopes in lupus antigens and HLA-DR determines autoantibody initiation and diversification’, which greatly advances understanding of four critical aspects of SLE that are included among these enigmas: Why is the susceptibility to develop SLE associated with the Major Histocompatibility class II allele desinated  HLA-DR3? What role does the recognition by specific T cell clones of self-peptides presented by HLA-DR3 molecules play in the process of epitope spreading that drives the progressive intensification of a seemingly inconsequential autoimmune response to become a virulent life-threatening autoimmune disease?…”

“…Provocatively, Zhou et al 1 observed that many T cell clonal members of this recognition network, which likely entered the T cell repertoire by being selected by self-Sm peptides during thymic development, also identified and responded to a variety of non-self-peptides encoded within the proteomes of a large number of different commensal and environmental microbes. Indeed, in some instances this cross-recognition was mirrored by the presence of antibodies that reacted with the parent microbial molecule.…”

Defining B cell tolerance checkpoints and their modulation by immunotherapy

“…While the current era of precision medicine turns its focus towards antigen-specific approaches, it is important to balance this view based on the disease to be treated. For example, in SLE, autoantibodies target multiple different antigens [232] and T cell epitopes have not been clearly defined [512]. It is not yet clear whether treating one or two epitopes with immunotherapy will be sufficient to halt or reverse pathology [396].…”