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Disease-specific T cell receptors maintain pathogenic T helper cell responses in postinfectious Lyme arthritis

ABSTRACT: Antibiotic-refractory Lyme arthritis (ARLA) is defined by persistent arthritis after sufficient antibiotic treatment of acute Lyme arthritis and is seen in approximately 10 % of patients with Lyme arthritis. Although some clinical and genetic risk markers for ARLA have been elucidated, whether chronic inflammation is sustained by persistent Borrelial antigens or triggered by autoantigens is not elucidated yet. Here, we show an oligoclonal expansion of peripheral T helper (TPH) cells in synovial fluid (SF) of pediatric ARLA patients. By in-depth bioinformatics analysis we identify a group of T cell receptors (TCRs) in this cell population shared between ARLA patients with a HLA-DRB1*11 background. By delineating surrogate markers for this convergent T cell response, we can show that these TCRs are specific for ARLA patients with HLA-DRB1*11 background compared to different autoimmune and infectious causes of arthritis and that those markers persist throughout disease course. Furthermore, combined single cell transcriptome and paired TCRα/β sequencing links the ARLA specific surrogate markers to cells with an inflammatory transcriptional program driven by TCR signaling – revealing possible therapeutic targets. Concluding, this study reveals an HLA-DRB1 restricted convergent TPH cell response in the joints of pediatric ARLA patients – suggesting a common persisting antigen as causative agent.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247675 | GEO | 2024/05/01

REPOSITORIES: GEO

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Project description:HLA-DR molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory arthritides, including in rheumatoid arthritis (RA) and Lyme arthritis (LA). In the current study, we identified HLA-DR-presented self-peptides (T cell epitopes) in ST, synovial fluid mononuclear cells (SF), and peripheral blood mononuclear cells (PB) from five patients with RA and eight with LA. Altogether, from 22 samples, 1,532 non-redundant HLA-DR-presented peptides were identified that were derived from 778 source proteins. Moreover, as the study progressed, application of newer, high sensitivity LC-MS instruments resulted in the identification of larger numbers of HLA-DR-presented peptides. Surprisingly, the source proteins for HLA-DR-presented peptides were as likely to have intracellular as extracellular locations. Although the number of peptides identified was greater in ST than in SF or PB, 68% of the peptides identified in SF were found in ST, and 55% of the peptides in PB were found in ST. Two RA patients had the same HLA-DR genotype (DRB1*0401 and 0101), and 44% of the peptides identified in these two patients were the same. In contrast, among the patients with RA or LA who had no shared HLA-DR alleles, only 6% of the peptides were the same. In the RA patients, HLA-DR-presented peptides were identified from source proteins that are thought to serve as potential autoantigens: collagen, enolase, fibrinogen, fibronectin, immunoglobulin and vimentin. Interestingly, peptides from these same source proteins were also commonly found in LA patients. However, citrullinated T cell epitopes were not identified in any patient. Thus, LC-MS/MS techniques are now sensitive enough to identify large numbers of T cell epitopes from tissue or fluids in individual patients. Importantly, analysis of SF or PB allowed us to identify a broader range of HLA-DR-presented self-peptides from individual patients and from patients seen earlier in the disease.

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Disease-specific T cell receptors maintain pathogenic T helper cell responses in postinfectious Lyme arthritis

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