Autoimmunity to synovial extracellular matrix proteins in patients with postinfectious Lyme arthritis

Abstract

BACKGROUND Autoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked upregulation of HLA-DR molecules, including in postinfectious Lyme arthritis (LA). However, the identity of HLA-DR–presented peptides, and therefore the reasons for these associations, has frequently remained elusive. METHODS Using immunopeptidomics to detect HLA-DR–presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with postinfectious LA, identified potential Borreliella burgdorferi –mimic ( Bb -mimic) epitopes, and characterized T and B cell responses to these peptides or proteins. RESULTS Of 24 postinfectious LA patients, 58% had CD4 + T cell responses to at least 1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to at least 1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or -DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb -mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4 + T cells in synovial fluid were T-bet–expressing Th1 cells, a small percentage were RoRγt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Tregs. CONCLUSION Autoreactive, proinflammatory CD4 + T cells and autoantibodies develop to ECM proteins in a subgroup of postinfectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity. FUNDING Supported by National Institute of Allergy and Infectious Diseases R01-AI101175, R01-AI144365, and F32-AI125764; National Institute of Arthritis and Musculoskeletal and Skin Diseases K01-AR062098 and T32-AR007258; NIH grants P41-GM104603, R24-GM134210, S10-RR020946, S10-OD010724, S10-OD021651, and S10-OD021728; and the G. Harold and Leila Y. Mathers Foundation, the Eshe Fund, and the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital.

Identification of disease-specific TCRs maintaining pathogenic T helper cell responses in postinfectious Lyme Arthritis

“…While we successfully characterized the T cell response throughout the chronic phase of arthritis, we did not have access to samples from the initial disease onset of patients who later developed ARLA. Although these limitations constrain interpretation, the convergent T cell response observed in ARLA patients during the late disease course would align well with the proposed epitope spreading model (7, 14). The observation that T cells carrying TCRs with known specificities against viral antigens were randomly distributed among various T cell clusters and not enriched in the expanded T PH effector cell cluster also refutes bystander activation as the primary mechanism by which T cells are recruited within the local T cell response.…”

“…Thus far, presumed targets of the pathological T-cell response in ARLA encompass a wide spectrum of antigens, ranging from Borrelia components (e.g. OspA) to autoantigens associated to vascular tissue (ECGF, annexin A2 and apoB-100) or extracellular matrix (fibronectin-1, laminin B2 and collagen) (14–17, 25, 32, 33). These diverse T cell responses have been integrated into a framework indicating that exaggerated immune reactions to OspA might disrupt T cell tolerance, triggering epitope spreading from Borrelia antigens to autoantigens like extracellular matrix proteins (7).…”

“…The synovial transcriptomic landscape in patients with ARLA is characterized by a pronounced IFN-γ expression signature and high frequencies of IFN-y secreting T cells are present in SF of these patients (41–43). Furthermore, autoreactive T cells, identified through peptide-MHC tetramers recognizing extracellular matrix proteins, are notably enriched in T-bet-expressing cells (14). This observation implies that the pathogenic T cell response in ARLA is mediated by Th-1 cells.…”

“…In individuals at risk, OspA appears to trigger an excessive immune response creating a highly inflammatory milieu that subsequently promotes epitope spreading of the immune response towards autoantigens (7). This autoimmune response seems to be mediated by T-bet and/or RORγt expressing Th cells and target extracellular matrix proteins as well as vascular autoantigens (14–18).…”

Antigenicity and immunogenicity of different morphological forms of Borrelia burgdorferi sensu lato spirochetes

“…On the other hand comparison of immunogenicity of tested morphological variants (aggregates, RB and spirals) did not show significant differences. Immunopathological inflammatory reaction can itself cause clinically manifest tissue damage, but it can also participate in triggering an autoimmune reaction, which is often discussed in connection with post-infectious complications of LD, mainly treatment-resistant Lyme arthritis 56 , 57 .…”