Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis

Abstract

Infection-induced autoimmunity is thought to be a contributing factor in antibiotic-refractory Lyme arthritis, but studies of autoimmunity have been hindered by difficulty in identifying relevant auto-antigens. We developed a novel approach that begins with the identification of T cell epitopes in synovial tissue using tandem mass spectrometry. Herein, we identified an immunogenic HLA-DR-presented peptide (T cell epitope) derived from the source protein matrix metalloproteinase-10 (MMP-10) from the synovium of a patient with antibiotic-refractory arthritis. This finding provided a bridge for the identification of autoantibody responses to MMP-10, the “first autoimmune hit” in a subgroup of patients with erythema migrans, the initial skin lesion of the infection. Months later, after priming of the immune response to MMP-10 in early infection, a subset of patients with antibiotic-responsive or antibiotic-refractory arthritis had MMP-10 autoantibodies, but only patients with antibiotic-refractory arthritis had both T and B cell responses to the protein, providing evidence for a “second autoimmune hit”. Further support for a biologically relevant autoimmune event was observed by the positive correlation of anti-MMP-10 autoantibodies with distinct synovial pathology. This experience demonstrates the power of new, discovery-based methods to identify relevant autoimmune responses in chronic inflammatory forms of arthritis.

Immunogenic HLA-DR-Presented Self-Peptides Identified Directly from Clinical Samples of Synovial Tissue, Synovial Fluid, or Peripheral Blood in Patients with Rheumatoid Arthritis or Lyme Arthritis

“…Similarly, among the five LA patients, at least one unique immunogenic HLA-DR-presented peptide was identified in each of three patients (LA1, LA4, and LA5). 22–24 Four of the six immunogenic peptides were identified by consensus match, and two were identified by manual inspection of sequences identified by only one program.…”

“…The peptides found to be immunogenic were derived from the source proteins endothelial cell growth factor (ECGF), 22 apolipoprotein B-100 (apoB-100), 23 matrix metalloproteinase-10 (MMP-10) 24 in LA; from annexin A2 in both RA and LA, 25 and from N -acetylglucosamine-6-sulfatase and filamin A in RA. 26 The MS/MS spectra and peptide sequences determined for these autoantigens are shown in Figure 3.…”

Two rheumatoid arthritis–specific autoantigens correlate microbial immunity with autoimmune responses in joints

“…We have developed an approach for antigen detection in chronic inflammatory arthritides, in which HLA-DRpresented peptides (T cell epitopes) are identified directly from patients' inflamed synovial tissue, synovial fluid mononuclear cells (SFMCs), or peripheral blood mononuclear cells (PBMCs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tested for immunogenicity using patients' samples (19)(20)(21)(22)(23)(24).…”

“…In addition, because of a limited number of cells, we did not include the testing of irrelevant control peptides in these experiments. However, we have previously shown that patients with RA do not have reactivity to peptides derived from endothelial cell growth factor (ECGF) or MMP-10 peptides (21,23). These autoantigens in LA are irrelevant in RA.…”

Cytogenetic Effects of Tick-Borne Transmitted Co- Or Monoinfections Depending on the Variants of Glutathione-S-Transferase Genes (Gstm1 or Gstt1) in the Patient’s Genotype

“…некоторых больных инициирует аутоиммунный процесс с образованием аутоантител к ДНК и цен-тромерной области хромосом, что также может способствовать их аномальному расхождению при делении клетки [15]. Известно, что группа ферментов глутатион-S-трансферазы, кодируемых генами GSTM1 и GSTT1, выполняют роль антиоксидантов, приводя-щих к снижению числа клеток с цитогенетически-ми нарушениями.…”