Background/Purpose:

Infection-induced autoimmunity has been hypothesized to have a pathogenic role in antibiotic-refractory Lyme arthritis (LA). We previously identified 3 autoantigens, endothelial cell growth factor, annexin A2, and apolipoprotein B-100, that are targets of T and B cell responses in Lyme disease patients. However, only about half of patients with antibiotic-refractory LA have one or more of these autoimmune responses. In the current study, we again used discovery-based proteomics and translational research to identify another novel autoantigen, matrix metalloproteinase-10 (MMP-10), in antibiotic-refractory LA. 

Methods:

HLA-DR-presented peptides were isolated and identified from the synovial tissue of a patient with antibiotic-refractory LA. Immunogenicity of the peptides was measured using the case patient’s PBMC in an IFN-γ ELISpot assay. Reactive peptides and their source proteins were then tested for T and B cell reactivity in large numbers of patients with early or late manifestations of Lyme disease, rheumatoid arthritis (RA), or healthy controls (HC). To gain insights into autoantibody-associated pathology, rankings of histologic findings in synovia were correlated with the magnitude of autoantibody responses.

Results:

Of the 124 HLA-DR-presented self-peptides identified from the synovial tissue of a patient with antibiotic-refractory LA, one peptide derived from MMP-10 caused his PBMC to secrete IFN-γ. When tested in additional patients, only 1 patient each with erythema migrans (EM), an early disease manifestation, or with antibiotic-responsive LA had low-level T cell reactivity with MMP-10 peptides, though 26% of patients with EM and 14% of those with antibiotic-responsive LA had autoantibody responses to full-length MMP-10. In contrast, 5 of 20 patients (25%) with antibiotic-refractory LA had robust T cell responses to MMP-10 peptides, and 25 of 114 patients (22%) with refractory arthritis had autoantibody responses to MMP-10. No HC and only 6% of RA patients had minimal autoantibody responses to this protein. Furthermore, only a few patients with LA had antibody reactivity to MMP-3 (stromelysin 1), a protein with 78% amino acid sequence homology to MMP-10, further demonstrating the specificity of reactivity with MMP-10. In refractory patients, the magnitude of the MMP-10 antibody response positively correlated with synovial lining layer thickness and fibroblast proliferation, and with greater staining for CXCL13 and larger numbers of plasma cells, suggestive of local antibody production.

Conclusion:

Identification of a single HLA-DR-presented peptide (T cell epitope) provided a bridge to the discovery of a broadly immunogenic autoantigen, MMP-10, in Lyme disease. B cell reactivity with this protein may develop early in the illness. Later in the infection, patients with antibiotic-refractory LA may have both T and B cell responses to MMP-10, and in these patients, the autoantibody response appears to become pathogenic. The specificity of this response (not found in RA) suggests that initial interaction between the spirochete and host at disease onset is critical in immunogenicity, and not simply abundance of MMP proteins.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/matrix-metalloproteinase-10-stromelysin-2-is-a-target-of-robust-autoimmune-t-and-b-cell-responses-in-antibiotic-refractory-lyme-arthritis-but-not-in-rheumatoid-arthritis/