Cell‐Mediated Cytotoxicity in Lyme Arthritis

Abstract

Objective Obliterative microvascular lesions are found in the synovial tissue of ~50% of patients with post‐antibiotic Lyme arthritis (LA) and correlate with autoantibodies to certain vascular antigens. In this study, we identified lymphocytes with cytotoxic potential that may also mediate this feature of synovial pathology. Methods The cytotoxic potential of lymphocytes and their T cell receptor (TCR) Vβ gene usage were determined using samples of peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) from patients with antibiotic‐responsive or post‐antibiotic LA. Cell phenotypes were analyzed using flow cytometry and intracellular cytokine staining. Immunohistochemistry was performed on post‐antibiotic synovial tissue samples. Results In SFMC and PBMC samples, the percentages of CD8+ T cells and double‐negative T cells (primarily γδ T cells) were greater among 22 patients with post‐antibiotic LA than in 14 patients with antibiotic‐responsive LA. Moreover, CD8+ T cells and γδ T cells often expressed cytotoxic mediators, granzyme A/granzyme B, and perforin. The same 3 TCR Vβ segments were over‐represented in both CD4+ T cells and CD8+ T cells in SFMC samples from post‐antibiotic LA patients. In synovial tissue samples from 3 patients with post‐antibiotic LA, CD8+ T cells intermixed with CD4+ T cells were seen around blood vessels, and 2 patients with microvascular damage had autoantibodies to vascular‐associated antigens. One of these 2 patients, the one in whom cytotoxicity appeared to be active, had complement (C5b–9) deposition on obliterated vessels. Very few natural killer cells or γδ T cells were seen. Conclusion We propose that CD8+ T cell–mediated cytotoxicity, CD4+ T cell help, autoantibodies to vascular antigens, and complement deposition may each have a role in microvasculature damage in post‐antibiotic LA.

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

“…We propose that these ECM-autoreactive T effector cells are drivers of persistent inflammatory synovitis, resulting in continued release of ECM autoantigens and a feedback loop of autoimmune inflammation. In addition, cytotoxic immune responses to vascular-associated autoantigens may lead to obliterative microvascular lesions in synovial tissue ( 19 ). These autoimmune inflammatory responses may be further enhanced by immune reactivity with spirochetal remnants, such as Bb peptidoglycan, which is uniquely difficult to clear ( 38 ).…”

“…With this approach, we previously reported the identification of 4 autoantigens in Lyme synovia: 3 related to the vasculature, endothelial cell growth factor (ECGF), annexin A2, and apolipoprotein B-100 (apoB-100), and 1 ECM proteinase, matrix metalloproteinase 10 (MMP-10). These proteins are each targets of T and B cell responses that correlate with synovial pathology in subgroups of LA patients (15)(16)(17)(18)(19).…”

Borrelia-specific antibody profiles and complement deposition in joint fluid distinguish antibiotic-refractory from -responsive Lyme arthritis

“…To contextualize these findings within the broader immune response, a recent study demonstrated C5b-9 deposition on obliterated blood vessels in the synovia in refractory LA, which correlated with autoantibody responses to certain vascular-associated autoantigens. 14 CD8 + T cells with cytotoxic potential surrounded these vessels and CD4 + T cells were intermixed with CD8 + T cells. Thus, complement activation by pathogen-associated immune complexes, while certainly not the sole contributor to persistent LA, may be implicated in pathology.…”

“… 7 , 13 For example, in approximately 50% of such patients, Lyme synovia show obliterative microvascular lesions, in which CD8 + T cell-mediated cytotoxicity, CD4 + T cell help, autoantibodies to vascular antigens, and complement deposition may each have a pathogenic role. 14 Additionally, both autoreactive and B.burgdorferi -specific humoral immune responses may be modulated by inhibitory FcγR2b, which human and animal models support as a regulator of the quality and magnitude of the humoral immune response. 15 …”