Differential Expression of NK Receptors CD94 and NKG2A by T Cells in Rheumatoid Arthritis Patients in Remission Compared to Active Disease

Ceara E Walsh,Douglas J Veale,Elizabeth J Ryan,Lucy Golden-Mason,Ursula Fearon,Barry Bresnihan,Cliona O’Farrelly,Oliver Fitzgerald,Johan K Sandberg

doi:10.1371/journal.pone.0027182

Ceara E Walsh, Douglas J Veale + Show 7 more

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https://doi.org/10.1371/journal.pone.0027182

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Abstract

ObjectiveTNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor+ T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal.MethodsPatients with RA were recruited for this study, (i) RA patients in clinical remission following a minimum of one year of TNFi therapy (n = −15); (2) Active RA patients, not currently or ever receiving TNFi (n = 18); and healthy control volunteers (n = 15). Patients in remission were divided into two groups: those who were maintained on TNFi and those who withdrew from TNFi and maintained on DMARDS. All patients underwent full clinical assessment. Peripheral blood mononuclear cells were isolated and NKR (CD94, NKG2A, CD161, CD69, CD57, CD158a, CD158b) expression on T-(CD3+CD56−), NK-(CD3−CD56+) and NKT-(CD3+CD56+) cells was determined by flow cytometry.ResultsFollowing TNFi withdrawal, percentages and numbers of circulating T cells, NK cells or NKT cell populations were unchanged in patients in remission versus active RA or HCs. Expression of the NKRs CD161, CD57, CD94 and NKG2A was significantly increased on CD3+CD56-T cells from patients in remission compared to active RA (p<0.05). CD3+CD56-T cell expression of CD94 and NKG2A was significantly increased in patients who remained in remission compared with patients whose disease flared (p<0.05), with no differences observed for CD161 and CD57. CD3+CD56− cell expression of NKG2A was inversely related to DAS28 (r = −0.612, p<0.005).ConclusionHigh CD94/NKG2A expression by T cells was demonstrated in remission patients following TNFi therapy compared to active RA, while low CD94/NKG2A were associated with disease flare following withdrawal of therapy.

Highlights

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis affecting 1% of the population
Fifteen patients in remission were recruited, ten (66%) patients were female with a mean (SEM) age of 50.27 (4.08) years, disease duration of 9.63 (1.96) years, Erythrocyte Sedimentation Rate (ESR) 8.73 (1.38) mm/hr, C-reactive protein (CRP) 6.00 (1.02) mg/L and 12 (80%) patients were rheumatoid factor positive (RF+)
One patient had a flare in disease activity two weeks after TNF inhibitors (TNFi) withdrawal, did not respond to corticosteroids and recommenced their TNFi

Summary

Introduction

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis affecting 1% of the population. Activated T cells and innate cells such as macrophages contribute to the development of synovial inflammation by secreting TNFa, a potent pro-inflammatory cytokine [2]. TNFa inhibits both bone formation and proteoglycan synthesis while inducing bone and proteoglycan resorption. It stimulates metalloproteinase and collagenase production, triggers inflammatory cytokine cascades and increases adhesion molecule expression by infiltrating immune cells. TNF inhibitors (TNFi) improve disease activity indices (clinical and laboratory) and inhibit radiographic progression [326]. The use of TNFi has revolutionised the treatment of RA patients, in patients with moderate to severe RA [327]

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