Expression of NKRs CD94, NKG2A, CD161 and CD57 in patients maintaining or withdrawing therapy

Expression of NKRs CD94, NKG2A, CD161 and CD57 in patients maintaining or withdrawing therapy. 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+CD56cell expression of NKG2A was inversely related to DAS28 (r = 0.612, p<0.005). == Conclusion == High 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. == Introduction == Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis affecting 1% of the population. Left untreated RA leads to joint deformity and disability[1]. RA is characterised by symmetrical erosive polyarthritis, with extra-articular manifestations in some patients. Activated T cells and innate cells such as macrophages contribute to the development of synovial inflammation by secreting TNF, a potent pro-inflammatory cytokine[2]. TNF inhibits both bone formation and proteoglycan synthesis while inducing bone and proteoglycan resorption. It also 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[3][6]. The use of TNFi has revolutionised the treatment of RA patients, particularly in patients with moderate to severe RA[3][7]. However, TNFi are expensive and have potential for serious side-effects. Prior to routine use of biologic therapies, Peptide YY(3-36), PYY, human the average annual medical cost for a patient with RA was $8500[8]. Studies have demonstrated mean annual costs of TNFi between $12,146 and $15,617 depending on the agent prescribed. When other expenses are taken into account, e.g. administration in an OPD setting and concomitant disease modifying anti-rheumatic drug (DMARD) use, the cost may rise to $18,046[9],[10]. An important goal for rheumatologists treating RA patients is to identify markers that can (1) predict response to TNFi, (2) predict remission rates and (3) predict those patients who can maintain remission following withdrawal of TNFi[11],[12]. Natural killer cells (NK), T cells and natural killer T (NKT) cells participate in aetiology and regulation of RA pathogenesis[13][16]. NK cells are key players in innate immunity, their primary function killing of virally infected or transformed Peptide YY(3-36), PYY, human cells. They can also regulate the adaptive immune response through their ability to produce cytokines. The activity of NK Peptide YY(3-36), PYY, human cells is tightly controlled through a variety of stimulatory, co-stimulatory and inhibitory receptors (NKRs)[17]. Dysregulated expression of NKRs and impairment of NK Peptide YY(3-36), PYY, human function have been demonstrated in RA. For example, increased expression of the CD94 receptor with concomitant reduction in the expression of inhibitory Killer Ig-Like Receptors (KIR) has been demonstrated in patients with RA[13]. In addition, Richter et al. have recently demonstrated that the NK receptor CD161 contributes to impairment of NK Peptide YY(3-36), PYY, human cell cytotoxicity and responsiveness to specific ligands in patients with RA[14]. T cells that co-express NKRs comprise approximately 515% of the peripheral T cell pool and have the ability to mediate functions of both T and NK cells. These cells may also express activatory or inhibitory NKRs e.g. CD94/NKG2A (inhibitory) or NKG2D (activatory) and are known as NK receptor+T cells (NKT cells)[18]. Levels of NKR+ T cells are increased in the peripheral blood and synovial tissue of patients with active RA[15],[19]. High levels of IL-15 and TNF in RA patients contribute to the expansion of the NKG2D+T cell population, cells that may have greater autoreactive potential due to their high expression of activatory receptors[15]. A significant proportion of T cells (CD4+CD28) expressing NKG2D display autoreactive responses against RA synovial fibroblasts[15],[20]. Furthermore increased expression of activatory KIR receptor KIR2DS2 on CD4+CD28cells have been shown to correlate with RA disease activity[21]. The aim of this study was FLJ39827 to examine NK receptor expression on lymphoid phenotypes in patients in TNFi-induced remission compared to active disease, and to investigate their expression in patients with continued remission.

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