Impaired sympathetic influence on the immune response in patients with rheumatoid arthritis due to lymphocyte subset-specific modulation of beta 2-adrenergic receptors.

SUMMARY Previous studies have demonstrated that an alteration of the interaction between the immune system and the autonomic nervous system may contribute to the pathogenesis of inflammatory arthritides. To address this issue further in patients with rheumatoid arthritis (RA), this study aimed at determining the modulation of b-adrenergic receptors (b2R) on lymphocyte subsets and its impact on cell reactivity. b2R were determined on CD4 + and CD8 + peripheral blood lymphocytes (PBL) and synovial fluid lymphocytes (SFL) from RA patients and normal donors. In parallel, the influence of catecholamines on OKT3-induced T-cell activation was studied. In patients with RA, b2R on SFL were significantly decreased compared to b2R on PBL. Furthermore, a disease activity-correlated significant decrease of b2R on CD8 + PBL was observed. This decrease of b2R was paralleled by a reduced suppressive eAect of catecholamines on OKT3-induced lymphocyte proliferation. Our data give further evidence for an impaired sympathetic influence on the immune response in RA. SINCE the observation that lymphocytes, monocytes/ macrophages and granulocytes possess receptors for catecholamines, mainly of the b2 subclass, an abundance of evidence has accumulated demonstrating that immune reactions are at least in part under control of the sympathetic nervous system [1,2]. Neurotransmitters and neurohormones influence the reactivity of the cells of the immune system, and cytokines interact with central neurones and modulate their activity [3]. The sympathetic nervous system and the immune system are anatomically linked by a dense innervation of the lymphatic tissues such as spleen, thymus and lymph nodes. In these tissues, lymphocytes and sympathetic nerve endings form contacts at a distance that is even shorter than that in synapses [4]. The aetiology of rheumatoid arthritis (RA) remains unknown and its pathogenesis is only incompletely understood. The important role of the nervous system in the pathogenesis of RA was first observed in patients who had additional upper motor neurone hemiplegia or poliomyelitis. In these patients, paralysed joints were spared from the inflammatory process [5]. Investigations on experimental arthritis and experimental allergic encephalomyelitis animal models suggested an influence of the sympathetic nervous system on the immune response in these immunologically mediated disorders [6]. Previous investigations from our group in patients with RA have demonstrated a decreased number of b2-adrenergic receptors (b2R) on peripheral blood mononuclear cells (PBMC) that correlated with the disease activity in these patients [7]. Therefore, the influence of the autonomic nervous system (ANS) may contribute to the alteration of the immune response in RA. To gain more insight into the pathophysiological role of the ANS in RA, we studied the b2R characteristics on CD4 + and CD8 + peripheral blood lymphocytes (PBL) and on synovial fluid lymphocytes (SFL), respectively. Results were correlated with plasma catecholamine levels, the total activity index of RA, and compared to the data determined in healthy donors (HD). In addition, in vitro experiments were performed to evaluate the impact of disease-related b2R modulation on lymphocyte function.