Impaired Sympathetic Influence on the Immune Response ... - CiteSeerX

British Journal of Rheumatology 1997;36:1262±1269

IMPAIRED SYMPATHETIC INFLUENCE ON THE IMMUNE RESPONSE IN PATIENTS WITH RHEUMATOID ARTHRITIS DUE TO LYMPHOCYTE SUBSET-SPECIFIC MODULATION OF b2-ADRENERGIC RECEPTORS C. G. O. BAERWALD, M. LAUFENBERG, T. SPECHT, P. VON WICHERT, G. R. BURMESTER* and A. KRAUSE* Department of Internal Medicine, Medizinische Poliklinik, Philipps-University, Marburg and *Department of Internal Medicine III, University Hospital ChariteÂ, Berlin, Germany 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 in¯ammatory 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 ¯uid lymphocytes (SFL) from RA patients and normal donors. In parallel, the in¯uence of catecholamines on OKT3-induced T-cell activation was studied. In patients with RA, b2R on SFL were signi®cantly decreased compared to b2R on PBL. Furthermore, a disease activity-correlated signi®cant decrease of b2R on CD8+ PBL was observed. This decrease of b2R was paralleled by a reduced suppressive e€ect of catecholamines on OKT3-induced lymphocyte proliferation. Our data give further evidence for an impaired sympathetic in¯uence on the immune response in RA. KEY WORDS: Rheumatoid arthritis, Lymphocyte subsets, b2-Adrenergic receptors, Catecholamines, Synovial ¯uid, Neuroimmunomodulation, T-cell function.

tions 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 in¯uence 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 ¯uid 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.

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 in¯uence 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 ®rst observed in patients who had additional upper motor neurone hemiplegia or poliomyelitis. In these patients, paralysed joints were spared from the in¯ammatory process [5]. Investigations on experimental arthritis and experimental allergic encephalomyelitis animal models suggested an in¯uence of the sympathetic nervous system on the immune response in these immunologically mediated disorders [6]. Previous investiga-

PATIENTS AND METHODS Patients and control subjects Thirty-seven consecutive patients with RA were investigated. The patients' demographic and clinical characteristics are outlined in Table I. In 24 patients (19 female, ®ve male), b2R were determined on CD4+ and CD8+ PBL only (group 1). In 13 additional RA patients (nine female, four male) with an accessible synovial e€usion, SFL and PBL were studied in parallel. All patients ful®lled the 1987 revised ACR criteria [8]. All patients were taking non-steroidal anti-in¯ammatory drugs. Thirty patients were on a disease-modifying therapy with sulphasalazine (n = 7), gold salts (n = 9), low-dose

Submitted 31 December 1996; revised version accepted 7 May 1997. Correspondence to: C. G. O. Baerwald, AG Rheumatologie, Medizinische Poliklinik, Philipps-University, 35033 Marburg, Germany.

# 1997 British Society for Rheumatology 1262

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BAERWALD ET AL.: b2-ADRENERGIC RECEPTORS IN RA

TABLE I Disease activity variables and clinical characteristics of patients with rheumatoid arthritis (RA) and normal subjects Variable

RA patients* (group 1, n = 24)

RA patients$ (group 2, n = 13)

Control subjects (group 3, n = 10)

Sex M/F Age (yr) Rheumatoid factor positive Duration of RA (yr) Ritchie index (points) ESR (mm/h) C-Reactive protein (mg/l) Haemoglobin (g/l) Total reactivity index}

5/19 542 2.4% (30±77) 21 9.22 1.8 (0.5±32) 15.02 1.4 (5±30) 34.92 5.0 (1±121) 34.92 6.2 (3±135) 127.82 3.2 (10.3±15.5) 7.22 0.9 (3±17)

4/9 53.323.8 9 5.221.1 17.421.9 48.626.8 35.327.1 13825.8 10.720.8

4/6 50.823.8 (31±66)

(22±71) (1±12) (2±26) (6±117) (8±136) (10.5±15.4) (6±20)

*Group 1 consisting of 24 RA patients for the determination of b2R on PBL subsets. $Group 2 included 13 di€erent RA patients with synovial e€usion for the determination of b2R on PBL and SFL. %Mean2 S.E.M. (range). }According to an arbitrary score using the Ritchie index, the duration of morning sti€ness, ESR, levels of CRP and haemoglobin. Each variable was graded from 0 to 4, points were then added to the TAI.

methotrexate (n = 12) or azathioprine (n = 4), respectively. Of those, 22 patients additionally received low-dose steroids (