Annals of the Rheumatic Diseases Leaders Do sex hormones modulate the synovial macrophages in rheumatoid arthritis ?

It is becoming apparent that various host influences are important determinants in the development of autoimmune diseases, including rheumatoid arthritis (RA). The organism responds to inflammatory stimula with coordinated series of adaptive responses involving the immune, nervous, and endocrine systems. Although immunogenetics may dominate the susceptibility to develop the disease, the most powerful additional factor recognised in the host is the sex of the patient. Recent epidemiological, clinical, and laboratory evidence has suggested that sex hormones play a central part in the immune response and the immune mediated pathological conditions. Overall, women have greater humoral and cellular immune responses and therefore may be more susceptible than men to autoimmune diseases, including RA. Women have higher immunoglobulin concentrations than men and produce greater antibody responses to various microorganisms after immunisation. Cell mediated immune response is also stronger in women as shown by a more eYcient rejection of allografts and relative resistance to immunotolerance. On the other hand, women have greater plasma corticotropin (ACTH) response to ovine corticotropin release hormone (CRH) and more prolonged increases in cortisol values, thus indicating CRH neuron activation by oestradiol. Conversely, androgens inhibit the hypothalamic-pituitary-adrenal axis (HPA) supporting the complex interactions existing between the immune response and neuroendocrine system. In synthesis, evidence suggests that physiological concentrations of oestrogens stimulate while male hormones suppress the immune response. As the distinct female preponderance in autoimmune diseases exists mainly during the reproductive ages, sex hormone concentrations and metabolism have been evaluated in the aVected patients (that is, RA, systemic lupus erythematosus (SLE)) and have often been found to be changed. In particular, low gonadal and adrenal androgens (testosterone (Tes)/dihydrotestosterone (DHT) and dehydroepiandrosterone sulphate (DHEAS), respectively), as well as reduced androgens/oestrogens ratio, have been detected in male and female RA patients, suggesting a reduction of the related immunosuppressive eVects. An important unknown factor in the pathogenesis of RA is the reason why immunological mediated inflammation begins and develops within joints. A central role in understanding RA pathogenesis lies in the comprehension of arthrotopism of antigens and inflammatory cells for joints and in learning what specific receptors and chemotactic gradients are active in focusing the immune mediated inflammation within joints. Undoubtedly the synovial tissue in RA can be regarded as the ‘target tissue’ in which the sexual dimorphism in immune response to relevant trigger antigens is present. In contrast with the cell centred models of RA pathogenesis in which proliferation of antigen specific T cells determines various manifestations of RA, synovitis such as B cell stimulation, leucocyte infiltration, and cytokine synthesis, a key role for synovial macrophages is outlined in which by paracrine and autocrine mechanisms the inflammatory changes in the RA synovium are maintained. 8 Furthermore, proinflammatory cytokines (for example, tumour necrosis factor á (TNFá), interleukin 1 (IL1), interleukin 6) released from the inflamed synovial tissue, reach the brain where they trigger various neuroendocrine counter-regulatory mechanisms and account for most of the HPA stimulation, including the increased release of neuropeptides such as CRH. 2 In the light of the above, a question arises: Is there evidence that sex hormones might modulate synovial macrophages in RA? To validate the possible sex hormone modulation of synovial macrophages, functional receptors for androgens and oestrogens must be present on these cells. Actually, androgen and oestrogen receptors have been described in both normal and RA synovial macrophages using double immunostaining techniques of synovial tissue cryosections. Biochemical characterisation confirmed the evidence of functional type I and II androgen and oestrogen binding sites in both cytosol and nuclear fractions of cultured normal and RA macrophages. 10 Interestingly, both receptor contents and binding aYnities of these cells were comparable to those previously reported in other well established sex hormone responsive cells and tissues. Furthermore, specific messenger ribonucleic acids (mRNA) for sex hormone receptors, encoding for a sequence of the DNA binding domain of the receptor protein, have Annals of the Rheumatic Diseases 1997;56:281–286 281