Peripheral blood T cell expansions in patients with Behc ¸et’s disease S. ESIN*², A. GU ¨ L‡, V. HODARA*, M. JEDDI-TEHRANI*, N. DILSEN‡, M. KONIC ¸E‡, R. ANDERSSON* & H.WIGZELL* *Microbiology and Tumourbiology Centre, Karolinska Institute, Stockholm, Sweden, and ² Electro-Neurophysiology Centre and ‡Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, University of Istanbul, Istanbul, Turkey (Accepted for publication 31 October 1996) SUMMARY Behc ¸et’s disease (BD) is a chronic multisystemic inflammatory disorder characterized mainly by recurrent oral and genital aphthous ulcerations and uveitis. Etiology and pathogenesis of BD remain unknown. T cell receptor (TCR) Va/Vb gene product expression as well as Jb gene segment expression in peripheral blood of BD patients were analysed to investigate the possible role of T lymphocytes in the etiopathogenesis of BD. Flow cytometry with 12 TCR V-specific MoAbs was used for TCRV analyses. Jb gene segment usage by T cell populations expressing certain Vbs was determined by polymerase chain reaction (PCR) technique with Vb- and Cb-specific primers, Southern blotting of PCR products, and subsequent hybridization with radiolabelled Jb gene segment-specific probes. Although 13 of the 23 BD patients exhibited increases in expression of one or more TCR V-gene products, only expansions among the CD4 þ T cell subset were significantly more frequent in BD patients (7/23) compared with healthy controls (0/15) (P ¼ 0 . 019). Six out of eight cases followed for up to 20 months had at least one expansion correlated with disease activity. A strict preference for particular Jb gene segments implicating clonality was apparent in all analysed T cell expansions and correlated well with disease activity. These results suggest a possible involvement of antigen-specific T lymphocytes in the pathogenesis of BD. Keywords T cell receptor autoimmunity Vb gene segment Jb gene segment Behc ¸et’s disease INTRODUCTION Behc ¸et’s disease (BD) is a chronic multisystemic inflammatory disorder characterized mainly by recurrent oral and genital aphthous ulcerations and uveitis. The clinical spectrum of BD is wide, involving skin, blood vessels, joints, nervous system, lungs and intestines [1]. BD is particularly frequent in countries along the Silk Route, from the Mediterranean area to Japan, and it is strongly associated with HLA-B51 [2,3]. Etiology and pathogenesis of BD remain unknown. A panel of infectious microorganisms, in parti- cular herpes simplex virus (HSV) and streptococci, have been implicated as causative agents of BD in genetically susceptible individuals [4,5]. There is evidence of immunological dysregula- tion, including neutrophil hyperfunction and several phenotypic and functional lymphocyte abnormalities, possibly resulting from complex interactions of genetic and environmental factors [6,7]. Most of the immunological studies suggest a central role for T cells in the pathogenesis of BD. A reduced CD4 þ /CD8 þ T cell ratio, due to both a decrease in CD4 þ T cells and a concomitant increase in CD8 þ T cells, has been demonstrated in BD patients [8]. Sig- nificantly lower CD4 þ CD45RA þ but similar CD4 þ CD29 þ T cell levels were recorded in peripheral blood lymphocytes of patients with active BD compared with healthy controls [8]. Functional studies on mononuclear cells of patients with BD revealed sig- nificant proliferative responses of T cells to peptides derived from both mycobacterial and human 65-kD heat shock proteins (hsp) [9]. Some of these peptides do induce uveitis in rats [10]. T cells from BD patients with uveitis, and to a lesser extent without uveitis, elicit proliferative responses to several uveitogenic pep- tides such as S antigen-derived peptide M and interphotoreceptor retinoid-binding protein [11]. Immunohistological studies of involved tissues such as oral ulcers, ocular lesions, erythema nodosum-like lesions, skin pathergy reaction and lesions of termi- nal ileum reveal a predominant T cell infiltration [11–13]. Besides ab þ T cells, increases in the gd þ T cell populations in peripheral blood and in inflammatory sites of BD patients have also been reported by several groups [14–16]. Moreover, gd þ T lymphocyte responses to particular hsp-derived peptides have been demon- strated to correlate with disease activity in BD patients [17]. Antigens are presented to T cells as peptides in the context of MHC molecules, and the specificity of T lymphocytes resides within the T cell receptor (TCR). Analyses of TCR V and J gene segment usages in human diseases of unknown etiology may provide clues to the nature of the triggering stimulus. T cells Clin Exp Immunol 1997; 107:520–527 520  1997 Blackwell Science Correspondence: Semih Esin, Karolinska Institute, Microbiology and Tumourbiology Centre, Box 280, 171 77 Stockholm, Sweden.