Journal of Autoimmunity (2002) 19, 233–240 doi:10.1006/jaut.2002.0620, available online at http://www.idealibrary.com on Restriction in the Usage of Variable  Regions in T-cells Infiltrating Valvular Tissue from Rheumatic Heart Disease Patients F. Figueroa 1 , M. Gonza ´lez 1 , F. Carrio ´n 1 , C. Lobos 1 , F. Turner 2 , N. Lasagna 1 and F. Valde ´s 1 1 Laboratory of Immunology, Faculty of Medicine, Universidad de los Andes and 2 Department of Cardiology, Hospital del To ´ rax and Hospital Dipreca, Santiago, Chile Received 8 February 2002 Accepted 10 September 2002 Key words: rheumatic fever, rheumatic heart disease, T cells, TCR V region, superantigen Rheumatic Heart Disease (RHD) is a delayed consequence of a pharyngeal infection with group A streptococcus (GAS), usually ascribed to a cross- reactive immune response to the host’s cardiac tissues. Several GAS proteins have been reported to be superantigens, also raising the possibility that T cells in RHD could be driven by superantigens. We therefore analysed the variable beta (V) repertoire of T cells infiltrating heart valves from chronic RHD patients undergoing elective valvular surgery. We analysed 15 valve speci- mens from patients with longstanding quiescent RHD and control valves from four non-rheumatic individuals. Total RNA was extracted from fresh valve tissue and employed to amplify 22 V genes by RT-PCR. In valvular tissue, a restricted number of only 2 to 9 V regions were detected as opposed to the findings in control valves. In 8 RHD valves, the expression of V1, 2, 3, 5.1, 7, 8, 9 or 14 was marked. These V regions have been related to GAS super- antigens. Our results evidence the presence of a restricted set of T lymphocytes in valvular tissue from a majority of patients with chronic RHD and suggest that valvular sequelae in these patients might be related to a local antigen or superantigen driven inflammatory process that persists even many years after the initial triggering event. © 2002 Elsevier Science Ltd. All rights reserved. Introduction Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD) continue to be the main cause of acquired heart disease among children and young adults in the world [1], accounting for the majority of cardiac operations in developing countries [2]. ARF is the consequence of a pharyngeal infection with Group A streptococcus (GAS) in a susceptible host, leading to an immune-mediated systemic disease with multi- organ involvement [3]. While most disease manifesta- tions are transient and leave no residua, rheumatic carditis, the most severe complication of ARF, can lead to valvular scarring with permanent sequelae in 35 to 79% of cases [4]. Current evidence suggests that the pathogenesis of heart damage in ARF is related to the occurrence of extensive immunological cross-reactivity between streptococcal components and host antigens such as cardiac myosin and valvular glycoproteins [5, 6]. This so-called molecular mimicry would therefore be responsible for the cross-reactive humoral and cellular immune response that is characteristic of ARF patients [7, 8]. This would also explain the inflammatory lesions that are typically found in both cardiac and valvular tissues [9]. Lymphocytic infiltrates have been identified in valvular tissue from patients with acute rheumatic carditis [10, 11] and also in valves removed 10–20 years after the initial attack of ARF [12]. In both cases, the cellular infiltrates are composed primarily of T cells [10, 12]. In addition, T-cell lines from affected heart valves have been shown to recognize rheuma- togenic strains of GAS [13] and also to cross-react with antigens derived from heart valve tissues and streptococcal M protein [14]. More recently, it has been shown that several strep- tococcal components, possibly including M protein [15], are superantigens [16–19]. These molecules inter- act with specific elements within the variable beta (V) region of the T-cell receptor (TCR), stimulating 5 to 20% of resting T cells, regardless of their antigenic specificity [20]. This mode of activation can cause expansion of potentially autoreactive T cells capable of triggering [21] or expanding a pathogenic auto- immune response in patients with ARF [22]. Only one group has published information concerning the usage of V genes in cardiac lesions from rheumatic Correspondence to: Fernando Figueroa M.D., Faculty of Medicine, Universidad de los Andes, Av San Carlos de Apoquindo 2200, 6782468 Las Condes, Santiago, Chile. Tel.: 56-2-214 1258; Fax: 56-2-214 1752; E-mail: ffiguero@uandes.cl 233 0896–8411/02/$-see front matter © 2002 Elsevier Science Ltd. All rights reserved.