43 Centro de Investigación en Inmunología y Dermatología, Departamento de Fisiología, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco, México. Abnormalities in Intracellular Processing and Expression of Interferon-γ Receptor in Adherent Cells from Lepromatous Leprosy Patients Celia Guerrero-Velázquez, Rocio I. Lopez-Roa, Vidal Delgado-Rizo, Cecilia M. Guillen-Vargas, Margarita Montoya-Buelna, and Mary Fafutis-Morris Peripheral blood mononuclear cells in lepromatous leprosy (LL) patients produce low levels of interferon-γ (IFN-γ ) and interleukin-12 (IL-12), and these cells exhibit partial or complete deiciency in the IL-12 receptor. The behavior of the IFN-γ receptor (IFN-γR) has not been described in cells from people with leprosy. We found higher levels of mRNA for IFN-γR1 and IFN-γR2 in adherent cells stimulated with IFN-γ and Mycobacterium leprae membrane proteins from LL patients compared with healthy subjects. Flow cytometry showed no sig- niicant difference in IFN-γR1 expression between LL patients and healthy subjects. Immunoblotting detected only the mature glycosylated form of the 61–67 kDa IFN-γR2 protein in healthy subjects. In contrast, cells from LL patients showed three different expression patterns: (1) the immature deglycosylated form of the 34.8 kDa IFN-γR2 protein, (2) the mature glycosylated 61–67 kDa form, and (3) both forms. Our data indicate the existence of abnormalities in the intracellular processing and protein expression of the IFN-γR in response to speciic stim- uli such as IFN-γand M. leprae membrane proteins in adherent cells of LL patients. Introduction L eprosy is a chronic granulomatous infection caused by Mycobacterium leprae, an intracellular parasite within the monocyte–macrophage system, which cannot eliminate the bacilli effectively (Abulaia and others 1990; Jacobson and Krahenbuhl 1999; Britton and Lockwood 2004). Leprosy induces a wide range of clinical, histological, and immunological manifestations, which are used to clas- sify the disease into ive types: tuberculoid leprosy (TT), borderline tuberculoid leprosy, borderline leprosy, border- line lepromatous leprosy, and lepromatous leprosy (LL). The cellular immune response predominates over the humoral immune response in TT patients and opposite in LL patients (Ridley and Jopling 1966; Ivanyi 1986; Ochoa and others 1996). An adequate immune response against intracellular par- asites involves interferon-γ (IFN-γ), interleukin-12 (IL-12), and IL-18 and their receptors. Mycobacteria-infected mac- rophages and dendritic cells produce IL-12 and IL-18, which synergize to activate T and natural killer (NK) cells through their speciic receptors, inducing the production of IFN-γ and promoting a Th1 response (Altare and others 1998b; Nakahira and others 2002). The IFN-γ receptor (IFN-γR) com- prises two α-chains (IFN-γR1) and two β-chains (IFN-γR2). Binding of IFN-γ to the IFN-γR in macrophages or dendritic cells causes the transcription of numerous genes, including those coding for IL-12 and IL-18; binding to the IFN-γR also results in autocrine activation of T and NK cells (Nakahira and others 2002). Patients with tuberculosis and other diseases caused by bacilli Calmette–Guerin (BCG) or atypical Mycobacteria, such as Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium avium, have low levels of IFN-γ and IL-12, as well as down-regulated expression of receptors of these cytokines (Newport and others 1996; Altare and others 1998a; Jouanguy and others 2000). Peripheral blood mononuclear cells (PBMC) from LL patients produce low levels of IFN-γ and IL-2 (Islas and oth- ers 1987; Fafutis and others 1999). This is a critical event for the production of IL-12, which remains low, and IL-12 con- centration does not achieve a normal level, even after exoge- nous addition of IFN-γ (Libraty and others 1997). JOURNAL OF INTERFERON & CYTOKINE RESEARCH Volume 30, Number 2, 2009 © Mary Ann Liebert, Inc. DOI: 10.1089/jir.2008.0121 RESEARCH REPORT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 06-JIR-2008_0121.indd 43 06-JIR-2008_0121.indd 43 8/8/2009 7:44:52 PM 8/8/2009 7:44:52 PM