Chemokines and chemokine receptors coordinate the inflammatory immune response in human cutaneous leishmaniasis Ana P. Campanelli a,d , Claudia I. Brodskyn c,e,f, *, Viviane Boaventura c , Claire Silva c , Ana M. Roselino b , Jackson Costa c , Ana Cristina Saldanha c , Luiz AntÕnio Rodrigues de Freitas c , Camila Indiani de Oliveira c , Manoel Barral-Netto c,e,f , JoÄo S. Silva a , Aldina Barral c,e,f a Department of Biochemistry and Immunology, School of Medicine of Ribeirâo Preto, University of Sâo Paulo, Brazil b Division of Dermatology, School of Medicine of Ribeirâo Preto, University of Sâo Paulo, Brazil c Centro de Pesquisa Gonåalo Moniz, FIOCRUZ-BA, Salvador, Bahia, Brazil d Department of Biological Sciences, Bauru Dental School, University of Sâo Paulo, Sâo Paulo, Brazil e Universidade Federal da Bahia, Salvador, Bahia, Brazil f Instituto de Investigaåâo em Imunologia, Instituto Nacional de Ciéncia e Tecnologia (INCT), Sâo Paulo, Sâo Paulo, Brazil ARTICLE INFO Article history: Received 18 December 2009 Accepted 9 September 2010 Available online 18 September 2010 Keywords: Chemokines Cutaneous leishmaniasis Inflammation ABSTRACT Cutaneous leishmaniasis (CL) includes different clinical manifestations displaying diverse intensities of dermal inflammatory infiltrate. Diffuse CL (DCL) cases are hyporesponsive, and lesions show very few lymphocytes and a predominance of macrophages. In contrast, localized CL (LCL) cases are responsive to leishmanial antigen, and lesions exhibit granulocytes and mononuclear cell infiltration in the early phases, changing to a pattern with numerous lymphocytes and macrophages later in the lesion. Therefore, different chemokines may affect the predominance of cell infiltration in distinct clinical manifestations. In lesions from LCL patients, we examined by flow cytometry the presence of different chemokines and their receptors in T cells, and we verified a higher expression of CXCR3 in the early stages of LCL (less than 30 days of infection) and a higher expression of CCR4 in the late stages of disease (more than 60 days of infection). We also observed a higher frequency of T cells producing IL-10 in the late stage of LCL. Using immunohistochemistry, we observed a higher expression of CCL7, CCL17 in lesions from late LCL, as well as CCR4 suggesting a preferential recruitment of regulatory T cells in the late LCL. Comparing lesions from LCL and DCL patients, we observed a higher frequency of CCL7 in DCL lesions. These results point out the importance of the chemokines, defining the different types of cells recruited to the site of the infection, which could be related to the outcome of infection as well as the clinical form observed.  2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Introduction Leishmaniasis, caused by protozoan parasites of the genus Leish- mania, is a major health problem in many regions of the world. Leishmania are protozoan parasites that infect human macrophages and cause a wide spectrum of clinical manifestations, including self-healing skin lesions, diffuse cutaneous disease, and mucosal disease (reviewed by Brodskyn et al. [1]). Cutaneous lesions begin at the site of parasite entrance as a small papule, which develops into a nodule that ulcerates in the center. The incubation period ranges from 2 weeks to several months (reviewed by Brodskyn et al. [1]). The most frequent aspect observed in cutaneous leishman- iasis (CL) cases is a single ulcer with elevated borders and a sharp crater. In the early phase of CL (early CL), lymphoadenopathy can precede the lesion, and we consider early lesions when patients presented lesions until 30 days of infection. In late CL lesions, lymphadenopathy is a rare event, and it is possible to observe a dense infiltration of cells and generally, lesions display more than 30 days of infection [2,3]. Diffuse CL is a rare presentation of human tegumentary leishmaniasis. The presence of multiple and nonulcerated nodules characterizes diffuse CL (DCL), a form that is resistant to a standard antileishmania therapeutic regimen and presents with frequent relapses [3]. In Brazil, there have been approximately 40 cases of DCL studied since 1945 at Uni- versidade Federal do MaranhÄo (UFMA) and CPqGM (Centro de Pes- quisa GonÈalo Moniz [3]. Whereas DCL is characterized by higher numbers of parasites and a lack of cell-mediated immunity to leishmanial antigen, CL leishmaniasis is generally accompanied by strong cellular re- sponses and few parasites in the lesions [4]. * Corresponding author. E-mail address: brodskyn@bahia.fiocruz.br (C.I. Brodskyn). A.P. Campanelli and C.I. Brodskyn contributed equally to this work. Human Immunology 71 (2010) 1220 –1227 Contents lists available at ScienceDirect 0198-8859/10/$32.00 - see front matter  2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.humimm.2010.09.002