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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0801212v1 183/1/718    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Almeida, A. S. Articles by Ho, J. L. PubMed PubMed Citation Articles by Almeida, A. S. Articles by Ho, J. L.

Tuberculosis Is Associated with a Down-Modulatory Lung Immune Response That Impairs Th1-Type Immunity

Alexandre S. Almeida^*,, Patrícia M. Lago^*, Neio Boechat^*, Richard C. Huard^*,, Luiz C.O. Lazzarini^*,, Adalberto R. Santos^¶, Marcelo Nociari, Hongxia Zhu, Beatriz M. Perez-Sweeney, Heejung Bang, Quanhong Ni, Jie Huang, Andrea L. Gibson, Vera C. Flores^*,, Lorena R. Pecanha^*, Afrânio L. Kritski^*, José R. Lapa e Silva^*, and John L. Ho^*

^*Institute of Thoracic Diseases and Clementino Fraga Filho University Hospital of Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Division of International Medicine and Infectious Disease, Department of Medicine and Division of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, New York, NY 10021; Clinical Microbiology Service, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY 10032; and ^¶Laboratory of Molecular Biology Applied to Mycobacteria, Oswaldo Cruz Institute, Rio de Janeiro, Brazil

Immune mediators associated with human tuberculosis (TB) remain poorly defined. This study quantified levels of lung immune mediator gene expression at the time of diagnosis and during anti-TB treatment using cells obtained by induced sputum. Upon comparison to patients with other infectious lung diseases and volunteers, active pulmonary TB cases expressed significantly higher levels of mediators that counteract Th1-type and innate immunity. Despite the concomitant heightened levels of Th1-type mediators, immune activation may be rendered ineffectual by high levels of intracellular (SOCS and IRAK-M) and extracellular (IL-10 and TGF-βRII, IL-1Rn, and IDO) immune suppressive mediators. These modulators are a direct response to Mycobacterium tuberculosis as, by day 30 of anti-TB treatment, many suppressive factors declined to that of controls whereas most Th1-type and innate immune mediators rose above pretreatment levels. Challenge of human immune cells with M. tuberculosis in vitro up-regulated these immune modulators as well. The observed low levels of NO synthase-2 produced by alveolar macrophages at TB diagnosis, along with the heightened amounts of suppressive mediators, support the conclusion that M. tuberculosis actively promotes ^–down-modulatory mediators to counteract Th1-type and innate immunity as an immunopathological strategy. Our data highlight the potential application of immune mediators as surrogate markers for TB diagnosis or treatment response.

Address correspondence and reprint requests to Dr. John L. Ho, Division of International Medicine and Infectious Disease, Weill Medical College of Cornell University, 1300 York Avenue, Room A-421, New York, NY 10021. E-mail address: millennium.john{at}gmail.com or Dr. José Roberto Lapa e Silva, Laboratório Multidisplinar de Pesquisa, Universidade Federal do Rio de Janeiro, Avenida Prof. Rodolpho Paulo Rocco 255, 21941-590 Rio de Janeiro, Rio de Janeiro, Brazil. E-mail address: jrlapa.ntg{at}terra.com.br.