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A Polymorphism in Human CD1A is Associated with Susceptibility to Tuberculosis

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      CD1 proteins are antigen-presenting molecules that evolved to present lipids rather than peptides to T cells. However, unlike major histocompatibility complex genes, CD1 genes show low rates of polymorphism and have not been clearly associated with human disease. We report that an intronic polymorphism in CD1A (rs411089) is associated with susceptibility to tuberculosis in two cohorts of Vietnamese adults (combined cohort odds ratio 1.78; 95%CI: 1.24-2.57; p=0.001). These data strengthen the hypothesis that CD1A-mediated lipid antigen presentation is important for controlling tuberculosis in humans.

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      Most cited references 16

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      Genetic dissection of immunity to mycobacteria: the human model.

      Humans are exposed to a variety of environmental mycobacteria (EM), and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. In addition, most of the world's population is occasionally exposed to human-borne mycobacterial species, which are less abundant but more virulent. Although rarely pathogenic, mildly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. Mycobacterium tuberculosis, M. leprae, and EM M. ulcerans are more virulent, causing tuberculosis, leprosy, and Buruli ulcer, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. The interindividual variability of clinical outcome is thought to result in part from variability in the human genes that control host defense. In this well-defined microbiological and clinical context, the principles of mouse immunology and the methods of human genetics can be combined to facilitate the genetic dissection of immunity to mycobacteria. The natural infections are unique to the human model, not being found in any of the animal models of experimental infection. We review current genetic knowledge concerning the simple and complex inheritance of predisposition to mycobacterial diseases in humans. Rare patients with Mendelian disorders have been found to be vulnerable to BCG, a few EM, and M. tuberculosis. Most cases of presumed Mendelian susceptibility to these and other mycobacterial species remain unexplained. In the general population leprosy and tuberculosis have been shown to be associated with certain human genetic polymorphisms and linked to certain chromosomal regions. The causal vulnerability genes themselves have yet to be identified and their pathogenic alleles immunologically validated. The studies carried out to date have been fruitful, initiating the genetic dissection of protective immunity against a variety of mycobacterial species in natural conditions of infection. The human model has potential uses beyond the study of mycobacterial infections and may well become a model of choice for the investigation of immunity to infectious agents.
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          Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells.

          Major histocompatibility complex (MHC) class I and class II molecules bind immunogenic peptides and present them to lymphocytes bearing the alpha beta T-cell antigen receptor (TCR). An analogous antigen-presenting function also has been proposed for the non-MHC-encoded CD1 molecules, a family of non-polymorphic, beta 2-microglobulin-associated glycoproteins expressed on most professional antigen-presenting cells. In support of this hypothesis, CD1 molecules are recognized by selected CD4-CD8- alpha beta or gamma delta TCR+ T-cell clones, and we have recently shown that CD1 molecules restrict the recognition of foreign microbial antigens by alpha beta TCR+ T cells. But the substantial structural divergence of CD1 from MHC class I and class II molecules, raises the possibility that the antigens presented by the CD1 system may differ fundamentally from those presented by MHC-encoded molecules. Here we report that a purified CD1b-restricted antigen of Mycobacterium tuberculosis presented to alpha beta TCR+ T cells is mycolic acid, a family of alpha-branched, beta-hydroxy, long-chain fatty acids found in mycobacteria. This example of non-protein microbial antigen recognition suggests that alpha beta TCR+ T cells recognize a broader range of antigens than previously appreciated and that at least one member of the CD1 family has evolved the ability to present lipid antigens.

            Author and article information

            [1 ]Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA
            [2 ]Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
            [3 ]Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam
            [4 ]Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
            [5 ]Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, United Kingdom
            Author notes
            Corresponding author: Chetan Seshadri, M.D., University of Washington School of Medicine, 750 Republican Street Seattle, WA, 98109. Phone: (206)-543-6709 ; Fax: (206)-616-4898 seshadri@
            Genes Immun
            Genes Immun.
            Genes and immunity
            16 January 2014
            06 February 2014
            April 2014
            01 October 2014
            : 15
            : 3
            : 195-198

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