Subject(s)
Genetic Predisposition to Disease , Leprosy/genetics , Leprosy/immunology , Mycobacterium leprae/immunology , Polymorphism, Genetic , ATP Binding Cassette Transporter, Subfamily B, Member 3 , ATP-Binding Cassette Transporters/genetics , Abatacept , Cation Transport Proteins/genetics , Complement C4b-Binding Protein , HLA Antigens/genetics , Histocompatibility Antigens/genetics , Humans , Immunoconjugates/genetics , Interleukin-10/genetics , Leprosy/microbiology , Membrane Glycoproteins/genetics , Microfilament Proteins , Molecular Chaperones , Proteins/genetics , Receptors, Cell Surface/genetics , Toll-Like Receptors , Tumor Necrosis Factor-alpha/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
We used human leprosy as a model to compare patterns of costimulatory molecule expression in respect to the clinical/immunologic spectrum of disease. We found that B7-1, B7-2, and CD28 transcripts dominated in tuberculoid leprosy patients, who have potent T cell responses to Mycobacterium leprae. In contrast, CTLA-4 was more strongly expressed in lesions from lepromatous patients, who manifest specific T cell anergy to the leprosy bacterium. T cell clones from tuberculoid lesions were CD4+CD28+ or CD4+CD28-, and T cell clones from lepromatous lesions were predominantly CD8+CD28-. The M. leprae-specific recall response of CD4+ T cell clones from tuberculoid lesions was blocked by anti-B7-1 mAb, but not by anti-B7-2 mAb or CTLA-Ig. However, anti-CD28 and anti-CTLA-4 mAbs did not block activation of clones from tuberculoid lesions, suggesting that B7-1 may utilize another costimulatory pathway. Peripheral blood T cell responses in the lepromatous form were strongly regulated by CD28 during T cell activation, in contrast to the tuberculoid form. Thus, B7-1 costimulation could play a role in maintaining a strong immune response to the pathogen.
Subject(s)
B7-1 Antigen/physiology , CD28 Antigens/physiology , CD4-Positive T-Lymphocytes/immunology , Immunoconjugates , Leprosy, Lepromatous/immunology , Leprosy, Tuberculoid/immunology , Abatacept , Antibodies, Blocking/pharmacology , Antigens, CD/biosynthesis , Antigens, Differentiation/biosynthesis , B7-1 Antigen/biosynthesis , B7-1 Antigen/immunology , B7-2 Antigen , CD28 Antigens/biosynthesis , CD4-Positive T-Lymphocytes/microbiology , CTLA-4 Antigen , Clone Cells , Humans , Immune Sera/pharmacology , Leprosy, Lepromatous/pathology , Leprosy, Tuberculoid/pathology , Leukocytes, Mononuclear/immunology , Lymphocyte Activation/immunology , Membrane Glycoproteins/biosynthesis , Mycobacterium leprae/immunology , Signal Transduction/immunology , Skin/immunology , Skin/pathologyABSTRACT
Two genetic loci, viz. COL3A and CTLA4, located within the chromosome 2q31-33 region in the vicinity of the proposed syntenic site of the mouse "Bcg" locus were genotyped by the polymerase chain reaction in leprosy patients and healthy individuals. All the subjects studied were assessed as in-vitro responders/non-responders to mycobacterial antigens. Simple sequence length polymorphism analysis revealed five (236 to 312 bp) and eight (84 to 120 bp) allelomorphs for COL3A and CTLA4, respectively. Our preliminary analysis showed a significant association between the 250-bp COL3A allelomorph in the homozygous condition and the multibacillary form of leprosy (P < 0.05: relative risk = 5.5). Another allelic (312 bp) variant of COL3A was significantly correlated with non-responsiveness to M. leprae antigens in vitro (P < 0.01). The 104-bp allelomorph of CTLA4 was not observed in any of the 25 cases of leprosy. This absence was statistically significant (P < 0.05) when compared with normal healthy controls and depicted a high relative risk (RR = 25.83). An additional observation of the predominance of a unique 84-bp CTLA4/CTLA4-like allelomorph was observed in the Indian subjects studied.