Immunological significance of Mycobacterium leprae cell walls.

Abstract

Cell walls of Mycobacterium leprae, prepared by differential solvent extraction, were shown to contain arabinogalactan, mycolates, and peptidoglycan. In addition, amino acid analysis revealed the unexpected presence of large amounts of protein that retained potent immunological reactivity. Purified cell walls stimulated proliferation of T cells from tuberculoid, but not from lepromatous leprosy, patients and elicited delayed-type hypersensitivity skin reactions in guinea pigs and patients sensitized to M. leprae. Analysis of the precursor frequency of antigen-reactive human peripheral T cells revealed that as many cells (41/6000) proliferate to antigen contained in cell walls as to intact M. keprae. Sequential removal of mycolates and arabinogalactan resulted in a large peptidoglycan-protein complex that retained all the immunological activity. This immunological reactivity and the inherent protein were destroyed by proteolysis. Thus, cell wall protein is a major contributor to cell-mediated immune reactivity to this pathogenic mycobacterium.Leprosy is a chronic infectious disease that afflicts 10-13 million people, primarily living in developing countries (1). Although the incidence of leprosy is declining in many parts of the world, largely due to greater control efforts, the cost of multidrug therapy to combat emergent drug resistance of Mycobacterium leprae is high, and the development of an effective vaccine is widely agreed to offer the best hope for disease eradication (2, 3). Because M. leprae is one of few major pathogens of man that has not been successfully cultivated in vitro, the principal available source of antigens for study and vaccines remains infected tissues of the nine-banded armadillo Dasypus novemcinctus, which is inevitably limited and costly. Consequently, immunological and molecular biological approaches that permit identification and production of protective antigens are needed. Thus far, using murine monoclonal antibodies, genes for six major antigens of M. leprae have been isolated from Agtll libraries (4).From a variety of studies, cell-mediated immunity, which is regulated by specifically sensitized T lymphocytes, is clearly required for protection and resistance to leprosy (1).The disease encompasses an immunological spectrum. At one pole, lepromatous leprosy, patients selectively lack cell-mediated immunity to antigens of M. leprae and fail to restrict the growth of the pathogen; at the tuberculoid end of the spectrum, the patients exhibit cell-mediated immunity to antigens of M. leprae and develop one or a few sharply defined local lesions that contain only few acid-fast bacilli. However, when we and other workers derived M. lepraespecific CD4 + (helper T cell) clones from strongly leprominpositive healthy contacts of lepromatous patients or from blood or lesions of patients with tuberculoid leprosy, only a small proportion of clones tested are responsive to the known serologically defined recombinant antigens (ref. 5; J.M.-K., R.L.M., and B.R.B., unpublished data).For m...

Target organ localization of memory CD4+ T cells in patients with chronic beryllium disease

“…For example, the frequency of CD4 + T cells specific for Mycobacterium leprae antigens in tuberculoid skin lesions was estimated to be 1 in 50, which was 100-fold higher than in the blood of the same individuals (30,31). In patients with treatment-resistant Lyme disease, CD4 + T cells specific for Borrelia burgdorferi peptide (OspA 164-183) were identified in the synovial fluid at frequencies ranging from 0.5% to 3.1% of CD4 + T cells (32).…”

Down‐Regulatory Effect of Mycobacterium leprae Cell Wall Lipids on Phagocytosis, Oxidative Respiratory Burst and Tumour Cell Killing by Mouse Bone Marrow Derived Macrophages

“…These results are relevant considering that polar and particularly phospholipids are currently described in the literature as inhibitory substances for macrophages and T cell functions [6,8,10,11,18,20,34,35,38].…”

“…In spite of the large volume of clinical and experimental investigations on the pathogenesis of leprosy [1][2][3][4][5][6][7][8][9][10][11], little is known about the mechanisms which contribute to the persistence of the bacterium in the host tissues. A peculiar aspect of Mycobacterium leprae inoculation in experimental animals is the mild inflammatory response observed at the site of inoculation.…”

A 46 kDa integral membrane protein from Mycobacterium leprae resembles a number of bacterial and mammalian membrane transport proteins

“…(1990) were able to purify the cell wall, cytoplasmic membrane and cytosolic protein fractions. It was shown that cell envelope protein preparations from M. leprae are capable of inducing a potent cell-mediated immune reaction to this mycobacterium (Mehra et al, 1989;Melancon-Kaplan et al, 1988). Strong and specific T cell responses to M. leprae cell envelope proteins were also demonstrated in paucibacillary leprosy patients and their contacts, but lack of such responses was observed in multibacillary leprosy patients (Roche et al, 1992).…”