Learning from lesions: patterns of tissue inflammation in leprosy.

Abstract

The clinical forms of leprosy constitute a spectrum that correlates closely with the degree of cellmediated immunity. Patients with tuberculoid leprosy develop strong cell-mediated responses and have only a few, localized lesions, whereas patients with multibacillary lepromatous leprosy are specifically unresponsive to antigens of Myobacterium leprae. T cells of the CD4+ subset predominate in tuberculoid lesions, whereas CD8+ cells predominate in lepromatous lesions. Monoclonal antibodies that distinguish subpopulations of CD4+ and CD8+ cells were used to analyze the distribution of T cells infiltrating lesions across the disease spectrum. In lepromatous lesions, T cells of T-suppressor phenotype (9.3-) were the predominant CD8+ cells and suppressor/inducer cells (2H4+, Leu-8+) represented half of the CD4+ subset. In tuberculoid lesions, helper T cells (CD4+4B4+) outnumbered suppressor/inducer T cells by 14:1, compared with a ratio of 1.2:1 in peripheral blood. Analysis of the precursor frequency of antigen-reactive T cells permitted us to estimate that there was a 100-fold enrichment of T cells able to proliferate in response to M. leprae antigens in tuberculoid lesions (2/100), when compared with blood from the same patients. The methods used here to characterize the T-lymphocyte subsets and frequency of antigen-reactive T cells in leprosy may be useful in analyzing imunological reactions occurring in lesions of other inflammatory and autoimmune diseases.There are at least two compelling reasons to study leprosy. The disease itself, affecting 10-15 million people worldwide, poses a significant health and economic burden on thirdworld countries. Second, because leprosy is a spectral disease in which pathology and immunology are inextricably related, it provides a unique critical model for investigating immunoregulatory mechanisms in humans.Leprosy is not a single critical entity but rather comprises a spectrum of clinical manifestations that correlate remarkably well with immunological responses to the organism (1). Patients with tuberculoid leprosy have a few localized lesions with rare organisms and a strong cell-mediated immune response directed against Myobacterium leprae antigens that ultimately kills and clears the bacilli, although often with concomitant injury to nerves. In contrast, lepromatous leprosy patients have numerous skin lesions containing extraordinarily high numbers of acid-fast bacilli and show specific immunological unresponsiveness to antigens of M. leprae in vivo and in vitro.The selective mechanisms of accumulation of lymphocytes, their antigen specificity, and immunological functions in inflammatory lesions of human infectious or autoimmune diseases remain largely unknown. Since the focal point of the immune response to M. leprae is the tissue granuloma, consisting of a collection of lymphocytes and macrophages, some of these questions can be approached directly through the study of cells infiltrating the lesions across the spectrum of leprosy.Immunohistological studies using m...

Immunological significance of Mycobacterium leprae cell walls.

“…Although this approach has been useful in murine systems (15, and has been used in man, [28][29][30] it has had only limited application in humans because of a larger number of cells proliferating to growth factors independently of antigen recognition. We recently developed a limiting-dilution assay to estimate the frequency of antigen-reactive T-cell precursors that virtually eliminates the background of antigenindependent proliferation, thus rendering the assay more sensitive and accurate (12). Results (Fig.…”

“…Lymphocyte Transformation and Precursor Frequency Analysis. The precursor frequency of human peripheral blood T lymphocytes reactive to various antigen preparations from M. leprae was determined by a modified limiting dilution procedure (12). Briefly, T lymphocytes were isolated from the blood of lepromin-positive tuberculoid leprosy patients or contacts, and replicate cultures were estab- Proc.…”

Divergent T-cell cytokine patterns in inflammatory arthritis.

“…However, the production of these cytokines is probably restricted to the minority of T cells that have recently undergone antigenic stimulation, and there is increasing evidence that only a few such cells are needed to maintain an inflammatory lesion. Thus only 2% of T cells from tuberculoid leprosy skin lesions respond to the bacterial antigen (42). In multiple sclerosis, the frequency of T cells responding to myelin-oligodendrocyte glycoprotein in the cerebrospinal fluid is 1:450 (43), and only 1:1000 T cells from synovial fluid in reactive arthritis respond to the bacterial antigen that triggered the disease (44).…”

Characterization of T Cell Receptor β Chains of Accumulating T Cells in Chronic Ongoing Myocarditis Demonstrated by Heterotopic Cardiac Transplantation in Mice

“…Some different V segments can be used to recognize one MHC-associated epitope, 12 and therefore we can postulate that there was a remarkable enrichment of T cells able to proliferate in response to viral antigens in the myocarditis lesions. 13 Barten et al examined the phenotypic and functional characteristics of activated T cells and recruited inactivated T cells at an inflammatory site using a V 4 + myelin basic protein-specific T cell clone in a passively transferred model of experimental allergic encephalomyelitis. 14 V 4 + T cells at the site of antigen expression (the spinal cord) demonstrated a higher level of LFA-1 and CD44, but lower levels of VLA-4 and intercellular adhesion molecule-1, than did V 4 + T cells in the spleen.…”