Search PubMed⌕ Search

Biomedical subjects

R L Modlin

Publications and source records attributed to R L Modlin.

At least 109 records · Page 6Linked to original sources
PubMed1991

Immunopathology of leprosy skin lesions.

These immunopathogenesis studies of leprosy have provided new insight into the immune response to M leprae at the site of disease activity, the skin lesions. The study of leprosy provides a model for studying the immune response to foreign pathogens as well as the immunopathologic study of skin lesions. Further developments in immunology and molecular biology will increase our ability to dissect such immune mechanisms. For example, the advent of the polymerase chain reaction will allow for a more complete elucidation of the cytokines in inflammatory skin lesions.

Erythema Nodosum↗
PubMed1990

Immunologic responsiveness in American cutaneous leishmaniasis lesions.

American cutaneous leishmaniasis is a disease of skin and mucous membranes in which T lymphocytes reactive to Leishmania (Viannia) braziliensis are thought to contribute to protective immunity. To characterize the nature of the T cell inflammatory infiltrate in American cutaneous leishmaniasis lesions, immunohistochemistry with mAb that define T cell subpopulations and in situ hybridization to detect mRNA coding for IFN-gamma were performed. In both localized cutaneous (LCL) and mucocutaneous (MCL) lesions, we observed a predominance of T memory (CD4+CD45RO+) as compared to T naive cells (CD+CD45RA+). The percentages of cells containing IFN-gamma mRNA were equivalent in both LCL and MCL lesions. T cells were extracted from LCL and MCL lesions and analysis indicated that T cells from both lesions had been stimulated by L. (V.) braziliensis in vivo and gave equivalent proliferative responses in vitro. The present data suggest that T memory cells, which are likely to elaborate IFN-gamma, are components of DTH response to L. (V.) braziliensis and participate in the pathogenesis of both LCL and MCL lesions.

Animals↗
PubMed1990

Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis.

TNF and IFN-gamma are thought to be involved in the immune response to mycobacterial infection because they exhibit antimycobacterial effects in vitro. To investigate the roles of these cytokines in vivo at the site of disease activity in human tuberculosis, we evaluated local cytokine production in patients with tuberculous pleuritis. Both TNF and IFN-gamma were selectively concentrated 5- to 30-fold in pleural fluid, compared to blood of the same patients. Messenger RNA for both cytokines was detected in pleural tissue by in situ hybridization, suggesting that selective cytokine concentration is due to local cytokine production. Two Mycobacterium tuberculosis cell wall components, the protein-peptidoglycan complex and lipoarabinomannan, caused dose-dependent release of TNF by pleural fluid mononuclear cells and may constitute the stimuli for TNF production in the pleural space. In contrast to results obtained for TNF release, the protein-peptidoglycan complex, but not lipoarabinomannan, stimulated IFN-gamma release by pleural fluid mononuclear cells. The clinical manifestations of tuberculous pleuritis, such as fever, exudative pleural effusion, and tissue necrosis, may be due to the effects of elevated local TNF concentrations, produced in response to mycobacterial cell wall components.

Cell Wall↗
PubMed1989

Characterization of T cell antigens associated with the cell wall protein-peptidoglycan complex of Mycobacterium tuberculosis.

Mycobacterium tuberculosis cell walls are likely to contain critical T cell Ag capable of inducing protective immunity against the development of tuberculosis in animal models. Therefore, we characterized cell wall-associated Ag that stimulate T lymphocytes in tuberculosis patients and clinically well tuberculin-positive individuals. A protein-peptidoglycan complex isolated from the M. tuberculosis cell wall had potent immunologic activity, evoking PBMC proliferative responses similar to those induced by sonicated whole M. tuberculosis. In order to characterize the immunoreactive protein determinants associated with the protein-peptidoglycan complex, T cell lines were established to cell wall Ag and used to probe M. tuberculosis proteins separated by SDS-PAGE. These T cell lines proliferated primarily to protein Ag of 10, 19, 23, 28, 30, 40 to 50, and 65 kDa. Cell wall-reactive T cell clones that recognized the 10-, 23-, 28-, and 30-kDa proteins as single bands on SDS-PAGE did so under reducing and nonreducing conditions, suggesting that these are not proteolytic fragments or subunits of larger protein aggregates. We propose that these protein monomers, when post-translationally complexed with peptidoglycan, are the key ingredients of the immunogenic protein-peptidoglycan complex. In order to assess the relationship of the cell wall-associated Ag to those secreted proteins from "early culture filtrates" of actively growing M. tuberculosis recently implicated in eliciting protective immunity, cell wall-reactive T cell clones were tested for their ability to recognize early culture filtrates. Results revealed that at least three proteins shared with the cell wall complex are contained within early culture filtrates. Our data indicate that antigenic determinants associated with the protein-peptidoglycan complex of the M. tuberculosis cell wall may be involved in protective immunity and hence are potential candidates for inclusion in an effective antituberculosis vaccine.

Antigens, Bacterial↗
PubMed1989

Lymphocytes bearing antigen-specific gamma delta T-cell receptors accumulate in human infectious disease lesions.

The majority of T cells bear the T-cell receptor (TCR) alpha beta complex which recognizes foreign antigen peptides only in the context of self major histocompatibility complex (MHC) molecules. Such T cells function in a variety of effector roles and secrete cytokines that mediate the activation and differentiation of other cells in the immune system. Recently, a small subpopulation T cells was found to bear a distinct TCR composed of gamma and delta subunits. In man, TCR gamma delta+ cells are distributed as approximately 5 per cent of the CD3+ cells in all organized lymphoid organs as well as in the skin- and gut-associated lymphoid tissues. Although a limited number of germ-line genes encode the TCR gamma and delta subunits, extensive junctional variation particularly in the delta gene, results in unprecedented diversity for this receptor. The nature of the specificity and immunological functions of these T cells remains enigmatic. We report here that in contrast to the normal low frequency of gamma delta-bearing cells in lymphoid tissues, peripheral blood, or normal skin, the frequency is increased five to eightfold in particular granulomatous reactions of leprosy. TCR gamma delta+ lymphocyte lines from these leprosy skin lesions proliferate in vitro specifically to mycobacterial antigens. This reactivity to foreign antigens appears to require presentation in the context of self-molecules. Moreover, culture supernatants from activated gamma delta T lymphocytes induce adhesion and aggregation of bone-marrow monocytes in the presence of granulocyte monocyte-colony stimulating factor (CSF), suggesting that products of gamma delta-bearing T cells may play a role in the immune response, possibly by stimulating granuloma formation.

Epitopes↗
PubMed1989

Analysis of naturally occurring delayed-type hypersensitivity reactions in leprosy by in situ hybridization.

Analysis of tissue lesions of the major reactional states of leprosy was undertaken to study the immune mechanisms underlying regulation of cell-mediated immunity and delayed-type hypersensitivity (DTH) in man. In situ hybridization hybridization of reversal reaction biopsy specimens for INF-gamma mRNA expression revealed a 10-fold increase in specific mRNA-containing cells over that observed in unresponsive lepromatous patients. Expression of huHF serine esterase, a marker for T cytotoxic cells, were fourfold increased in reversal reaction and tuberculoid lesions above that detected in unresponsive lepromatous individuals. Immunohistology of reversal reactions confirmed a selective increase of Th and T cytotoxic cells in the cellular immune response. Of interest, the microanatomic location of these serine esterase mRNA-containing cells was identical to the distribution of CD4+ cells. Analysis of erythema nodosum leprosum (ENL) lesions revealed differences in the underlying immune processes in comparison with reversal reaction lesions. Although phenotypic Th cells predominated in ENL lesions, IFN-gamma and serine esterase gene expression were markedly reduced. We suggest that reversal reactions represent a hyperimmune DTH response characterized by a selective increase of CD4+ IFN-gamma producing cells and T cytotoxic cells, which result in the clearing of bacilli and concomitant tissue damage. In contrast, ENL reactions may be viewed as a transient diminution of Ts cells and activity leading to a partial and transient augmentation in cell-mediated immunity, perhaps sufficient to result in antibody and immune complex formation, but insufficient to clear bacilli from lesions.

Esterases↗
PubMed1989

Isolation and characterization of the highly immunogenic cell wall-associated protein of Mycobacterium leprae.

In a recent study, we demonstrated that certain reactivities crucial to the immune response in leprosy are due to protein associated with the cell wall peptidoglycan "core" of Mycobacterium leprae. We now describe a primary method for the isolation of a highly immunogenic, large molecular-size, cell wall protein (CW-P) complex from M. leprae, freed of soluble proteins, bound mycolates, arabinogalactan, and much of the peptidoglycan. The complex is of apparent relative molecular size 2 x 10(6) to 20 x 10(6) Da, is distinguished by a high content of Ala, Gly, Leu, Asx, and Glx, and some peptidoglycan, and represents up to 7% of the bacterial mass. It is stable to a variety of dissociation and reductive processes and, in accord with its size, is not resolvable by polyacrylamide gel electrophoresis. The mAb to the CW-P complex also react with the heat shock 65-kDa protein of M. leprae. Conversely, antibodies that recognize internal epitopes within the polypeptide chain of the heat shock protein also react with CW-P; however, antibodies that recognize the N and C termini of the 65-kDa protein fail to react with CW-P, and some anti-CW-P mAb do not recognize any of the soluble proteins of M. leprae. Alternate methods to derive the large peptidoglycan-associated protein result in lower yield and less of the associated heat shock protein, implying that the 65-kDa protein may not be crucial to the immunogenicity of the complex. In an accompanying paper, we demonstrate that T cell clones raised to CW-P also selectively recognize soluble proteins, primarily of 7-kDa and 16-kDa size. Thus, the image of the CW-P complex of M. leprae is of a few immunoreactive polypeptides in avid association with a modicum of peptidoglycan to which the 65-kDa polypeptide may be variably attached, perhaps due to involvement in assembly of the complex.

Amino Acids↗
PubMed1989

Compartmentalization of a CD4+ T lymphocyte subpopulation in tuberculous pleuritis.

The study of T lymphocytes from pleural fluid and tissue of patients with tuberculous pleuritis provides an opportunity to evaluate the human immune response to infection at the site of disease activity. Therefore, we investigated the phenotype and function of CD4+ pleural fluid cells from patients with tuberculous pleuritis. Pleural fluid was enriched with CD4+CDw29+ T lymphocytes, which are thought to represent "memory" T cells. Immunoperoxidase staining of pleural tissue confirmed the predominance of CD4+CDw29+ T lymphocytes at the site of disease activity. CD4+ subpopulations were evaluated for their ability to contribute to a cell-mediated immune response against Mycobacterium tuberculosis by assaying immune function in vitro. Pleural fluid-derived CD4+CDw29+ cells, but not CD4+CDw29- lymphocytes, proliferated vigorously and produced high levels of IFN-gamma when stimulated with purified protein derivative of M. tuberculosis. CD4+CDw29+ clones produced IFN-gamma specifically in response to purified protein derivative of M. tuberculosis but not to an irrelevant Ag, tetanus toxoid. IFN-gamma levels were markedly elevated in pleural fluid, compared to peripheral blood, suggesting production of this lymphokine in vivo at the site of tissue inflammation. The sum of these data indicate that, in tuberculous pleuritis, CD4+CDw29+ cells are concentrated at the site of disease activity, produce IFN-gamma and are likely to play an important role in the local human cell-mediated immune response to M. tuberculosis.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1989

CD2 expression and function in lepromatous leprosy.

Leprosy is a spectral disease in which clinical presentation is thought to be related to the host immune response. Previous investigations have suggested that selective unresponsiveness to Mycobacterium leprae in patients with lepromatous leprosy is due to the presence of M. leprae-specific T-suppressor cells. However, it has recently been suggested that CD2 modulation was the mechanism for the observed impaired immune response in lepromatous patients. Therefore, we studied the expression of CD2 and CD3 on lymphocytes in lepromatous skin lesions and peripheral blood mononuclear cells (PBMC). Using immunohistochemical techniques, we found that virtually all of the CD3+ cells in leprosy skin lesions expressed CD2. In addition, indirect immunofluorescence flow cytometry demonstrated that most CD3+ cells in the peripheral blood possessed the CD2 marker, suggesting that CD2 expression of T-lymphocytes is normal. T-cell activation using paired anti-T11(2) and anti-T11(3) or anti-CD3 monoclonal antibodies demonstrated similar 3H-thymidine incorporation and gamma interferon production in the PBMC of lepromatous patients in comparison with the PBMC of their contacts and tuberculoid patients. However, lepromatous PBMC did not proliferate or produce gamma interferon in response to M. leprae. Our data suggest not only that CD2 expression is normal on T lymphocytes in lepromatous leprosy skin lesions but also that CD2 expression in peripheral blood lymphocytes is functional in T-cell activation. Defective CD2 modulation does not appear to be the mechanism for specific unresponsiveness in lepromatous leprosy.

Antibodies, Monoclonal↗
PubMed1989

Transpleural gradient of 1,25-dihydroxyvitamin D in tuberculous pleuritis.

We used tuberculous pleuritis as a model to study the compartmentalization and potential immunoregulatory role of 1,25-dihydroxyvitamin D [1,25-(OH)2-D] in human granulomatous disease. In tuberculous pleuritis, mean concentrations of total 1,25-(OH)2-D were elevated in pleural fluid, compared to blood (67 pg/ml vs. 35 pg/ml). Concentrations of albumin, protein and 25-hydroxyvitamin D (25-OH-D) were lower in pleural fluid than blood, suggesting that accumulation of binding proteins does not explain the transpleural gradient of 1,25-(OH)2-D. The mean free 1,25-(OH)2-D concentration in pleural fluid was increased 5.3-fold over that in serum. 1,25-(OH)2-D3 inhibited PPD-induced proliferation of pleural fluid mononuclear cells, antigen-reactive lines and T lymphocyte clones derived from a single cell. Patient-derived PPD-reactive lines expressed a high-affinity intracellular binding moiety for 1,25-(OH)2-D3. Pleural fluid mononuclear cells and PPD-reactive lines did not metabolize 25-OH-D3 to 1,25-(OH)2-D3. The sum of these data suggests that concentration of 1,25-(OH)2-D in pleural fluid of tuberculosis patients is probably due to local hormone production by pleural tissue-based inflammatory cells that are not present in significant numbers in pleural fluid. Elevated concentrations of 1,25-(OH)2-D in pleural fluid may exert receptor-mediated inhibition of antigen-induced proliferation by pleural fluid lymphocytes. Inhibition of lymphocyte proliferation and lymphokine production may prevent tissue destruction from an uncontrolled inflammatory response.

Calcitriol↗
PubMed1989

Potentiation of the macrophage 25-hydroxyvitamin D-1-hydroxylation reaction by human tuberculous pleural effusion fluid.

1,25-Dihydroxyvitamin D [1,25-(OH)2D] is classically viewed as a steroid hormone of renal origin that regulates mammalian and avian mineral ion homeostasis. More recently, 1,25-(OH)2D has been shown to be produced by and act on human inflammatory cells in vitro, suggesting that the hormone may be an important modulator of the host immune response. We have recently detected high concentrations of 1,25-(OH)2D in the pleural fluid (PF) of patients with tuberculous pleuritis. Working on the hypothesis that tuberculous PF contained a soluble cytokine which stimulated 1,25-(OH)2D production by tissue (pleura)-based macrophages, we examined the potential for PF from five patients with tuberculous pleuritis to potentiate 1,25-(OH)2D synthesis by heterologous pulmonary alveolar macrophages (PAM) from patients with sarcoidosis; PAM from patients with active pulmonary sarcoidosis constitutively express a 25-hydroxyvitamin D3-1-hydroxylation reaction in vitro. We demonstrated that tuberculous PF had a concentration-dependent potentiating effect on PAM 1,25-(OH)2D synthesis. The potentiating activity was positively correlated to the interferon-gamma (IFN gamma) concentration of the PF (r = 0.98; P less than 0.01) and was inhibited by 49-89% after coincubation with anti-IFN gamma monoclonal antibody (1:20,000-1:200 dilution). These data suggest that IFN gamma may be an important peripleural regulator of macrophage 1,25-(OH)2D synthesis in patients with tuberculous pleuritis and a high pleural fluid 1,25-(OH)2D concentration.

Biological Factors↗
PubMed1989

Leprosy.

Explore the source record for details and available documents.

Antibodies, Bacterial↗
PubMed1988

Learning from lesions: patterns of tissue inflammation in leprosy.

The clinical forms of leprosy constitute a spectrum that correlates closely with the degree of cell-mediated 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 immunological reactions occurring in lesions of other inflammatory and autoimmune diseases.

Antibodies, Monoclonal↗
PubMed1988

Immunological significance of Mycobacterium leprae cell walls.

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 (approximately equal to 1/6000) proliferate to antigen contained in cell walls as to intact M. leprae. 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.

Amino Acids↗
PubMed1988

Predictors of short-term prognosis in patients with pulmonary tuberculosis.

We evaluated 191 consecutive adults with pulmonary tuberculosis in order to develop methods to determine which patients should be initially hospitalized. Using stepwise discriminant analysis, we found the six factors that were most strongly associated with an unfavorable short-term outcome (respiratory failure or death): lymphopenia, advanced age, concomitant smear-positive extrapulmonary tuberculosis, alcoholism, a high percentage of neutrophils on the differential white blood cell count, and lack of radiographic evidence of cavitation. We derived a scoring system incorporating these variables and separated patients into high- and low-risk groups. The system was prospectively validated by applying it to a separate group of 179 patients. Lymphocyte-transformation tests in 32 patients revealed an association between clinical markers of poor prognosis and minimal lymphocyte proliferation to a heat-killed strain of Mycobacterium tuberculosis.

Adolescent↗