In Situ Localization of T Lymphocytes in Disseminated Coccidioidomycosis

Modlin, Robert L.; Segal, Gary P.; Hofman, Florence M.; Walley, Michael S.; Johnson, Royce H.; Taylor, Clive R.; Rea, Thomas H.

doi:10.1093/infdis/151.2.314

Cited by 18 publications

(9 citation statements)

References 12 publications

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“…In particular, Modlin and colleagues' data from humans principally consisted of skin biopsies from patients with disseminated coccidioidomycosis (13). The finding of a positive ratio of CD4 ϩ to CD8 ϩ lymphocytes and the production of IFN-␥ in the mantle region of granulomata in the present study are consistent with a reaction favoring a strong cellular immune response.…”

Section: Cd25supporting

confidence: 85%

Cellular Immune Suppressor Activity Resides in Lymphocyte Cell Clusters Adjacent to Granulomata in Human Coccidioidomycosis

Li¹,

Dial²,

Schmelz

et al. 2005

Infect Immun

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The in situ immunologic response in human coccidioidomycosis remains undefined. To explore this further, pulmonary necrotizing coccidioidal granulomata were examined using immunohistochemical staining for lymphocyte subsets and for the cytokines interleukin-10 (IL-10) and gamma interferon (IFN-␥). Discrete perigranulomatous lymphocytic clusters were seen in eight of nine tissues examined. In these tissues, T lymphocytes (CD3 ؉ ) significantly outnumbered B lymphocytes (CD20 ؉ ) in the mantle area of the granulomata (P ‫؍‬ 0.028), whereas the clusters were composed of roughly equal numbers of T and B lymphocytes. While the number of cells in the mantle expressing IL-10 was similar to those in the perigranulomatous clusters, there were significantly more cells expressing IFN-␥ in the mantle than in the clusters (P ‫؍‬ 0.037). Confocal microscopy revealed that CD4؉ T lymphocytes and B lymphocytes are associated with IL-10 production. CD4؉ CD25 ؉ T lymphocytes were identified in the perigranulomatous clusters but were not associated with IL-10 production. This is the first report noting perigranulomatous lymphocyte clusters and IL-10 in association with human coccidioidal granulomata and suggests that down-regulation of the cellular immune response is occurring within coccidioidal granulomata.Coccidioidomycosis is a fungal infection of increasing importance in the southwest United States (4). In the vast majority of cases, infection is acquired by inhalation of the fungus. Two-thirds of individuals who become infected are asymptomatic, their only evidence of infection being the expression of delayed-type hypersensitivity in response to a coccidioidal skin test. A variety of studies have indicated that protective immunity in human coccidioidomycosis is associated with an appropriate cellular immune response. Smith and colleagues demonstrated that persistent expression of delayed-type hypersensitivity presaged a good outcome, while failure to develop this response was associated with disseminated disease (20). More recently, in vitro studies have shown that peripheral blood T lymphocytes from individuals with well-controlled infection produce gamma interferon (IFN-␥) in response to coccidioidal antigen, while cells from individuals with disseminated disease do not (1). Failure of T lymphocytes to react to coccidioidal antigen in vitro is associated with a poorer clinical score among those with disseminated disease (2).The hallmark of a robust T-lymphocyte response is the granuloma (10), and the formation of necrotizing granulomata as a response to pulmonary coccidioidomycosis has long been associated with a strong cellular immune response and control of coccidioidal disease (6). However, the precise immunological events associated with this response have been largely unexplored. Modlin and colleagues, in work published in 1985 (13), described a distinct pattern of cellular response in a single human pulmonary granuloma. In this pattern, CD4 ϩ lymphocytes were dispersed throughout the granuloma, while CD8 ϩ lymphocytes...

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Section: Cd25supporting

confidence: 85%

Cellular Immune Suppressor Activity Resides in Lymphocyte Cell Clusters Adjacent to Granulomata in Human Coccidioidomycosis

Li¹,

Dial²,

Schmelz

et al. 2005

Infect Immun

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“…Patients with tuberculoid leprosy, tuberculosis and pulmonary coccidioidomycosis have shown a particular pattern of T lymphocyte distribution in the granulomas. As the host response in these diseases is partly effective against the pathogen, the granulomatous pattern with T helper/inducer cells and macrophages in the center of the lesion and suppressor/cytotoxic cells at the periphery, suggests an in situ regulatory arrangement which promotes isolation and lysis of the etiologic agent [8][9][10].…”

Section: Resultsmentioning

confidence: 99%

“…Immunopathologic studies of other human granulomatous diseases have shown that the efficacy of the host response is related to the presence and distribution of T lymphocytes in the inflammation mounted to counteract the pathogen [8,10]. No similar work has been done on granulomas caused by P. brasiliensis . We have studied the number and distribution pattern of T lymphocyte subsets in granulomas observed in biopsy specimens from patients with paracoccidioidomycosis.…”

mentioning

confidence: 99%

In situlocalization of T lymphocyte subsets in human paracoccidioidomycosis

Moscardi-Bacchi¹,

Soares

Mendes³

et al. 1989

Med Mycol

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lmmunohistochemical techniques using monoclonal antibodies to T lymphocyte subsets were used to characterize granulomas caused by Paracoccidioides brasiliensis. Punch biopsies of skin or mucosa from eight patients and of lymph nodes from two patients with disseminated paracoccidioidomycosis were studied. The T lymphocytes were distributed either in a localized pattern related to epithelioid granulomas or in a diffuse arrangement, predominantly around the vessels. In the granulomas, T cells formed a peripheral mantle surrounding central aggregates of macrophages. The majority of lymphocytes were T-helper cells with few suppressor cells. In contrast, patients presented with a decreased number of peripheral Thelper lymphocytes and a corresponding decrease in helper-suppressor cell ratios. There was no clear-cut relationship between tissue helper-suppressor cell ratios and the level of cellular immunodepression of the patients. The lowest P. brasiliensis antibody titers were detected in patients with the highest tissue helper-suppressor cell ratios. The distribution pattern of T lymphocytes in P. brasiliensis granulomas, with a predominance of helper phenotype, suggests that these cells are actively involved in the disease process.Paracoccidioidomycosis is a systemic disease caused by Paracoccidioides brasiliensis and is characterized mainly by involvement of the skin, mucosa, lungs, lymph nodes and adrenal glands. The histopathologic findings consist of epithelioid granulomatous inflammation with variable numbers of lymphomononuclear and polymorphonuclear cells.It has previously been shown that T lymphocytes from patients with paracoccidioidomycosis have a decreased reactivity to P. brasiliensis antigens, unrelated common antigens and mitogens, by several tests in vivo and in vitro [13]. The cell-mediated immunosuppression has been explained by a variety of potential mechanisms including host-produced serum-factors, immune complexes and suppressor cell populations [1,12,13].

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“…Numerous studies have demonstrated that animals that lack T cells are more susceptible to infection with these fungi than are those with immunocompetent T cells Beaman et al 1979;Beck et al 1996;Gomez et al 1988;Hill and Harmsen 1991;Huffnagle et al 1991;Menacci et al 1994Menacci et al , 1996Modlin et al 1985;Mody et al 1993;Tewari et al 1978). Numerous studies have demonstrated that animals that lack T cells are more susceptible to infection with these fungi than are those with immunocompetent T cells Beaman et al 1979;Beck et al 1996;Gomez et al 1988;Hill and Harmsen 1991;Huffnagle et al 1991;Menacci et al 1994Menacci et al , 1996Modlin et al 1985;Mody et al 1993;Tewari et al 1978).…”

Section: Cellular Immunity (T-cell Mediated Immunity)mentioning

confidence: 99%