The Pathology of Lymphocytes, Histiocytes, and Immune Mechanisms in Mycobacterium tuberculosis Granulomas

Abstract

Granuloma formation is the pathologic hallmark of tuberculosis. Few studies have detailed the exact production of cytokines in human granulomatous inflammation and little is known about accessory molecule expressions in tuberculous (TB) granulomas. We aimed to identify some of the components of the immune response in granulomas in HIV-positive and -negative lymph nodes. We investigated the immunohistochemical profiles of CD4+, CD8+, CD68+, Th-17, Forkhead box (FOXP3) cells, accessory molecule expression (human leukocyte antigen [HLA] classes I and II), and selected cytokines (interleukins 2, 4, and 6 and interferon-γ) of various cells, in granulomas within lymph nodes from 10 HIV-negative (−) and 10 HIV-positive (+) cases. CD4+ lymphocyte numbers were retained in HIV− granulomas, whereas CD4+:CD8 + cell were reversed in HIV+ TB granulomas. CD68 stained all histiocytes. Granulomas from the HIV+ group demonstrated a significant increase in FOXP3 cells. Interleukin-2 cytoplasmic expression was similar in both groups. Interferon-gamma (IFN-γ) expression was moderately increased, IL-6 was statistically increased and IL-4 expression was marginally lower in cells from HIV− than HIV+ TB granulomas. Greater numbers of cells expressed IFN-γ and IL-6 than IL-2 and IL-4 in HIV− TB granulomas. This study highlights the varied cytokine production in HIV-positive and -negative TB granulomas and indicates the need to identify localized tissue factors that play a role in mounting an adequate immune response required to halt infection. Although TB mono-infection causes variation in cell marker expression and cytokines in granulomas, alterations in TB and HIV coinfection are greater, pointing toward evolution of microorganism synergism.

Pulmonary granuloma is not always the tuberculosis hallmark: pathological findings of different tuberculosis stages in New and Old World Nonhuman Primates naturally infected with the Mycobacterium tuberculosis Complex

“…Prior studies with experimental infections of Mycobacterium tuberculosis Complex (MTBC) in nonhuman primates (NHPs) have described the morphological heterogeneity of tuberculosis (Capuano et al, 2003;Lin et al, 2014;Cadena et al, 2017). In humans, pulmonary granuloma formation is considered the pathological hallmark of tuberculosis (Wadee and Wadee, 2021). In NHPs infected with MTBC, a large spectrum of lesions can be seen within and between monkeys of the same stage classi cation as well described in humans (Capuano et al, 2003;Lin et al, 2009;Flynn and Klein 2011).…”

In silico agent-based modeling approach to characterize multiple in vitro tuberculosis infection models

“…Granulomas are spatially organized structures, with a core of macrophages and a cuff including CD4+ and CD8+ T cells [74]. The center of the granuloma is a more pro-inflammatory environment, while the cuff has more anti-inflammatory cytokines [75,76].…”

In silicoagent-based modeling approach to characterize multiplein vitrotuberculosis infection models

“…(65,66) Granulomas are spatial organized structures, with a core of macrophages and a cuff including CD4+ and CD8+ T cells. (67) The center of the granuloma is a more pro-inflammatory environment, while the cuff has more anti-inflammatory cytokines. (68,69) Higher frequencies of pro-inflammatory cytokines or lymphocytes are correlated with lower bacterial burden, but it is suggested that a balance of pro-and anti-inflammation is necessary to limit both bacterial Our model similarly provides dynamic information at the cellular scale.…”