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Background:  Human immunodeficiency virus type 1 (HIV)-infected persons are more susceptible to tuberculosis than HIV-uninfected persons. Low peripheral CD4 + T-cell count is not the sole cause of higher susceptibility, because HIV-infected persons with a high peripheral CD4 + T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV-uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis-associated granulomas., Methods:  We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4 + T-cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas., Results:  HIV increased M. tuberculosis numbers and reduced CD4 + T-cell counts within granulomas. Peripheral CD4 + T-cell depletion correlated with granulomas that contained fewer CD4 + and CD8 + T cells, less interferon γ, more neutrophils, more interleukin 10 (IL-10), and increased M. tuberculosis numbers. M. tuberculosis numbers correlated positively with IL-10 and interferon α levels and fewer CD4 + and CD8 + T cells. ART reduced IL-10 production., Conclusions:  Peripheral CD4 + T-cell depletion correlated with increased M. tuberculosis presence, increased IL-10 production, and other phenotypic changes within granulomas, demonstrating the HIV infection progressively changes these granulomas., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The endoplasmic reticulum (ER) stress pathway known as the Unfolded Protein Response (UPR) is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB) with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection., Principal Findings: Here we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153), phosphorylated inositol-requiring enzyme 1 alpha (Ire1α) and eukaryotic initiation factor 2 alpha (eIF2α), and activating transcription factor 3 (ATF3) are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb). These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation., Conclusions: In summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in advanced granulomas might favor dissemination of the bacteria. Therefore future work is needed to determine if ER-stress is causative for apoptosis and plays a role in the host response to infection.

Hepatic granulomas were present in 3.7% of liver biopsies from a 6-year Greek study. The majority of cases were due to autoimmune disease (primary biliary cirrhosis), followed by sarcoidosis and idiopathic causes. Infections were infrequent. This profile is similar to series from the USA, Ireland and Scotland. It contrasts dramatically with series from Turkey and Saudi Arabia where infectious aetiologies form the majority of cases, and autoimmune cases are not reported. Tuberculosis and schistosomiasis are the most prevalent infections. The patient sex and age differ strikingly in some series. The series were tabulated for easy comparison.