Pathogenesis Of Granuloma Research Articles

Early secreted antigenic target of 6-kDa of Mycobacterium tuberculosis induces transition of macrophages into epithelioid macrophages by downregulating iNOS / NO-mediated H3K27 trimethylation in macrophages

BackgroundTuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Granuloma is a pathological feature of tuberculosis and is a tight immune cell aggregation caused by Mtb. The main constituent cells are macrophages and their derivative cells including epithelioid macrophages. However, the molecular mechanism of the transition has not been reported. The purpose of this study was to investigate whether early secreted antigenic target of 6-kDa (ESAT6) can induce the transition of bone marrow-derived macrophages (BMDMs) into epithelioid macrophages and its possible molecular mechanism. MethodsThe recombinant ESAT6 protein was obtained from E.coli carrying esat6 gene after isopropyl β-d-thiogalactopyranoside (IPTG) induction. BMDMs were isolated from bone marrow of mice hind legs. Cells viability was detected by Cell Counting Kit 8 (CCK8) assays. The expression levels of mRNA and proteins were detected by qPCR and Western blot, or evaluated by flow cytometry. The expression level of nitric oxide (NO) was measured with a nitric oxide indicator. ResultsESAT6 could significantly induce mRNA and protein expression levels of a group of epithelioid macrophages marker molecules (EMMMs), including E-cadherin, junction plakoglobin, ZO1, desmoplakin, desmoglein3 and catenin porteins, in BMDMs. These events could be abrogated in macrophage from TLR2 deficiency mice. ESAT6 could also markedly induce iNOS/NO production that could significantly inhibit trimethylation of H3K27 in the cells. ESAT6-induced expressions of epithelioid macrophages marker molecules were significantly inhibited in the presence of H3K27 histone demethylase inhibitor GSK J1. Furthermore, ROS scavenging agent N,N'-Dimethylthiourea (DMTU) could markedly inhibit the transition induced by ESAT6 in macrophages. ConclusionThis study demonstrates that ESAT6 bound with TLR2 can activate iNOS/NO and ROS signalings to reduce the trimethylation of H3K27 resulting in the increment of EMMMs expression that is beneficial to the transition of macrophages into epithelioid macrophages. However, hypoxia can inhibit this transition event. This study has provided new evidence of pathogenesis of granuloma caused by Mtb and also proposed new ideas for the treatment of TB.

What is new in the histogenesis of granulomatous skin diseases?

A granuloma is a form of inflammation, which predominantly consists of macrophages. It typically develops when the immune system attempts to enclose substances that are usually insoluble and cannot be eliminated to prevent the spread of these substances to the other body compartments. According to the source of the substances, granulomatous diseases can be divided into two groups: infectious and non-infectious. The mechanisms of infectious granuloma formation have been widely investigated because of its easy reproducibility in experimental models, both invivo and invitro. On the contrary, mechanisms of non-infectious granuloma formation have not been well investigated because of the difficulty to reproduce this formation in experimental models. In this article, we review our recent understanding of the histogenesis and pathogenesis of granuloma formation, confirmed from studies of infectious granulomas, and we present potential hypotheses of the histogenesis and pathogenesis of non-infectious granulomas based on clinical investigations.

Features of Granulematous Inflammation in Crohn’s Disease

The Crohn’s disease is a multisystem chronic idiopathic disease from inflammatory bowel disease group, which is characterized by the development of immune granulomatous inflammation with the formation of non-necrotizing epithelioid cell sarcoid granulomas as in the wall of the intestine, and extra-intestinal. Granulomas are found, on average, in half of patients with Crohn’s disease, and is twice more often at children, and also in operational material, in comparison with biopsy. Communication of development of granulomas with the autophagy-related genes is revealed and possibility of existence of two phenotypes or genotypes of a disease, depending on existence of a granulematous inflammation though it is impossible to exclude that in some cases granulomas remained not found. Further researches will allow to specify the frequency of development and pathogenesis of granulomas, and also their clinical and predictive value.

The immunopathology of liver granulomas in primary biliary cirrhosis

Liver granulomas and elevated serum IgM are commonly observed in patients with primary biliary cirrhosis (PBC) but their pathogenetic significance remains largely unknown. To address this issue we performed an extensive immunostaining and colocalization study of markers associated with dendritic cells and IgM in a large cohort of tissue samples from PBC and control livers as well as from non-hepatic granulomatous diseases. First, the classical dendritic cell CD11c marker is highly expressed and more sensitive than classical hematoxylin-eosin staining in detecting granulomas associated with PBC and other conditions. Second, PBC cases with CD11c-positive granulomas have significantly higher serum IgM levels and earlier disease stages. Third, granulomas from PBC and other diseases demonstrate markers of dendritic cell immaturity, i.e. CD11b, reduced MHC II, IL-23, CCR7 and CD83 expression, and elevated C1q expression. Lastly, B cells and IgM-positive plasma cells are largely represented around PBC granulomas along with macrophages. In conclusion, our comprehensive immunohistochemical study suggests that dendritic cells are key to the pathogenesis of granulomas, regardless of their origin. More specifically, PBC liver granulomas may result from the interaction between immature dendritic cells and IgM.

Health Effects of Nanoparticles and Nanomaterials (III) Toxicity and Health Effects of Nanoparticles

As described before in the first Frontier Report of this series, there are two types of nanoparticles to be considered in hygiene science; One is the environmental nanoparticle emitted from automobiles and the other is the manufactured nanoparticle. In general nanoparticles (less than 100 nm) are reported to be permeable through cell membrane and tissues and their large surface area is responsible for the greater toxicity compared to larger particles. However, there are contradictory reports on the health effects of nanoparticles. Recent reports suggest that carbon nanotubes, fiber-shaped biopersistent nanoparticles, resemble asbestos in the pathogenesis of granuloma and mesothelioma. As such we summarize health effects of environmental and manufactured nanoparticles in the literature so far including our studies, in this report.

Molecular identification of bacterial 16S ribosomal RNA gene in liver tissue of primary biliary cirrhosis: is Propionibacterium acnes involved in granuloma formation?

The etiopathogenesis of primary biliary cirrhosis (PBC) remains speculative. Epithelioid granulomas are often found in the vicinity of damaged interlobular bile ducts in PBC, raising the possibility of a reaction to microbial materials. In this study, we tried to detect and identify bacterial DNA within granulomatous lesions in PBC. Using liver sections from 9 patients with PBC and 13 control livers, granuloma in portal tracts, portal tracts without granuloma, and adjacent hepatic parenchyma were selectively microdissected from sections, and then DNA was extracted from them. First, part of the bacterial 16S ribosomal RNA (rRNA) gene was amplified from DNA samples extracted from 5 PBC and 6 control livers, and their amplicons were sequenced for the identification of bacterial species. Several indigenous bacteria were identified. Among them, Propionibacterium acnes (P. acnes) was detected as a major clone in 20% to 50% of sequenced clones from granuloma of PBC, but the detection rate of P. acnes was 0% to 20% in those cloned from adjacent hepatic parenchyma of PBC. Then, a P. acnes-specific PCR was performed using all microdissected samples. Distinct PCR products were identified in epithelioid granuloma in all 9 PBC cases. The result that P. acnes DNA is present as a major clone in granulomas of PBC, suggest that P. acnes is involved in the pathogenesis of granuloma in PBC.

Quantitive analysis of the immunocompetent cells in periapical granuloma: Correlation with the histological characteristics of the lesions

Granuloma formation includes an immune response in oral tissues to various microorganisms and their products. The immunocompetent cells of both series (T and B) are present in the periapical lesions. In order to further analyze the relative contribution and pathophysiological significance of the T cell subsets in granuloma formation, we undertook the quantitative analysis of the CD3-positive, CD4-positive, CD8-positive and Ig-positive cells in these lesions by using indirect immunofluorescence. Evidence is provided showing predominance of T cells in diffuse and B cells in focal mononuclear infiltrates. CD8-positive cells were more frequent in diffuse infiltrates and in particular in granulomas with distinct epithelium while CD4-positive cells were more numerous in focal infiltrates. It appears that the presence and ratios of different subsets of immunocompetent cells reflects the pathogenesis of granuloma and transformation to cyst.

Granuloma fissuratum of the ears lasting 20 years.

Chronic infection and dermal sensitivity to metals are important factors in the pathogenesis of granuloma físsuratum. The primary event is probably the fissure which may be due to the spectacle frames or to post-auricular seborrhoeic dermatitis.