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Central giant cell granuloma is an eccentric jaw lesion that mystifies dental profession. Its pathogenicity remains a conundrum and requires differentiation from other similar lesions to develop an effective treatment plan. This case report reviews a case of central giant cell granuloma in a 52-year-old male who presented with a swelling on the right angle of mandible. The surgically curetted and reconstructed lesion resulted in the best esthetic and functional form with no recurrence during follow-up.

Key Points The tuberculous granuloma has long been considered a key host-protective immunological structure that restricts mycobacteria even under circumstances in which it fails to eradicate them. It was thought historically to be a relatively static structure and to require interactions between mycobacteria and the host adaptive immune system for its formation. Recent advances, particularly in live imaging technology, reveal that the granuloma is a highly dynamic structure, with cells moving in and out of it and throughout the structure. These cellular dynamics resemble in some ways the movement of lymphocytes in lymph nodes, and indeed granulomas can contain tertiary lymphoid structures. Bona fide granulomas can form in the sole context of innate immunity and, rather than being mycobacterium-restricting structures, early granulomas actually expand the infection by promoting the phagocytosis of apoptotic infected macrophages by multiple newly arriving macrophages. The bacterial secreted protein ESAT6 induces host production of matrix metalloproteinase 9 (MMP9) by epithelial cells surrounding the nascent granuloma to induce the chemotaxis of these new macrophages. The granuloma also disseminates infection through the egress of infected macrophages to new sites. Granuloma expansion and dissemination can occur during effective antibiotic treatment through the participation of macrophages containing drug-tolerant bacteria. The onset of adaptive immunity a few weeks after infection can thwart bacterial proliferation in the granuloma but often fails to eradicate infection. Its failure to sterilize infection is attributed to multiple complex mechanisms that result in the delayed arrival and activation of effector T cells. An understanding of the host pathways that are exploited by mycobacteria to first expand and disseminate infection in the granuloma and to then prevent adaptive immune mechanisms from eradicating infection could provide new host-targeting therapies for tuberculosis. These might be useful not only to shorten the long treatment required for drug-sensitive tuberculosis but also to provide much-needed therapies against drug-resistant tuberculosis. Finally, this understanding might suggest entirely new ways to think about tuberculosis vaccines. This Review argues against the historical view of the granuloma as a host-protective structure and provides evidence that the innate immune mechanisms of tuberculous granulomas are involved in the expansion and dissemination of infection. The granuloma, which is a compact aggregate of immune cells, is the hallmark structure of tuberculosis. It is historically regarded as a host-protective structure that 'walls off' the infecting mycobacteria. This Review discusses surprising new discoveries — from imaging studies coupled with genetic manipulations — that implicate the innate immune mechanisms of the tuberculous granuloma in the expansion and dissemination of infection. It also covers why the granuloma can fail to eradicate infection even after adaptive immunity develops. An understanding of the mechanisms and impact of tuberculous granuloma formation can guide the development of therapies to modulate granuloma formation. Such therapies might be effective for tuberculosis as well as for other granulomatous diseases.

Background Signal regulatory protein alpha (SIRPα) is an important regulator of innate and adaptive immune responses by promoting T cell and macrophage activation and macrophage adhesion (multi-nucleated giant cell formation) while preventing phagocytic cell death to sustain inflammatory responses. Methods We determined whether SIRPα is expressed in sarcoidosis tissue and whether ELA026, a humanized SIRP-blocking Ab, suppresses sarcoidosis granuloma formation by attenuating inflammation, promoting cell death, and suppressing adhesion during granuloma formation. Results Based upon immunohistochemistry, SIRPα stained in greater abundance in giant cells, monocytes, macrophages and dendritic cells in sarcoidosis lung tissue than in normal lung, lung cancer, non-granulomatous lung diseases and non-sarcoidosis granulomatous diseases. All these differences were statistically significant except for non-sarcoidosis granulomatous lung diseases. We then leveraged an ex vivo human granuloma model, wherein PBMCs from sarcoidosis patients are activated to form granulomas within 7 days, to determine whether ELA026 attenuated granuloma formation, based upon MIPAR image analysis, and associated cytokine responses. A matching isotype antibody (ELA099) that does not bind SIRPs was a negative control; prednisone was a positive control. As hypothesized, pre-treatment (day 0) or post-treatment (day 4) with ELA026 or prednisone (not ELA099) caused dose-dependent suppression of sarcoidosis granuloma formation by day 7. Unexpectedly, ELA026 only modestly reduced TNFα production when used as a pre-treatment and did not suppress IL-1β release or promote cell death, as reflected by no LDH release. Conclusions SIRPα is robustly expressed in monocyte/macrophage lineages within human sarcoidosis tissues, and inhibition of SIRPs (ELA026) suppresses sarcoidosis granuloma formation by preventing macrophage adhesion/aggregation.

Purpose A subset of patients with common variable immunodeficiency (CVID) develops granulomatous and lymphocytic interstitial lung disease (GLILD), a restrictive lung disease associated with early mortality. The optimal therapy for GLILD is unknown. This study was undertaken to see if rituximab and azathioprine (combination chemotherapy) would improve pulmonary function and/or radiographic abnormalities in patients with CVID and GLILD. Methods A retrospective chart review of patients with CVID and GLILD who were treated with combination chemotherapy was performed. Complete pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans of the chest were done prior to therapy and >6 months later. HRCT scans of the chest were blinded, randomized, and scored independently (in pairs) by two radiologists. The differences between pre- and post-treatment HRCT scores and PFT parameters were analyzed. Results Seven patients with CVID and GLILD met inclusion criteria. Post-treatment increases were noted in both FEV1 ( p  = 0.034) and FVC ( p  = 0.043). HRCT scans of the chest demonstrated improvement in total score ( p  = 0.018), pulmonary consolidations ( p  = 0.041), ground-glass opacities ( p  = 0.020) nodular opacities ( p  = 0.024), and both the presence and extent of bronchial wall thickening ( p  = 0.014, 0.026 respectively). No significant chemotherapy-related complications occurred. Conclusions Combination chemotherapy improved pulmonary function and decreased radiographic abnormalities in patients with CVID and GLILD.

AimsSchistosomiasis remains endemic in various parts of the world, and insights into pathogen immunobiology are mainly based on experimental models, while studies on human tissues are limited. Methods We explored the role of immune checkpoint pathway by evaluating the immunohistochemical expression of programmed death-ligand 1 (PD-L1) in a retrospective cohort of patients with bilharzial cystitis. Inflammation severity by conventional histology and staining intensity by immunohistochemistry were assigned three-tier scores (0/1+/2+), and a cut-off for staining percentage was set at 5%. Results 38 biopsies from 31 patients were considered adequate for evaluation, and positive staining was detected in 80.6% of patients (34 biopsies). High expressors (22.6%) showed strong positive membranous staining (score 2+) with high staining density (more than 5% of inflammatory cells). Low expressors (58.1%) showed mild/moderate staining (score 1+) predominantly in less than 5% of the cells (91.6%) or expressed restricted cytoplasmic staining (6/31). All high expressors showed severe inflammation (score 2+) (p<0.001), and viable ova were only observed in these cases. Calcified ova were associated with mild/moderate inflammation or absent/minimal inflammation, correlating with low expressors or non-expressors (19.4%), respectively. Conclusion Schistosomal granuloma exhibits upregulated PD-L1 expression proportional to inflammation severity and pathogen viability, highlighting a critical immune checkpoint engagement in disease pathology.

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

The development of granulomas with central necrosis harboring Mycobacterium tuberculosis (Mtb) is the hallmark of human tuberculosis (TB). New anti-TB therapies need to effectively penetrate the cellular and necrotic compartments of these lesions and reach sufficient concentrations to eliminate Mtb. BTZ-043 is a novel antibiotic showing good bactericidal activity in humans in a phase IIa trial. Here, we report on lesional BTZ-043 concentrations severalfold above the minimal-inhibitory-concentration and the substantial local efficacy of BTZ-043 in interleukin-13-overexpressing mice, which mimic human TB pathology of granuloma necrosis. High-resolution MALDI imaging further reveals that BTZ-043 diffuses and accumulates in the cellular compartment, and fully penetrates the necrotic center. This is the first study that visualizes an efficient penetration and accumulation of a clinical-stage TB drug in human-like centrally necrotizing granulomas and that also determines its lesional activity. Our results most likely predict a substantial bactericidal effect of BTZ-043 at these hard-to-reach sites in TB patients. Therapy of tuberculosis is challenging, mainly due to complex structures of necrotic granulomas that often impair drug delivery. In this work, the authors show that the drug BTZ-043 fully penetrates necrotic granulomas and has potent lesional antibacterial activity.

Background Invasive Cerebral Aspergillosis (ICA) is a rare fungal infection affecting the brain, primarily seen in individuals with compromised immune systems. Despite various treatment options, substantial cerebral granulomas caused by ICA still result in high mortality and recurrence rates. Case presentation We report a rare instance of ICA in a 30-year-old pregnant woman. The infection initiated in the nasal cavity and progressed to form a large intracranial granuloma, leading to brain herniation. Diagnosis was confirmed through histopathology, Polymerase Chain Reaction (PCR), and metagenomic next-generation sequencing (mNGS) following decompressive craniotomy and sinus window drainage surgery. Prompt administration of antifungal medication resulted in a favorable prognosis. Conclusion This case highlights the critical roles of mNGS and PCR in the early diagnosis of ICA, as well as the pivotal importance of surgical interventions and prompt initiation of antifungal therapy in enhancing patient outcomes.

The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecular mechanisms of granuloma genesis in patients with sarcoidosis in response to putative disease-causing mycobacterial antigens. Peripheral blood mononuclear cells (PBMCs) from patients with active sarcoidosis and from normal, disease-free control subjects were incubated for 7 days with purified protein derivative-coated polystyrene beads. Molecular responses, as reflected by differential expression of genes, extracellular cytokine patterns, and cell surface receptor expression, were analyzed. Unbiased systems biology approaches were used to identify signaling pathways engaged during granuloma formation. Model findings were compared with human lung and mediastinal lymph node gene expression profiles. Compared with identically treated PBMCs of control subjects (n = 5), purified protein derivative-treated sarcoidosis PBMCs (n = 6) were distinguished by the formation of cellular aggregates resembling granulomas. Ingenuity Pathway Analysis of differential expression gene patterns identified molecular pathways that are primarily regulated by IL-13, which promotes alternatively activated (M2) macrophage polarization. M2 polarization was further demonstrated by immunohistochemistry performed on the in vitro sarcoidosis granuloma-like structures. IL-13-regulated gene pathways were confirmed in human sarcoidosis lung and mediastinal lymph node tissues. The in vitro human sarcoidosis granuloma model provides novel insights into early granuloma formation, particularly IL-13 regulation of molecular networks that regulate M2 macrophage polarization. M2 macrophages are predisposed to aggregation and multinucleated giant cell formation, which are characteristic features of sarcoidosis granulomas. Clinical trial registered with www.clinicaltrials.gov (NCT01857401).

Using a model of tuberculosis in zebrafish, granuloma formation is shown to coincide with hypoxia and angiogenesis; furthermore, the pharmacological inhibition of the pro-angiogenic VEGF pathway reduces infection burden, suggesting a possible treatment strategy in patients with the disease. Angiogenesis in tuberculous granulomas Tuberculosis infections are often associated with the generation of masses of inflamed tissue known as tuberculous granulomas. Using intravital imaging in the zebrafish– Mycobacterium marinum infection model, this study shows that granuloma formation coincides with hypoxia and the induction of the pro-angiogenic molecule VEGF. Pharmacological inhibition of the VEGF pathway prevents vascularization of the granuloma tissue and reduces infection burden. Anti-angiogenic therapies also synergize with anti-tubercular treatments, suggesting possible alternatives to conventional therapy in the event of antibiotic resistance. Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis 1 , 2 . Here we examine the development and consequences of vascularization of the tuberculous granuloma in the zebrafish– Mycobacterium marinum infection model, which is characterized by organized granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis 2 . Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule Vegfaa. Pharmacological inhibition of the Vegf pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergize with the first-line anti-tubercular antibiotic rifampicin, as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations 3 . Our data indicate that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting tuberculosis therapy, particularly in extensively drug-resistant disease for which current antibiotic regimens are largely ineffective.