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Sarcoidosis is a chronic granulomatous disorder of unknown aetiology that can affect any organ, commonly the lungs, and is characterised by the presence of non-caseating granulomas. Neurosarcoidosis can affect the nervous system in 10% of cases and ocular involvement can range from 25% - 60%. We present the case of a 37 year old female who presented with incidental severe bilateral papilledema and a left lower motor nerve seventh palsy. The rest of her examination was unremarkable. CT, CT venogram and MRI head showed no abnormality. CT TAP revealed left hilar lymphadenopathy and endoscopic bronchial ultrasound (EBUS) with histology revealed non caseation granulomas cinching the diagnosis of sarcoidosis. CSF was also supportive showing lymphocytic pleocytosis. After extensive workup she was treated as neurosarcoid with ocular involvement with high dose steroids and had complete resolution of her facial nerve palsy and improvement in her optic disc swelling bilaterally. Our case highlights sarcoidosis as an unusual but treatable cause for papilledema.justine.edwards1@nhs.net

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.

Pyogenic granuloma (PG) is a benign vascular lesion found predominantly in the oral cavity. Characterized by rapid growth and propensity to bleed, PG presents diagnostic challenges due to its similarity and alarming proliferation. This narrative review synthesizes current knowledge on the epidemiology, etiopathogenesis, clinical manifestations, and management of oral PG, with emphasis on recent advances in diagnostic and therapeutic approaches. The epidemiology of the injury is meticulously analyzed, revealing a higher incidence in women and a wide range of ages of onset. It delves into the etiopathogenesis, highlighting the uncertainty surrounding the exact causal factors, although historical attributions suggest an infectious origin. It exhaustively analyzes the clinical and histopathological aspects of oral PG, offering information on its various presentations and the importance of an accurate diagnosis to guide effective treatment. It details treatment strategies, emphasizing the personalized approach based on individual patient characteristics. This comprehensive review consolidates current knowledge on oral PG, highlighting the need for further research to clarify its pathogenesis and optimize treatment protocols.

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.

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.