Granulomatous Response Research Articles

SIVmac239 infection dysregulates anti-mycobacterial immunity at the granuloma level and contributes to severe tuberculosis in cynomolgus macaques

Abstract Tuberculosis (TB) is a global pandemic caused by Mycobacterium tuberculosis (Mtb) infection that is characterized by formation of lung lesions called granulomas. TB has a synergistic relationship with HIV and TB often occurs in HIV-infected individuals with near normal CD4+ T cell counts. Despite the importance of this co-infection to public health, interactions between HIV and lesion-level immunity remain poorly understood. To address this issue, we used SIVmac239-infected or SIV-negative Mauritian cynomolgus macaques with active TB to identify which cell types are infected in granulomas and how SIV modulates local immunity. Using RNAscope and immunohistochemistry, we found that CD11c+ macrophages were the most-commonly infected cell type in granulomas. To identify how viral infection changes the immune landscape in granulomas, we performed a transcriptional analysis on RNA isolated from lung granulomas. We found that SIV infection downregulated large numbers of macrophage-activating cytokines and receptors, toll-like receptors, and T cell activation markers. In contrast, anti-viral responses including type 1 interferons and receptors expressed by NK cells were upregulated. IL-10 was among the genes that were not differentially regulated. Pathway analysis indicated that many pathways were downregulated, including pathways associated with Th1-, Th2-, and NFkB-mediated responses. These data suggest that SIV infection deactivates protective responses in granulomas but activates antiviral responses that are counterproductive in TB while leaving detrimental IL-10 expression intact. We hypothesize that this disequilibrium leads to an inability to kill bacteria and restrict dissemination that exacerbates TB.

Mice infected with the hypervirulent Mycobacterium tuberculosis HN878 strain develop lung lesions resembling human tubercle granulomas

Abstract The aerosol infection of mice with lab-adapted Mycobacterium tuberculosis (Mtb) strains in not an ideal model to study the immune parameters crucial for structural organization of protective human tuberculosis (TB) granulomas. Since experimentation in larger animals that mimic human lung granulomatous responses is expensive, a cost-effective animal model recapitulating morphological aspects of human granulomas is needed. Here, we addressed whether the use of hypervirulent Mtb strains could be a better strategy to improve the mouse model of TB. Hence, we infected C57BL/6 mice with a low dose of aerosolized Mtb HN878 and histologically analyzed infected lung tissues at different time points after infection. We found that granulomas that developed early after Mtb HN878 infection resemble human and NHPs granulomas, except for the lack of multinucleated giant cells. These structures displayed a central core of macrophages surrounded by a lymphocyte cuff. Immunofluorescence analysis showed that the presence of Mtb within mouse human-like granulomas was restricted to the central core area where some macrophages also expressed iNOS. Furthermore, increased formation of B cell lymphoid follicles expressing CXCL13 and germinal center markers was observed at the peripheral lymphocyte cuffs of human-like granulomas. As B cell follicles are indicators of protective immunity in humans, we addressed whether their formation was crucial for Mtb control. In Ighm−/− B cell deficient mice, we found an increased susceptibility to Mtb HN878 infection and enhanced lung inflammation at 50 days post-infection as compared to wild-type mice. Thus, our data supports the use of Mtb HN878 infection to model human TB granuloma formation in mice.

Defective Granuloma Formation in Elderly Infected Patients.

Granulomas are compact structures formed in tissues by the immune system in response to aggressions. The in vitro formation of granulomas using circulating mononuclear cells is an innovative method to easily assess the immune response of patients. Monitoring the efficiency of mononuclear cells from patients to form granulomas in vitro would help improve their therapeutic management. Circulating mononuclear cells from 23 elderly patients with sepsis and 24 elderly controls patients were incubated with Sepharose beads coated with either BCG or Coxiella burnetii extracts. The formation of granulomas was measured over 9 days. Most healthy elderly patients (92%) were able to form granulomas in response to BCG and Coxiella burnetii extracts compared to only 48% of infected elderly patients. Undernutrition was significantly associated with impaired granuloma formation in healthy and infected patients. Granulomas typically comprise epithelioid cells and multinucleated giant cells, however, these cells were not detected in samples obtained from patients unable to form granulomas. We also found that the impairment of granuloma formation was associated with reduced production of tumor necrosis factor without overproduction of interleukin-10. Finally, all genes specifically modulated in granulomatous cells were down-modulated in patients with defective granuloma formation. TNFSF10 was the only M1 gene markedly upregulated in patients who did not form granulomas. Our study suggest that defective granuloma formation may be a measurement of altered activation of immune cells which can predispose to nosocomial infections in elderly patients.

Difficultés diagnostiques de la bérylliose pulmonaire chronique en France

The epidemiology of chronic beryllium disease (CBD) in France is poorly understood. The aim of this study was to determine the number of prevalent cases of CBD in France between 2010 and 2014. We conducted a national survey using a specific questionnaire distributed by the professional pathology services. In total, 33 CBD cases were reported in France, with a diagnosis established between 1982 and 2014. 85% (28/33) of CBD cases resulted from professional exposure and mostly concerned foundry workers (39%). A definite diagnosis defined by the association of an abnormal beryllium lymphocyte proliferation test and of a granulomatous inflammatory response in the lung, was obtained in 29/33 cases (88%). The other cases were probable CBD, defined by a granulomatous lung disease with a beryllium exposure, but without evidence of beryllium sensitisation. The diagnosis of granulomatous disease was confirmed a mean of 4 years after the end of exposure. The median delay between diagnosis of a granulomatous disease and diagnosis of CBD was 2 years (range 0-38 years). A genetic predisposition was found in 14 of 17 tested patients (82%). In this study, we report 33 cases of CBD followed in France between 2010 and 2014. The poor understanding of CBD and the exposure leading to it, the late development after the end of exposure, the complexity of the diagnosis and the similarities with sarcoidosis may explain the small number of cases reported.

Investigation into the Pathology of Idiopathic Systemic Amyloidosis in Four Captive Badgers (Meles meles)

Systemic idiopathic amyloidosis was described in four captive badgers (Meles meles). Two animals (B1 and B2) were not enrolled in any trial, while animals B3 and B4 took part in a vaccine efficacy study and had been challenged with Mycobacterium bovis. A full set of tissues was collected and processed routinely for histopathological, immunohistochemical and ultrastructural studies. Splenomegaly was found in three out of four animals. Histopathological evaluation revealed congophilic, permanganate-resistant systemic amyloid deposits in the tissues of all badgers. Animals B2 and B4 displayed a marked granulomatous response to amyloid within the spleen. Animals B1 and B2 also displayed clinicopathological findings suggestive of chronic kidney disease. Ultrastructural examination identified peculiar star-shaped arrays of amyloid. Immunohistochemical studies were unrewarding. Systemic amyloidosis should be considered among the differentials of wasting in captive badgers.

Galectins, Eosinophiles, and Macrophages May Contribute to Schistosoma japonicum Egg-Induced Immunopathology in a Mouse Model.

Schistosomiasis is a severe public health problem, which can cause tissue fibrosis and can even be fatal. Previous studies have proven that galectins and different kinds of cells involve in the regulation of tissue fibrosis process. In this study, outbred Kunming mice were infected with Schistosoma japonicum (S. japonicum). Our results showed that compared with uninfected mice, there were severe egg granulomatous inflammation and tissue fibrosis in the livers, spleens, and large intestines of S. japonicum-infected mice at 8 weeks post-infection (p.i.), and the number of eosinophils by hematoxylin and eosin staining and CD68 macrophage-positive area by immunohistochemical staining were significantly increased. Detected by using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), at 8 weeks after S. japonicum infection, the mRNA expression levels of galectin (Gal)-1, Gal-3, CD69, eosinophil protein X (EPX), and chitinase 3-like protein 3 (Ym1) were significantly increased in liver, spleen, and large intestine; eotaxin-1 (CCL11) and eosinophil cationic protein were significantly increased in both liver and spleen; eotaxin-2 (CCL24) and Arginase1 (Arg1) were significantly increased in both spleen and large intestine; and CD200R was significantly increased in both liver and large intestine. However, interleukin (IL)-1ß and inducible nitric oxide synthase (iNOS) were only significantly increased in liver. The M2/M1 ratio of CD200R/CD86 genes was significantly increased in liver, and ratios of Ym1/IL-1β and Ym1/iNOS were significantly increased in liver, spleen, and large intestine of S. japonicum-infected mice. Ex vivo study further confirmed that the levels of Gal-1, Gal-3, CD200R, Arg1, and Ym1 were significantly increased, and the ratios of CD200R/CD86 and Ym1/IL-1β were significantly increased in peritoneal macrophages isolated from S. japonicum-infected mice at 8 weeks p.i. In addition, correlation analysis showed that significant positive correlations existed between mRNA levels of Gal-1/Gal-3 and EPX in liver, between Gal-3 and Ym1 in both liver and large intestine, and between Gal-3 and CD200R in peritoneal macrophages of S. japonicum-infected mice. Our data suggested that Gal-1, Gal-3, eosinophils, and macrophages are likely involved in the development of egg granulomatous response and fibrosis induced by S. japonicum infection.

T Lymphocyte-Mediated Liver Immunopathology of Schistosomiasis.

The parasitic worms, Schistosoma mansoni and Schistosoma japonicum, reside in the mesenteric veins, where they release eggs that induce a dramatic granulomatous response in the liver and intestines. Subsequently, infection may further develop into significant fibrosis and portal hypertension. Over the past several years, uncovering the mechanism of immunopathology in schistosomiasis has become a major research objective. It is known that T lymphocytes, especially CD4+ T cells, are essential for immune responses against Schistosoma species. However, obtaining a clear understanding of how T lymphocytes regulate the pathological process is proving to be a daunting challenge. To date, CD4+ T cell subsets have been classified into several distinct T helper (Th) phenotypes including Th1, Th2, Th17, T follicular helper cells (Tfh), Th9, and regulatory T cells (Tregs). In the case of schistosomiasis, the granulomatous inflammation and the chronic liver pathology are critically regulated by the Th1/Th2 responses. Animal studies suggest that there is a moderate Th1 response to parasite antigens during the acute stage, but then, egg-derived antigens induce a sustained and dominant Th2 response that mediates granuloma formation and liver fibrosis. In addition, the newly discovered Th17 cells also play a critical role in the hepatic immunopathology of schistosomiasis. Within the liver, Tregs are recruited to hepatic granulomas and exert an immunosuppressive role to limit the granulomatous inflammation and fibrosis. Moreover, recent studies have shown that Tfh and Th9 cells might also promote liver granulomas and fibrogenesis in the murine schistosomiasis. Thus, during infection, T-cell subsets undergo complicated cross-talk with antigen presenting cells that then defines their various roles in the local microenvironment for regulating the pathological progression of schistosomiasis. This current review summarizes a vast body of literature to elucidate the contribution of T lymphocytes and their associated cytokines in the immunopathology of schistosomiasis.

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response.

Cording was the first virulence factor identified in Mycobacterium tuberculosis (Mtb). We aimed to ascertain its role in the induction of active tuberculosis (TB) in the mouse strain C3HeB/FeJ by testing the immunopathogenic capacity of the H37Rv strain. We have obtained two batches of the same strain by stopping their growth in Proskauer Beck liquid medium once the mid-log phase was reached, in the noncording Mtb (NCMtb) batch, and two days later in the cording Mtb (CMtb) batch, when cording could be detected by microscopic analysis. Mice were challenged with each batch intravenously and followed-up for 24 days. CMtb caused a significant increase in the bacillary load at an early stage post-challenge (day 17), when a granulomatous response started, generating exudative lesions characterized by neutrophilic infiltration, which promoted extracellular bacillary growth together with cording formation, as shown for the first time in vivo. In contrast, NCMtb experienced slight or no bacillary growth and lesions could barely be detected. Previous Bacillus Calmette-Guérin (BCG) vaccination or low dose aerosol (LDA) Mtb infection were able to delay the progression towards active TB after CMtb challenge. While BCG vaccination also reduced bacillary load when NCMtb was challenged, LDA did not, and its proliferative lesions experienced neutrophil infiltration. Analysis of lung cytokine and chemokine profiles points to their capacity to block the production of CXCL-1 and further amplification of IL-1β, IL-17 and neutrophilic extracellular trap formation, all of which are essential for TB progression. These data highlight the key role of cording formation in the induction of active TB.

Sevelamer-associated gastric erosions in a hemodialysis patient: A case report and brief literature review

Introduction: The use of sevelamer as a phosphate binder in chronic kidney disease patients with hyperphosphatemia is typically associated with mild gastrointestinal adverse events. However, recent reports indicate that its effect may be considerably more damaging. Case Report: We describe the incidental finding of sevelamer crystals in the gastric mucosa of a 55-year-old female patient on maintenance hemodialysis. The patient was subjected to gastroscopy as part of anemia investigation which revealed mild gastritis and presence of linear mucosal erosions at the pyloric antrum. Pathology reported extended granulomatous foreign body response in the gastric mucosa. Giant cell histiocytes were identified containing crystalline material with irregularly shaped fish scales. Pathology findings were consistent with lesions described in recent literature as induced by sevelamer crystals. Sevelamer administration was immediately stopped and a follow-up gastroscopy after 12 months showed improvement of the lesions. Conclusion: A thorough literature review reveals that sevelamer-associated mucosal injury has been identified as the underlying cause of several acute gastrointestinal events as well as chronic persistent symptomatology. Currently, its prevalence in hemodialysis patients is largely unknown due to lack of routine endoscopic assessment, however it may be significantly higher than expected. Therefore, timely diagnosis and appropriate management of sevelamer-associated injury require a high index of clinical suspicion, especially for patients with a history of long-term sevelamer use.

A SYNCHRONOUS PARACOCCIDIOIDOMYCOSIS AND SQUAMOUS CELL CARCINOMA: A CASE REPORT

A 51-year-old white man presented with a 3-month history of oral pain. He was edentulous and his intraoral examination revealed a mulberrylike granulomatous lesion on the right superior alveolar ridge and 2 adjacent ulcerations on the right upper lip. Biopsies of the oral lesions were performed revealing a granulomatous inflammatory response positive for Paraccocidioides brasiliensis. Systemic investigation showed pulmonary involvement. He was treated with itraconazole. A synchronous actinic cheilitis was detected. After 12 months of follow-up, a persistent white, rough, scaly area developed on the left vermilion lower lip and an incisional biopsy was performed. Histopathologic analysis demonstrated solar elastosis and superficially invasive squamous cell carcinoma. The patient was referred to a head and neck surgeon and vermilionectomy was the treatment employed. No recurrence was observed after a 7-month follow-up. This case report emphasizes the importance of global clinical evaluation and patient follow-up aiming at early oral lesion diagnosis.

High content analysis of granuloma histology and neutrophilic inflammation in adult zebrafish infected with Mycobacterium marinum

Infection of zebrafish with natural pathogen Mycobacterium marinum is a useful surrogate for studying the human granulomatous inflammatory response to infection by Mycobacterium tuberculosis. The adaptive immune system of the adult stage zebrafish offers an advance on the commonly used embryo infection model as adult zebrafish form granulomas with striking similarities to human-M. tuberculosis granulomas. Here, we present workflows to perform high content analyses of granulomas in adult zebrafish infected with M. marinum by cryosectioning to take advantage of strong endogenous transgenic fluorescence adapted from common zebrafish embryo infection tools. Specific guides to classifying granuloma necrosis and organisation, quantifying bacterial burden and leukocyte infiltration of granulomas, visualizing foam cell formation, analysing extracellular matrix remodelling and granuloma fibrosis are also provided. We use these methods to characterize neutrophil recruitment to M. marinum granulomas across time and find an inverse relation to granuloma necrosis suggesting granuloma necrosis is not a marker of immunopathology in the natural infection system of the adult zebrafish-M. marinum pairing. The methods can be easily translated to studying the zebrafish adaptive immune response to other chronic and granuloma-forming pathogens.

Modelling Bovine Granuloma Formation In Vitro upon Infection with Mycobacterium Avium Subspecies Paratuberculosis.

Mycobacterium avium subspecies paratuberculosis (Map) causes chronic granulomatous disease in cattle and ruminant livestock, causing substantial economic losses. Current vaccines delay clinical signs but cannot train the immune system to fully eradicate latent Map. During latency, Map uses host defenses, cage-like macrophage clusters called granuloma, as incubators for months or years. We used an in vitro model to investigate the early coordination of macrophages into granuloma upon Map infection over ten days. We found that at multiplicities of infection (MOI; Map:macrophages) of 1:2 and below, the macrophages readily form clusters and evolve pro-inflammatory cytokines in keeping with a cell-mediated immune response. At higher MOIs, viability of host macrophages is negatively impacted. At 1:4 MOI, we quantified viable Map in our model and confirmed that intracellular Map reproduced over the first five days of infection. Host cells expressed Type 1-specific cytokines, and Map-infected macrophages displayed reduced motility compared to Map-exposed, uninfected macrophages, suggesting an important role for uninfected macrophages in the early aggregative response. Reported is the first in vitro JD granuloma model capturing Map and macrophage viability, size distribution of resulting clusters, motility of monocyte-derived macrophages, and cytokine response during clustering, allowing quantitative analysis of multiple parameters of the Map-specific granulomatous response.

A CASE OF STIMULANT DESIGNER DRUG-INDUCED SARCOIDOSIS

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Sarcoidosis, a well-recognized cause of systemic granulomatous disease, has both infectious and non-infectious etiologies. Current literature suggests industrial dust exposure can lead to granulomatous disease, particularly involving the lung. However, there is currently no report of systemic granulomatous disease caused by stimulant designer drugs, such as 4-methylcathinone (4-MEC), which have become a growing public health concern in recent years. We present a patient diagnosed with granulomatous liver disease resembling sarcoid, following exposure to 4-MEC. CASE PRESENTATION: A 30-year-old man of Peruvian descent with a history of intravenous 4-MEC use, presented with 5 months of sweats and 25-pound weight loss. He denied recent travel or occupational exposures. Physical exam revealed massive hepatosplenomegaly. Initial workup was significant for elevated liver-specific alkaline phosphatase. Imaging showed diffuse abdominal lymphadenopathy. Extensive workup was negative for infections, hematologic malignancies and autoimmune diseases. Liver biopsy revealed non-caseating granulomas and refractile material. The diagnosis of a sarcoid-like reaction to particulate matter from 4-MEC injection was made. DISCUSSION: The etiology of sarcoidosis is unclear, making it a diagnosis of exclusion. It is therefore important to have a broad differential diagnosis, ruling out the presence of infectious agents such as mycobacteria, fungi and parasites, environmental and occupational exposures such as beryllium, organic antigens, autoimmune diseases and various medications, all of which can cause a granulomatous response. Our patient’s only significant exposure was to 4-MEC, a synthetic derivative of the pharmacologically active alkaloid, cathinone, which is a stimulant similar to 3,4-Methylenedioxymethamphetamine (MDMA). In sarcoidosis, elevated alkaline phosphatase is a more common laboratory abnormality than elevated transaminases. This combined with the absence of liver lesions should prompt a workup for a systemic disease process. Non-caseating granulomas are the hallmark histologic feature of sarcoidosis. Possible pathophysiologic explanations for sarcoid-like reactions include: the formation of non-caseating granulomas with secretion of lysozyme, collagenase and angiotensin-converting enzyme (ACE) in response to foreign particles of 4-MEC; or rapid influx of neutrophils around the foreign body resulting in macrophage activation, similar to talc granulomatosis. CONCLUSIONS: The etiology of sarcoidosis remains an enigma. Our case highlights the disease pathophysiology, emphasizes the importance of maintaining a broad differential diagnosis, and encourages consideration of other factors such as stimulant designer drugs in the etiology of non-caseating granulomatous disease. Reference #1: Dubaniewicz A. [The diagnostic algorithm of practice in pulmonary and extrapulmonary sarcoidosis]. Pol Merkur Lekarski. 2018 Mar 27;44(261):101-109. Review. Polish. PubMed PMID: 29601557. Reference #2: Pereiro T, Golpe A, Lourido T, Valdés L. Extrapulmonary Tumors and Sarcoidosis. An Incidental or Real association? Arch Bronconeumol. 2018 Oct;54(10):531-533. https://doi.org/10.1016/j.arbres.2018.01.036. Epub 2018 Mar 6. English, Spanish. PubMed PMID: 29523377. Reference #3: Chopra A, Nautiyal A, Kalkanis A, Judson MA. Drug-Induced Sarcoidosis-Like Reactions. Chest. 2018 Sep;154(3):664-677. https://doi.org/10.1016/j.chest.2018.03.056. Epub 2018 Apr 24. Review. PubMed PMID: 29698718 DISCLOSURES: No relevant relationships by Thomas Botta, source=Web Response No relevant relationships by Ishwar Giri, source=Web Response No relevant relationships by Viren Kaul, source=Web Response No relevant relationships by Jishu Motta, source=Web Response No relevant relationships by Rahila Ogunnaike, source=Web Response No relevant relationships by Lauren Pischel, source=Web Response No relevant relationships by Rutvik Shah, source=Web Response No relevant relationships by Sophia Shimer, source=Web Response

1823 Esophagitis in Immunocompromised Patient From Strongyloides Reactivation

INTRODUCTION: Strongyloides Stercoralis infection affects as many as 30 million people in 70 countries worldwide. It also can undergo cycles of autoinfection leading to chronic disease. This infection is usually asymptomatic and may remain undetected for decades. However, in patients who are immunocompromised, such as patient’s undergoing chemotherapy, receiving long-term corticosteroids, transplant patient, or patient with HIV; severe infection can occur and result in mortality rates as high as 87%. Strongyloidiasis is difficult to diagnose as the parasite load is low and the larval output is irregular. CASE DESCRIPTION/METHODS: 79-year-old Chinese migrant man with metastatic lung adenocarcinoma who was recently started on Erlotinib, presented with nausea, vomiting, diarrhea, generalized weakness, and epigastric pain. He had White Blood Cell count of 7.6 with 6.6% Eosinophils. X-ray and Computed Tomography imaging did not show any changes from prior studies. Esophagogastroduodenoscopy was performed afterwards which showed esophagitis, gastritis, duodenal ulcer and duodenitis. Subsequently, biopsies of the duodenal and esophageal mucosa revealed parasitic larvae consistent with Strongyloides Stercoralis (Figure 1). The patient was started on Ivermectin and had resolution of his symptoms on follow up. Erlotinib was resumed after discharge. DISCUSSION: Although differential diagnosis for esophagitis in immunocompromised patients is broad, our patient was interestingly diagnosed with Strongyloides induced esophagitis via biopsy. The larvae of Strongyloides have potential ability to invade and survive for extended periods in human tissue. They have obligatory tissue phase in which the larvae follows from the portal of entry and eventually to trachea and lung. Depressed cell-mediated immunity secondary to malignant tumor, combined with protein-calorie malnutrition, led to lack of granulomatous immune response to larvae in our patient. Several immunodiagnostic assays have been found ineffective in detecting disseminated infection. Although it is important to detect latent S. Stercoralis infections before administering chemotherapy or before the onset of immunosuppression in patients at risk, a specific and sensitive diagnostic test is lacking. When acute esophagitis does present, it may be severe and disabling, and could result in hospitalization, placement of a feeding tube in the stomach or parenteral nutrition, and steady supportive care. Biopsy, cytology, and culture are recommended for suspected cases.

Recombinant Sj16 protein with novel activity alleviates hepatic granulomatous inflammation and fibrosis induced by Schistosoma japonicum associated with M2 macrophages in a mouse model

BackgroundPotent granulomatous inflammation responses induced by schistosome eggs and resultant fibrosis are the primary causes of morbidity in schistosomiasis. Recombinant Sj16 (rSj16), a 16-kDa protein of Schistosoma japonicum produced in Escherichia coli, has been demonstrated to have novel immunoregulatory effects in vivo and in vitro. Thus, this study investigated the anti-inflammatory and anti-fibrotic effects of rSj16 treatment in S. japonicum-infected mice and demonstrated the immune modulation between the schistosome and the host.MethodsSchistosoma japonicum infected mice were treated with the rSj16 protein and Sj16 peptide at different time points post-infection to assess their efficacy at the optimal time point. Sj16 peptide and/or Praziquantel (PZQ) treatments were initiated at week 5 post-infection to compare the therapeutic efficacy of each regimen. Hepatic granulomatous inflammation, fibrosis and cytokine production (pro-inflammatory, Th1, Th2, Th17 and regulatory cytokines IL-10) were detected. Moreover, M2 macrophages were measured to illuminate the mechanisms of Sj16.ResultsThe rSj16 protein and Sj16 peptide had significant protective effects in S. japonicum-infected mice, as shown by decreased granuloma formation, areas of collagen deposition and inhibition of pro-inflammatory Th1, Th2 and Th17 cytokine production. These protective activities were more obvious when animals were treated with either the Sj16 protein or peptide at early stages post-infection. Interestingly, the combined treatment of PZQ and Sj16 was more effective and upregulated IL-10 production than administration of PZQ alone in infected mice. Furthermore, the Sj16 treatment alleviated the pathological effects associated with activated M2 macrophages.ConclusionsThis study demonstrates the anti-inflammatory and anti-fibrotic effects of rSj16 in schistosomiasis. Therefore, the combination of rSj16 with PZQ could be a viable and promising therapeutic strategy for schistosomiasis. In addition, this investigation provides additional information on schistosome-mediated immune modulation and host-parasite interactions.

Schistosoma japonicum Infection Promotes the Response of Tfh Cells Through Down-Regulation of Caspase-3-Mediating Apoptosis.

CD4+ T follicular helper (Tfh) cells, a new subset of immune cells, have been demonstrated to be involved in granulomatous responses to Schistosoma japonicum (S. japonicum) infection. However, the role and underlying mechanisms of Tfh cell aggregation in S. japonicum infection remain incompletely understood. In this study, we provide evidence that S. japonicum infection enhances the accumulation of Tfh cells in the spleen, lymph nodes, and peripheral blood of C57BL/6 mice. Infection-induced Tfh cells exhibited more potent effects directly on B cell responses than the control Tfh cells (P < 0.05). Furthermore, reduced apoptosis of Tfh cells was found both in S. japonicum infected mice and in soluble egg antigen (SEA) treated Tfh cells (P < 0.05). Mechanistic studies reveal that caspase-3 is the primary drivers of down-regulated apoptotic Tfh cell death in S. japonicum infection. In summary, this study demonstrates that Tfh cell accumulation might have an impact on the generation of immune responses in S. japonicum infection, and caspase-3 signaling mediated apoptosis down-regulation might responsible for the accumulation of Tfh cell in this course.

Inhaled Furan Selectively Damages Club Cells in Lungs of A/J Mice.

Furan, a possible human carcinogen, is a product of incomplete combustion and is present in cigarette smoke, engine exhaust, and processed food. Oral administration induces liver toxicity and carcinogenesis in F344 rats and B6C3F1 mice. To assess possible adverse effects from inhalation, A/J mice were nose-only exposed for 3 hours to furan (0, 30, 75, 150, 300, or 600 ppmv) and euthanized after 24 hours, 48 hours, or 1 week. Histopathology evaluation revealed bronchiolar club cell necrosis (diffuse, marked) with airway denudation following exposure to 300 and 600 ppmv furan with evidence of club cell regeneration and partial repair after 1 week. Initial signs of hepatotoxicity were observed in the 150 ppmv furan-exposed group. Acute necrosis and mineralization were observed in livers at 24 and 48 hours with hepatocyte regeneration by 1-week postexposure in mice exposed to 300 and 600 ppmv furan; the 300 ppmv exposed group had multifocal mineralization that evoked a mild granulomatous response. Measurement of urinary furan metabolites confirmed that the mice metabolized furan to the toxic intermediate, cis-2-butene-1,4-dial. These observations indicate that inhaled furan is toxic to lungs with club cells as the target as well as liver.

Man of Steel Syndrome: Silicone and Mineral Oil Injections With Associated Hypercalcemia, Hypophosphatemia, and Proximal Muscle Weakness.

ABSTRACTSilicone/mineral oil‐induced granulomas have been described as an inflammatory granulomatous response when silicone/mineral oil is injected for cosmetic purposes. These sclerosing granulomas can lead to hypercalcemia. Here we present a 33‐year‐old man with hypercalcemia, hypophosphatemia, progressively worsening fatigue, severe proximal muscle weakness, and depression. He had an athletic build with increased muscle bulk and several areas of indurated, nontender, firm, well‐circumscribed lesions in the subcutaneous tissue of his anterior pectoralis, triceps, and biceps bilaterally because of injecting himself with silicone/mineral oil‐based product into his muscles. Sclerosing granulomas were diagnosed on the MRI. He had extremely low or undetectable serum levels of 25‐hydroxyvitamin D [25(OH)D], and persistently elevated serum levels of 1,25‐dihydroxyvitamin D [1,25(OH)2D] and calcium. He developed hypophosphatemia associated with elevated levels of fibroblast growth factor 23 (FGF‐23) and severe proximal muscle weakness. Treatment with systemic steroids, furosemide, calcitonin, ketoconazole, and denosumab resulted in a significant decrease in his serum calcium, but with minimal impact on his hypophosphatemia and fatigue.Correcting his severe vitamin D deficiency with small doses of vitamin D and raising his blood level of 25(OH)D from undetectable to 10 ng/mL without significantly affecting his serum calcium or phosphate was effective in reversing his severe proximal muscle weakness, permitting him to lift his head and to be free of his wheelchair. Although measurement of the 1,25(OH)2D level is not mandatory in all cases of hypercalcemia, it is indicated in a patient who has low serum PTH levels. Clinicians need to be aware that vitamin D deficiency can cause severe proximal muscle weakness such that the patient is unable to lift his head from his chest or ambulate. This may lead to a psychiatric disorder misdiagnosis. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

A case report of eumycetoma in the thigh: an unusual presentation as a lump

Mycetoma is a chronic disease, which is endemic in tropical and subtropical countries. Mycetoma is a chronic subcutaneous infection caused by Actinomycetes or fungi. This infection results in a granulomatous inflammatory response in the deep dermis and subcutaneous tissue, which can extend to the underlying bone. Mycetoma is characterized by the formation of grains containing aggregates of the causative organisms that may be discharged onto the skin surface through multiple sinuses. Here we report an unusual presentation of eumycetoma in the thigh of a 41 year old male rural industrial worker hailing from South India.

Chromoblastomycosis complicated with co-morbidities, curbed by cryotherapy: a case report

&lt;p&gt;Chromoblastomycosis is a chronic mycosis affecting skin and subcutaneous tissue. Treatment of chromoblastomycosis is challenging due to refractory nature of the condition and varied antifungal sensitivity of the organism. Though systemic antifungals are commonly used modality of treatment, there is no “gold standard” treatment. The array of treatment options include chemotherapy and physical methods (cryosurgery/ CO2 laser/superficial X-rays/ surgical excision), either alone or in combination. A 60 year old male farmer presented with history of congestive cardiac failure (CCF), presented with gradually increasing painful, reddish elevated skin lesions over right knee since 2 years. On examination, there was a well-defined solitary, tender plaque of size 2×3 cm with smooth surface, elevated peripheral margin. Blood investigations were within normal limits except for deranged LFT. Diagnosis of chromoblastomycosis was made based on KOH mount which revealed typical sclerotic bodies and histopathology which revealed neutrophilic abscesses, muriform cells, mixed granulomatous response. In view of his comorbidities like congestive cardiac failure and deranged liver function test, we couldn’t consider the possibility of systemic drugs like Itraconazole. So, he was treated only with liquid nitrogen cryotherapy on a weekly basis for 8 weeks. Marked improvement in lesion was observed after 8 sittings. In our case, due to cardiac complications and deranged liver function test we treated the patient with cryotherapy solely and achieved marked improvement in skin lesions. Cryotherapy alone serves as an effective treatment modality when systemic antifungals can’t be given.&lt;/p&gt;