scholarly journals Malignancy induced haemophagocytosis by erthroid cells and its transformation into a multinucleated giant cells – A unique clinical image

2021 ◽  
Vol 5 (1) ◽  
pp. 007-007

Haemophagocytosis is a dysregulated immune condition characterised by both inflammation and uncontrolled activation of macrophages and T-cells, which causes aberrant cytokine release, leading to cytokine storm [1] it can be primary or secondary, depending upon the etiology.

2020 ◽  
Vol 127 (Suppl_1) ◽  
Yao Yan

Background: Giant-cell myocarditis (GCM) is a rare disease with a poor prognosis. The typical pathological features of GCM include an infiltration of multinucleated giant cells accompanied by numerous inflammatory immune cells. However, the etiology and pathophysiology of GCM remain largely unclear. Methods: Eight patients with pathological diagnoses with GCM underwent heart transplantation at our center. Hematoxylin- eosin (H-E) and Masson’s tri-chrome staining were performed on biopsies of the free walls of the right and left ventricles and interventricular septa of the original hearts to determine the characteristic distribution of cardiac lesions and the composition of infiltrating immune cells. A multiplex immunohistochemistry and multispectral imaging analysis were applied to further classify the specific types of inflammatory immune cells. Results: Inflammation found in a descending frequency gradually from the epicardium to the endocardium in the free wall of the left ventricle, but concentrated on the surface of right ventricular septum. Typical inflammatory infiltration and pathological changes were observed in the right-sided ventricular septum samples from all 8 patients. Numerous inflammatory immune cells, particularly CD4 + T cells, were detected in the lesion, which surrounded the emerging multinucleated giant cells. CD8 + T cells and a small number of regulatory T cells were scattered in the periphery. Conclusions: In GCM, cardiac lesions appear to concentrate particularly beneath the epicardium of the left ventricular free wall and the right side of the ventricular septum. These findings provide a rationale for the diagnostic use of conventional endocardial biopsy. The findings further suggest that myocardial injury is mediated by a variety of lymphocytes, especially CD4 + T cells.

2022 ◽  
Vol 12 ◽  
Laura Hunter ◽  
Suzie Hingley-Wilson ◽  
Graham R. Stewart ◽  
Sally A. Sharpe ◽  
Francisco Javier Salguero

Non-human primate models of Tuberculosis (TB) are one of the most commonly used within the experimental TB field because they closely mimic the whole spectrum of disease progression of human TB. However, the early cellular interactions of the pulmonary granuloma are still not well understood. The use of this model allows investigation into the early interactions of cells within pulmonary granulomas which cannot be undertaken in human samples. Pulmonary granulomas from rhesus and cynomolgus macaques from two timepoints post infection were categorised into categories 1 – 6 (early to late stage granulomas) and immunohistochemistry was used to identify CD68+ macrophages, CD3+ T cells and CD20+ B cells. Multinucleated giant cells and acid-fast bacilli were also quantified. At week four post infection, cynomolgus macaques were found to have more CD68+ cells than rhesus in all but category 1 granulomas. Cynomolgus also had a significantly higher percentage of CD20+ B cells in category 1 granulomas. At week twelve post infection, CD68+ cells were most abundant in category 4 and 5 granulomas in both species; however, there were no significant differences between them. CD3+ T cells and CD20+ B cells were significantly higher in the majority of granuloma categories in cynomolgus compared to rhesus. Multinucleated giant cells and acid-fast bacilli were most abundant in categories 5 and 6 at week 12 post challenge in both species. This study has identified the basic cellular composition and spatial distribution of immune cells within pulmonary granulomas in both rhesus and cynomolgus macaques over time. The data from this study will add to the knowledge already gained in this field and may inform future research on vaccines and therapeutics for TB.

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-17
Radhika Gali ◽  
David Alejos ◽  
Ioannis Mantzaris

PD-1 inhibitors have emerged as an important class of immunotherapy drugs and several agents, such as nivolumab, are now FDA approved for the treatment of various malignancies, including classical Hodgkin lymphoma (cHL). By blocking the interaction of PD-1 with its ligands, PD-1 inhibitors unleash T-cells to attack neoplastic cells, but also interfere with immune self-recognition of healthy tissue. PD-1 inhibitors can thus lead to toxicity by immune attack of several organ systems. Less frequently, an exaggerated immunological response known as cytokine release syndrome (CRS) can develop. Unhindered T-cell activation leads to activation of bystander immune (dendritic cells, macrophages) and non-immune cells (endothelial cells) and ultimately massive release of a range of cytokines . CRS can be life-threatening, leading to hemodynamic instability, liver dysfunction, DIC and multiorgan failure. A limited number of CRS cases in patients treated with immune checkpoint inhibitors (ICIs) have been reported to date. Almost all cases have early-onset CRS with a median of 4 weeks from treatment initiation. Late-onset CRS has been documented in only one case of a patient with melanoma treated with nivolumab. No obvious risk factors for CRS have yet been identified in the context of ICIs, although high burden of disease has been linked to higher rates and severity with other immunotherapies, such as bispecific antibodies and CAR-T cells, which can explain the early-onset of the syndrome. We now report another case of late-onset CRS with nivolumab, this time in a patient with cHL and HIV. CRS coincided with loss of HIV control due to a period of non-compliance with anti-retroviral therapy (ART), which likely contributed to the development of cytokine storm. A 28-year-old female with HIV infection on ART and chemotherapy-refractory stage IV cHL on cycle 11 of nivolumab, with a favorable response, was admitted with worsening fatigue, subjective fevers, diarrhea and mild headaches. She was febrile, hypotensive and tachycardic (Figure 1). Physical exam was essentially normal. Laboratory work-up showed new transaminitis, elevated LDH and slightly prolonged PT; she was not neutropenic. She was hypothyroid due to non-compliance with levothyroxine for nivolumab-related hypothyroidism. Newly elevated HIV VL along with dropping CD4 count and CD4/CD8 ratio were noted (Table 1). She reported recent non-compliance with ART. She continued to have unremitting high fevers with persistent hypotension after 24 hours of IV hydration, anti-pyretics and broad-spectrum antibiotics. CRS was suspected. Adrenal insufficiency and hypophysitis were ruled out. CRP was elevated to 9mg/dl. She was started on methylprednisolone 1 mg/kg/day. She clinically improved within 5 hours of first steroid dose (Figure 1) and was discharged 2 days later on a 2-week-long steroid taper. Re-challenge with nivolumab approximately 1 month later, with undetectable HIV viral load, led to no recurrent events. She remains on treatment and in complete metabolic remission after 2.5 years of therapy. HIV infection leads to disturbed T-cell homeostasis, generating a systemic inflammatory environment and shifted profiles of inflammatory markers. Untreated infection leads to massive depletion of both HIV-infected and uninfected bystander CD4 cells, inverted CD4/CD8 ratio, impaired CD8 T cell function with increased expression of immune checkpoint proteins (such as PD-1) and elevated plasma levels of cytokines including INF-g, TNF and IL-6. It is possible that loss of HIV control in our case, promoted an evolving state of immune dysregulation with low CD4/CD8 ratio, increased PD-1 expression and elevated cytokines, which under the pressure of PD-1 inhibition led to an uncontrolled immune stimulation, culminating in a cytokine storm. Initial ICI cancer trials have largely excluded HIV patients, but their safety is increasingly recognized in this population. Our case highlights the nuances around safety and efficacy of immunotherapy in HIV. Nivolumab was highly efficacious and well-tolerated while ART maintained viral suppression. CRS coincided with loss of virologic control and did not recur upon re-challenge, once HIV infection was controlled. We conclude that continuous viral suppression may be key for the safe implementation of ICIs, and likely other forms of immunotherapy, in patients with cancer and HIV. Disclosures No relevant conflicts of interest to declare.

2017 ◽  
Vol 91 (24) ◽  
Lucie Bracq ◽  
Maorong Xie ◽  
Marie Lambelé ◽  
Lan-Trang Vu ◽  
Julie Matz ◽  

ABSTRACT HIV-1-infected macrophages participate in virus dissemination and establishment of virus reservoirs in host tissues, but the mechanisms for virus cell-to-cell transfer to macrophages remain unknown. Here, we reveal the mechanisms for cell-to-cell transfer from infected T cells to macrophages and virus spreading between macrophages. We show that contacts between infected T lymphocytes and macrophages lead to cell fusion for the fast and massive transfer of CCR5-tropic viruses to macrophages. Through the merge of viral material between T cells and macrophages, these newly formed lymphocyte-macrophage fused cells acquire the ability to fuse with neighboring noninfected macrophages. Together, these two-step envelope-dependent cell fusion processes lead to the formation of highly virus-productive multinucleated giant cells reminiscent of the infected multinucleated giant macrophages detected in HIV-1-infected patients and simian immunodeficiency virus-infected macaques. These mechanisms represent an original mode of virus transmission for viral spreading and a new model for the formation of macrophage virus reservoirs during infection. IMPORTANCE We reveal a very efficient mechanism involved in cell-to-cell transfer from infected T cells to macrophages and subsequent virus spreading between macrophages by a two-step cell fusion process. Infected T cells first establish contacts and fuse with macrophage targets. The newly formed lymphocyte-macrophage fused cells then acquire the ability to fuse with surrounding uninfected macrophages, leading to the formation of infected multinucleated giant cells that can survive for a long time, as evidenced in vivo in lymphoid organs and the central nervous system. This route of infection may be a major determinant for virus dissemination and the formation of macrophage virus reservoirs in host tissues during HIV-1 infection.

1992 ◽  
Vol 175 (6) ◽  
pp. 1685-1695 ◽  
J O Hill

The possible mechanisms by which CD4+ T cells prevent the dissemination of Cryptococcus neoformans from the primary site of infection in the respiratory tract were examined. It was found that even before fungicidal mechanisms are fully induced in the lungs, the host generates a CD4+ T cell-dependent inflammatory response that sequesters yeast within the pulmonary alveoli. This confinement is evident histopathologically and demonstrable objectively as a rapid decline in the ability to dislodge yeast from the lungs by bronchopulmonary lavage. One striking component of this response is the enclosure of cryptococci within multinucleated giant cells in granulomas. Studies in severe combined immunodeficient mice that were engrafted with selected lymphocyte subpopulations show that B cells, and hence anti-Cryptococcus antibodies, are not necessary for the CD4+ T cell-dependent responses that isolate and subsequently destroy this opportunistic pathogen in the lung parenchyma.

2019 ◽  
Vol 72 (12) ◽  
Olena O Dyadyk ◽  
Anastasiia Hryhorovska

Introduction: Tenosynovial giant cell tumor (TSGCT) (synonym – pigmented villonodular synovitis) – is a rare benign proliferative lesion of the synovial sheath, localized in the joint capsule, bursa or tendon sheath and characterized by locally destructive growth. Depending on the prevalence within the joint elements, the presence of a capsule around the tumor, histophotographic features of cell structure and clinical behavior TSGCT can be divided to localized or diffuse type. The aim of the study was researching of histopathological properties of diffuse-type TSGCT, determine the parameters its morphological indicators and to find out the correlation between these morphological and clinical parameters. Materials and methods: The research material was used biopsy (resect) of pathological lesions from 50 patients who were diagnosed and histologically verified diffuse-type TSGCT. Microscopic examinations of the stained sections and their photo archiving were carried out with use of a Olympus-CX 41 light optical microscope. Group measurable parameters (mean values and Pearson tetrachoric index (association coefficient) were calculated in groups of comparison for morphological and clinical indices of TSGCT. The mean values were compared by Student’s test, P value of ≤0.1 was considered statistically significant. Results:Correlation analysis of indicators that accounted for the pairs of cases «clinic – morphology» revealed the relationships, that had the highest parameters of the association coefficient between such indicators: «presence of villous growths» - «severity of hemosiderosis» (if hypertrophied synovial villi available, with vascular injection and pronounced proliferation of synovial cells, there is also a significant accumulation of hemosiderin pigment); «presence of villous growths» - «type of predominant cellular proliferates» (if cells of TSGCT diffuse type consists of monotonous sheets of stromal cells, with uniform, oval to reniform nuclei, the proliferation of villi in synovial layer is non-distinctive); «presence of nodes» - «kind of stroma» (if nodes predominate, their histological structure is mainly represented by polymorphic clusters of synovitis cells in the form of cells, strands, chains, solid formations, among immature connective tissue with low hyalinosis); «cell size (area, cm²)» - «severity of haemosiderosis» and «cell size (area, cm²)» - «the number of multinucleated giant cells» (there is a pronounced deposition of pigment and accumulation of osteoclast-like multinucleated giant cells type, although usually their number is relatively small compared to the localized type of TSGCT). Conclusions: Morphological parameters, that we have identified, characterize pathological changes in the tissues of TSGCT; careful analysis of the frequency of their occurrence in the different comparison groups made it possible to establish intergroup differences and correlations between individual indicators, which were previously unknown or not obvious. Our study was determine to analyze of incidence rates and correlation relationships, revealed some previously unknown differences and dependencies that are important for understanding the pathogenesis, improvement of diagnosis and prognosis of diffuse-type TSGCT.

K Yang ◽  
K Reddy ◽  
BH Wang ◽  
A Cenic ◽  
LC Ang ◽  

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumefactive lesion with unclear pathogenesis. It is diagnosed by pathological findings of the typical histological features that include granular amorphous cores with palisading spindle to epithelioid cells, variable fibrous stroma, foreign-body reaction with giant cells, and calcification/ossification occasionally with psammoma bodies. However, its histopathology may be variable and currently immunohistochemistry plays a limited role in its diagnosis and understanding the pathogenesis. In this study, we examined 6 cases of CAPNONs including 3 intracranial and 3 spinal epidural lesions (age range: 59–69 years; 3 males and 3 females). Immunohistochemistry revealed that all CAPNON cores contain abundant positive deposits of neurofilament protein (NFP), which was supported by electron microscopy finding of filaments (8–13 nm in diameter). In comparison, no NFP positivity was found in 5 psammomatous/metaplastic meningiomas or 7 intervertebral tissue lesions with calcification/ossification. In addition, CAPNON cellular areas showed variable numbers of CD8+ cytotoxic T-cells with less CD4+ T-cells and a decreased ratio of CD4/CD8+ cells, versus the intervertebral tissue lesions without CD8+ or CD4+ cells. Our findings suggest that NFP may be a principal constituent of CAPNONs, and thus involved in the pathogenesis of CAPNON. Given the decreased CD4/CD8 ratio, the pathogenic process of CAPNON is possibly immune- mediated.LEARNING OBJECTIVESThe presentation will enable the learner to: 1.Discuss histopathological features of calcifying pseudoneoplasm of the neuraxis (CAPNON) with variation of non-core components.2.Explore diagnostic and pathogenic roles of immunohistochemical markers including neurofilament protein and CD4/CD8 in CAPNON.

Drug Research ◽  
2021 ◽  
Ashif Iqubal ◽  
Farazul Hoda ◽  
Abul Kalam Najmi ◽  
Syed Ehtaishamul Haque

AbstractCoronavirus disease (COVID-19) emerged from Wuhan, has now become pandemic and the mortality rate is growing exponentially. Clinical complication and fatality rate is much higher for patients having co-morbid issues. Compromised immune response and hyper inflammation is hall mark of pathogenesis and major cause of mortality. Cytokine release syndrome (CRS) or cytokine storm is a term used to affiliate the situation of hyper inflammation and therefore use of anti-cytokine and anti-inflammatory drugs is used to take care of this situation. Looking into the clinical benefit of these anti-inflammatory drugs, many of them enter into clinical trials. However, understanding the immunopathology of COVID-19 is important otherwise, indiscriminate use of these drugs could be fetal as there exists a very fine line of difference between viral clearing cytokines and inflammatory cytokines. If any drug suppresses the viral clearing cytokines, it will worsen the situation and hence, the use of these drugs must be based on the clinical condition, viral load, co-existing disease condition and severity of the infection.

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