Materiały źródłowe

• #1 Castleman Disease Pathogenesis – PubMed

  https://pubmed.ncbi.nlm.nih.gov/29157613/

  Castleman disease (CD) describes a group of heterogeneous disorders with common lymph node histopathologic features, including atrophic or hyperplastic germinal centers, prominent follicular dendritic cells, hypervascularization, polyclonal lymphoproliferation, and/or polytypic plasmacytosis. […] The cause and pathogenesis of the four subtypes of CD (unicentric CD; human herpesvirus-8-associated multicentric CD; polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes [POEMS]-associated multicentric CD; and idiopathic multicentric CD) vary considerably. […] This article provides a summary of our current understanding of the cause, cell types, signaling pathways, and effector cytokines implicated in the pathogenesis of each subtype.

• #2 Castleman Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK576394/

  Castleman disease is a lymphoproliferative disorder with a nondefinite etiology and can be classified into subtypes based on clinical and histological manifestations. […] There is very little knowledge available about the etiology of this disorder, but some evidence that has been collected claims it to be a result of impaired immunoregulation that causes abundant proliferation of B lymphocytes and plasma cells in lymphoid organs. These conditions can result from chronic low-grade inflammation, lymphoid-hamartomatous hyperplasia, viral infections, abnormal modulation of cytokines, and angiogenesis. […] Pathogenetically, plasma cell Castleman disease correlates with the overproduction of IL-6 and overexpression of IL-6 receptors that lead to the proliferation of B lymphocytes, vasculogenesis, resulting in a series of systemic symptoms such as fever, anemia, hypoproteinemia, and proteinuria. In some cases of mixed CD, IL-6 increase also is found to favor hepcidin production from the liver that can cause iron-deficiency anemia.

• #3 Castleman disease – Wikipedia

  https://en.wikipedia.org/wiki/Castleman_disease

  Castleman disease describes a group of rare lymphoproliferative disorders that involve enlarged lymph nodes, and a broad range of inflammatory symptoms and laboratory abnormalities. Whether Castleman disease should be considered an autoimmune disease, cancer, or infectious disease is currently unknown. […] All forms involve overproduction of cytokines and other inflammatory proteins by the body’s immune system as well as characteristic abnormal lymph node features that can be observed under the microscope. […] The exact cause of UCD is unknown, but appears to be due to a genetic change that occurs in the lymph node tissue, most similar to a benign tumor. […] In this form, patients have multiple regions of enlarged lymph nodes with characteristic microscopic features, flu-like symptoms, and organ dysfunction due to excessive cytokines or inflammatory proteins.

• #4 Castleman disease – Wikipedia

  https://en.wikipedia.org/wiki/Castleman_disease

  A cancerous cell population found in patients with POEMS syndrome can cause MCD in a fraction of patients by producing cytokines that initiate a cytokine storm. […] HHV-8-associated MCD patients have multiple regions of enlarged lymph nodes and episodic inflammatory symptoms due to uncontrolled infection with HHV-8. […] Though all forms of MCD involve excessive production of cytokines and a cytokine storm, iMCD has important differences in symptoms, disease course, and treatment from POEMS-associated MCD and HHV-8-associated MCD. […] The clinical utility of subtyping Castleman disease by histologic features is uncertain, as histologic subtypes do not consistently predict disease severity or treatment response. […] Staining with latency-associated nuclear antigen (LANA-1), a marker for HHV-8 infection, should be measured in all forms of Castleman disease but is positive only in HHV-8-associated MCD.

• #5 Castleman Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2219018-overview

  The pathophysiology of Castleman disease (CD) varies between subtypes. […] Unicentric CD (UCD) pathophysiology is poorly understood. The lymph node is characterized by abnormal features that include small or large germinal centers, follicular dendritic cell (FDC) prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. Patients sometimes experience inflammatory symptoms, which are believed to be caused by elevated IL-6 levels in the blood. These symptoms typically resolve after lymph node excision. […] HHV-8associated MCD pathophysiology is well understood: Immunocompromise due to HIV or other causes enables the uncontrolled infection and replication of HHV-8 in lymph node plasmablasts and B cells, which signal for viral IL-6 and other proinflammatory cytokines. Depletion of B cells with rituximab typically results in resolution of symptoms.

• #6 Pathology Outlines – Castleman disease

  https://www.pathologyoutlines.com/topic/lymphnodescastleman.html

  Etiopathogenesis remains not well known […] Recent evidence suggests that UCD may be a neoplastic process involving follicular dendritic cells […] Among UCD patients, 17% have shown to harbor mutations in the gene PDGFRB encoding platelet receptor growth factor β […] iMCD is proposed to involve autoinflammatory or autoimmune diseases, paraneoplastic syndromes or an unidentified viral infection leading to polyclonal lymphoproliferation and hypercytokinemia […] Current concept is that a cytokine storm due to increased production of IL6 is associated with Castleman disease since patients have elevated levels of IL6 and symptoms improve with IL6 suppression […] VEGF, IL1, IL2, CXCL13 and TNF have also been shown to play a role in the pathogenesis of iMCD […] T cell activation, and activation of mTOR, JAK / STAT3 and type I interferon signaling pathways also thought to be pathogenetic mechanisms

• #7 Monoclonality and cytogenetic abnormalities in hyaline vascular Castleman disease | Modern Pathology

  https://www.nature.com/articles/modpathol2013202

  However, the findings of genetic changes preceding the morphologically stromal overgrowth may elicit the idea that the genetic alteration of stromal cells is a leading event in hyaline vascular Castleman disease. […] The compressed sinuses are a characteristic feature of hyaline vascular Castleman disease and are probably related to stromal proliferation. […] As hyaline vascular Castleman diseases of larger size and with stromal overgrowth were monoclonal in almost all cases, it indicates that the monoclonal proliferation of stromal cells become more prominent with time. […] In conclusion, our results show that most cases of hyaline vascular Castleman disease are monoclonal proliferations, most likely of stromal cell origin, as the lymphoid cells are polyclonal.

• #8 Castleman Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK576394/

  The genome of the human lymphotropic virus HHV-8 in HHV-8 associated CD encodes a viral analog (vIL)-6 of IL-6 that further stimulates angiogenesis, hematopoietic and lymphocytic activity. […] IL-6 has proven to be a specific biomarker for this disease, contributing to its pathogenesis, symptomatology, and histopathology. However, raised blood levels of IL-6 and soluble IL-2 receptor (sIL2R), VEGF, IgA, IgE, lactate dehydrogenase, -2-microglobulin do not specifically indicate the presence of this disease but are essential for supporting its diagnosis.

• #9 Update and new approaches in the treatment of Castleman disease | JBM

  https://www.dovepress.com/update-and-new-approaches-in-the-treatment-of-castleman-disease-peer-reviewed-fulltext-article-JBM

  The discovery of the link to HHV-8 and the causal role of IL-6 have provided valuable insights into CD pathophysiology and formed a foundation for development of new treatment strategies and ongoing research. […] In MCD, it appears that HHV-8 appears to preferentially infect IgM-positive memory B-cells, inducing their proliferation and differentiation into the characteristic plasmablast phenotype observed. […] In both latent and lytic phases, a recurring theme is the distinctive ability of HHV-8 to produce viral homologs of endogenous human regulatory proteins, facilitating a variety of functions, including viral persistence, inhibition of apoptosis, and cytokine generation. […] One of the earliest links between IL-6 and CD was the demonstration that the site of excess IL-6 production in CD patients was within the germinal centers of involved lymph nodes.

• #10 Pathology Outlines – Castleman disease

  https://www.pathologyoutlines.com/topic/lymphnodescastleman.html

  HHV8 MCD occurs in HIV positive or negative individuals infected with HHV8 […] HHV8 infected B cells in the mantle zones show expression of IgM lambda immunoglobulins […] HHV8 encodes several viral genes; the resulting viral proteins and microRNAs stimulate cell growth, proliferation and cell survival among the infected cells, as well as among the neighboring cells by a paracrine mechanism […] HHV8 viral lytic protein expression is proposed to be the contributing pathobiological factor of HHV8 MCD […] High viral load in patients with HHV8 MCD suggests active viral replication […] HHV8 viral protein vIL6 is expressed in high levels in plasmablasts surrounding lymphoid follicles […] Additionally, human cytokines are elevated in patients with HHV8 MCD, which is thought to be driven by the virus […] Inflammatory cytokines like hIL6 and vIL6 cause anemia, fever and hypoalbuminemia.

• #11 Diagnosis and Management of Castleman Disease- Cancer Therapy Advisor

  https://www.cancertherapyadvisor.com/features/diagnosis-and-management-of-castleman-disease/

  HIV-associated MCD is uniformly associated with HHV-8 infection, although its prevalence in HIV-negative MCD varies by the local prevalence rate of HHV-8. Plasma levels of HHV-8 DNA correlate with clinical symptoms and predict relapse rates in HIV-associated MCD. […] In patients with HHV-8-positive MCD, HHV-8-infected vascular and lymphoid cells express a viral analog of IL-6 (vIL-6), which likely contributes to the pathogenesis of this significant subset of Castleman disease. Both human IL-6 and vIL-6 are sufficient to induce disease flares in HIV-associated MCD and promote the expression of proinflammatory cytokines during disease flares.

• #12 Cutaneous Disorders Associated with Castleman’s Disease | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3253

  Castlemans disease is a rare disease of the lymph nodes and related tissues, presenting as angiofollicular or giant lymph node hyperplasia. […] The pathogenesis of CD is not yet fully understood. Fajgenbaum Shilling attempted to classify the pathogenesis according to the CD subtype. Viral, neoplastic, and reactive inflammatory mechanisms have all been proposed as aetiological mechanisms in UCD. In HHV-8-associated MCD, the HIV infection or immune-deficient condition is thought to drive the clinicopathological symptoms of CD. In addition, an increased level of vascular endothelial growth factor (VEGF) or activation of other factors by viral G-protein coupled receptors may be involved in HHV-8-associated MCD pathology, and increased human interleukin (IL)-6 and viral IL-6 may drive B-cell proliferation or related symptoms. In POEMS-related MCD, VEGF, IL-6, IL-12, transforming growth factor-1 (TGF-1), and tumour necrosis factor- (TNF-) may be induced by the production of mediators from monoclonal plasma cells.

• #13 Idiopathic multicentric Castleman disease: pathogenesis, clinical presentation and recommendations for treatment based on the Castleman Disease Collaborative Network (CDCN) | Ostrowska | Acta Haematologica Polonica

  https://journals.viamedica.pl/acta_haematologica_polonica/article/view/74863

  Castleman disease is a very rare, lymphoproliferative disease, driven by dysregulation of the cytokine interleukin 6 (IL-6) and other proinflammatory cytokines with the development of symptoms of systemic inflammation, reactive proliferation of lymphocytes, and damage to numerous organs. […] HHV-8 infection plays a major role in the pathogenesis of human immunodeficiency virus (HIV+) multicentric Castleman disease (MCD). […] The aetiology of the idiopathic form of MCD (HIV/HHV-8 negative) is unknown. […] Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease.

• #14 Castleman Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2219018-overview

  HHV-8negative/idiopathic MCD (iMCD) pathophysiology is poorly understood. Patients experience atypical CD-like lymphoproliferation, which occurs along with systemic inflammatory signs and symptoms (fevers, weight loss, fatigue, night sweats), abnormal blood cell counts, and multiple organ system dysfunction. The pathophysiology of the disease is caused by excess IL-6 in a portion of patients. […] Inhibition of IL-6 with siltuximab is effective in approximately 34-44% of patients. The pathophysiology in the remaining patients who do not improve with IL-6 inhibition is not known but is suspected to involve cytokines or mechanisms other than IL-6 excess.

• #15 Castleman Disease Pathogenesis | Sustainable Development Goals – Resource Centre

  https://sdgresources.relx.com/articles/castleman-disease-pathogenesis

  The CD research community, led by the CDCN, recently proposed 4 candidate etiologic drivers of iMCD pathogenesis: iMCD may be due to (A) self-reactive antibodies, (B) germline mutations in genes regulating inflammation, (C) acquired oncogenic mutations […] The pathogenesis of unicentric CD (adenopathy of a single region of lymph nodes) is most likely driven by a neoplastic follicular dendritic cell population. […] HHV-8associated multicentric CD (adenopathy of multiple regions of lymph nodes) pathogenesis is virally driven, whereas polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS)associated multicentric CD (MCD) pathogenesis is driven by a monoclonal plasma cell population. […] Idiopathic MCD is poorly understood, although clinical data suggest a pathologic role for interleukin-6 in a subset of patients.

• #16 Castleman Disease in the 21st Century: An Update on Diagnosis, Assessment, and Therapy – Hematology & Oncology

  https://www.hematologyandoncology.net/archives/july-2010/castleman-disease-in-the-21st-century-an-update-on-diagnosis-assessment-and-therapy/

  IL6 plays a central role in the pathophysiology of CD. […] Excess IL6 induces a pro-inflammatory syndrome that leads to severe constitutional symptoms, with elevation of acute phase reactants. IL6 also induces the secretion of VEGF, which can be found in the supernatant of cultured cells derived from CD lymph nodes. […] The crucial role of IL6 in CD is underscored by several observations. Symptoms wax and wane in accordance with IL6 levels. […] The trigger of excess IL6 production in HIV-negative CD is not fully understood. […] Polymorphisms have been described in the IL6 promoter, IL6R, and gp130, which increase IL6 levels and/or signaling. […] The lymph node histology in CD can have similarities to abnormalities found in chronic viral infections, and the discovery of HHV8 in HIV-positive CD has already been alluded to. The HHV8-genome encodes a number of homologs of human cellular genes, including viral IL6 (vIL6), which induces proliferation of HHV8-infected cells.

• #17 Biomarkers and Signaling Pathways Implicated in the Pathogenesis of Idiopathic Multicentric Castleman Disease/Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Renal Insufficiency, and Organomegaly (TAFRO) Syndrome

  https://www.mdpi.com/2227-9059/12/6/1141

  The cytokine storm, with IL-6 as a protagonist, precipitates a hyperinflammatory milieu that is characteristic of the disease. […] IL-6, a pleiotropic inflammatory cytokine, interacts with a variety of cells, including immune cells, hematopoietic progenitors, and cells within the liver and epidermis, among others. It operates through IL-6R and gp130 molecules, employing both classical signaling and trans-signaling modalities. […] The role of IL-6 in TAFRO syndrome is more complex. Although IL-6 is strongly associated with the symptomatology and progression of the IPL subtype of iMCD, its role in TAFRO syndrome pathogenesis is less clear. […] Recent advancements in the treatment of idiopathic multicentric Castleman disease (iMCD) have pointed to the efficacy of sirolimus, an mTOR inhibitor, particularly in cases that have not responded to traditional IL-6 inhibitors.

• #17 Biomarkers and Signaling Pathways Implicated in the Pathogenesis of Idiopathic Multicentric Castleman Disease/Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Renal Insufficiency, and Organomegaly (TAFRO) Syndrome

  https://www.mdpi.com/2227-9059/12/6/1141

  Idiopathic multicentric Castleman disease (iMCD) and TAFRO syndrome present a variety of symptoms thought to be caused by excessive inflammatory cytokines and chemokines, but the underlying mechanisms are unknown. […] Elevated levels of cytokines, including IL-1β, TNF-α, IL-10, and IL-23, as well as chemokines like CXCL13 and CXCL-10 (especially in iMCD-TAFRO), SAA, and VEGF, have been linked to the disease’s pathology. Recent research has identified key signaling pathways including PI3K/Akt/mTOR and JAK-STAT3, as well as those regulated by type I IFN, as crucial in iMCD-TAFRO. […] The causes of iMCD and TAFRO syndrome are unknown, but they are thought to be pathogen etiologies or paraneoplastic phenomena associated with clonal cellular proliferation. There may also be a role for autoimmune or autoinflammatory processes. The disease is characterized by the widespread proliferation of lymphocytes and a significant increase in cytokines, particularly IL-6.

• #18 Castleman Disease | AVAHO

  https://www.mdedge9-ma1.mdedge.com/fedprac/avaho/article/102230/lymphoma-plasma-cell-disorders/castleman-disease

  An understanding of the disease pathogenesis has led to the discovery of therapeutic agents that target human herpesvirus-8 replication, CD20, and IL-6 and IL-6R antibodies. […] Interleukin-6 (IL-6) and a viral analog of IL-6 play major role in the pathogenesis by stimulating a widespread inflammatory response that results in systemic manifestations. […] There is dysregulation and overproduction of IL-6, which further stimulates the production of acute-phase reactants, resulting in various systemic manifestations. […] There is increased expression of IL-1 and IL-6, upregulation of IL-6 secondary to interaction of IL-1 with nuclear factor-kappa B (NF-kappa B), thus stimulating B-cell proliferation. […] IL-6 binding to IL-6 receptor (IL6-R) results in downstream activation of transcription Janus kinases/signal transducers and activators of the transcription pathway.

• #19 Castleman Disease | MDedge

  https://community.the-hospitalist.org/content/castleman-disease

  An understanding of the disease pathogenesis has led to the discovery of therapeutic agents that target human herpesvirus-8 replication, CD20, and IL-6 and IL-6R antibodies. […] Interleukin-6 (IL-6) and a viral analog of IL-6 play major role in the pathogenesis by stimulating a widespread inflammatory response that results in systemic manifestations. […] There is dysregulation and overproduction of IL-6, which further stimulates the production of acute-phase reactants, resulting in various systemic manifestations. […] There is increased expression of IL-1 and IL-6, upregulation of IL-6 secondary to interaction of IL-1 with nuclear factor-kappa B (NF-kappa B), thus stimulating B-cell proliferation. […] IL-6 binding to IL-6 receptor (IL6-R) results in downstream activation of transcription Janus kinases/signal transducers and activators of the transcription pathway.

• #20

  https://journals.lww.com/jpat/fulltext/2020/24030/castleman_s_disease.57.aspx

  Excess IL6 induces a pro-inflammatory syndrome that leads to severe constitutional symptoms, with the elevation of acute-phase reactants. IL6 also induces the secretion of VEGF, which can be found in the supernatant of cultured cells derived from CD lymph nodes. […] Autoimmune phenomena, such as cytopenias, are thought to arise due to IL6-induced immune dysregulation. IL6 is a potent growth and survival factor for B-lymphocytes and plasma cells, and it is at least partially responsible for lymph node hyperplasia in CD. […] Pathogenesis, by acting as a promoter of the terminal B-cell differentiation and by stimulation of plasma cell proliferation and production of immunglobulins. […] Furthermore, by stimulating the production of acute-phase proteins, IL-6 is responsible for part of the clinical manifestations. […] The increased production of VEGF has been strongly related to the manifestations of POEMS syndrome. […] HHV-8 uses the same signaling pathway, due to the presence of a human IL-6 mimic.

• #21 Castleman Disease | AVAHO

  https://www.mdedge9-ma1.mdedge.com/fedprac/avaho/article/102230/lymphoma-plasma-cell-disorders/castleman-disease

  This promotes the transcription of genes encoding the acute-phase reactant proteins. […] Hence, interfering with IL-6 transduction by blocking downstream signals are potential therapeutic targets. […] The mitogen-activated protein kinase cascade, the rapidly accelerated fibrosarcoma kinases, and the overexpression of the endothelial growth factor receptor (EGFR), all contribute to disease pathogenesis by promoting increased B-cell proliferation and vascular EGFR mediated angiogenesis. […] In HHV-8 associated MCD, the virus replicates within lymph node plasmablasts, causing increased production of viral IL-6 analog, human IL-6, and other proinflammatory proteins resulting in B-cell and plasma-cell proliferation, increased vascular endothelial growth factor secretion and angiogenesis. […] The HHV-8 infected plasmablasts are marked by variable expression of CD20, and therefore, anti-CD20 is also shown to be an effective treatment. […] The calmodulin/calcineurin nuclear factor assists in the proliferation of HHV-8, thereby making calcineurin another potential target for the antiviral proliferation.

• #22

  https://haematologica.org/article/view/haematol.2021.280370

  We report here for the first time the whole lymph node transcriptomes of UCD and iMCD, in order to generate insights into the pathogenesis of this poorly understood disease and identify potential targets for novel therapeutic strategies. […] We demonstrate that the transcriptomes of both UCD and iMCD are enriched for elements of the complement cascade. […] The increased transcription of complement-related genes in Castleman lymphadenopathy and evidence of complement activation within the characteristically abnormal germinal centers raise the possibility of complement activation as a possible mediator of the inflammatory manifestations of UCD and iMCD. […] Our findings raise the possibility of previously unrecognized disease mediators as potential therapeutic targets, such as elements of the complement cascade, CXCL13, and angiogenic signaling through FLT1 and APLNR.

• #23

  https://www.jci.org/articles/view/131332

  In this issue, Fajgenbaum et al. identify the mTOR pathway as a pharmacologically targetable pathway within IL-6 blockaderefractory iMCD. […] Fajgenbaum et al. successfully employ a precision medicine approach to identify and target the mTOR pathway in 3 IL-6 blockaderefractory patients with iMCD.

• #24 Key mechanism of cytokine storm in Castleman disease | ScienceDaily

  https://www.sciencedaily.com/releases/2020/05/200507164001.htm

  When Castleman Disease patients have a flare of their symptoms, they experience a cytokine storm inside their bodies — a hyper-response from the immune system that can cause a fever, organ failure, and even death. […] Now researchers at the Perelman School of Medicine at the University of Pennsylvania say they know what’s happening at the cellular level of the immune system when these cytokine storms occur, and the answer not only informs future potential Castleman therapies but may also provide new insight into why similar events take place in COVID-19 patients. […] Previous research has shown the cytokine storm is tied to a cytokine, or inflammatory mediator, called interleukin-6 (IL-6), which in turn is connected to another pathway called mTOR. This study advanced these findings further and discovered a particular group of cytokines called Type-I Interferons are highly active when patients are in flare. They also found that another pathway called JAK seems to be a critical mediator of the cytokine storm.

• #25 Biomarkers and Signaling Pathways Implicated in the Pathogenesis of Idiopathic Multicentric Castleman Disease/Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Renal Insufficiency, and Organomegaly (TAFRO) Syndrome

  https://www.mdpi.com/2227-9059/12/6/1141

  Despite the benefits of IL-6 inhibition in iMCD management, it may not prove beneficial for all individuals. […] The study also unveiled an association between the expression of IFN-I response genes and the mTOR gene signature in classical monocytes. Notably, when monocytes and T cells from iMCD-TAFRO patients in remission were stimulated with IFN-I in vitro, an augmented mTOR activation was detected, as compared to healthy individuals. […] These findings suggest that Tph cells and their production of CXCL13 play a significant role in iMCD-NOS, supporting the disease’s classification as an immunoregulatory disorder. […] Collectively, several studies have found that CXCL13, VEGF, NPS-PLA2, SAA, and IGFBP-1 are commonly elevated in patients with iMCD, implying that these substances may play a role in iMCD pathogenesis.

• #26 Castleman Disease | MDedge

  https://www.mdedge.com/content/castleman-disease

  This promotes the transcription of genes encoding the acute-phase reactant proteins. […] Hence, interfering with IL-6 transduction by blocking downstream signals are potential therapeutic targets. […] The mitogen-activated protein kinase cascade, the rapidly accelerated fibrosarcoma kinases, and the overexpression of the endothelial growth factor receptor (EGFR), all contribute to disease pathogenesis by promoting increased B-cell proliferation and vascular EGFR mediated angiogenesis. […] In HHV-8–associated MCD, the virus replicates within lymph node plasmablasts, causing increased production of viral IL-6 analog, human IL-6, and other proinflammatory proteins resulting in B-cell and plasma-cell proliferation, increased vascular endothelial growth factor secretion and angiogenesis. […] The HHV-8–infected plasmablasts are marked by variable expression of CD20, and therefore, anti-CD20 is also shown to be an effective treatment. […] The calmodulin/calcineurin nuclear factor assists in the proliferation of HHV-8, thereby making calcineurin another potential target for the antiviral proliferation.

• #27 Castleman’s disease—a two compartment model of HHV8 infection | Nature Reviews Clinical Oncology

  https://www.nature.com/articles/nrclinonc.2010.103

  Castleman’s disease is a primary infectious disease of the lymph node that causes local symptoms or a systemic inflammatory syndrome. […] Viral interleukin 6 (vIL-6) produced during the replication of human herpesvirus type 8 (HHV8) is the key driver of systemic inflammation and cellular proliferation. […] Infection by human herpesvirus type 8 drives systemic inflammation and cellular proliferation via viral interleukin-6 (vIL-6). Complementing HIV infection always induces multicentric plasma cell disease. […] Infection is propagated in two cellular compartments: lymphovascular endothelial cells and plasma cell precursors. They differ in proliferation dynamics and vIL-6 production resulting in pleiomorphic pathological and clinical presentations.

• #28

  https://haematologica.org/article/view/haematol.2022.280902

  Much progress has been made in our understanding of Castleman disease over the past 60-70 years since it was first described in 1954. Castleman disease is a heterogeneous group of lymph node disorders with shared pathological findings. […] UCD and iMCD have remained poorly understood disorders in terms of molecular pathogenesis, cellular etiology and signaling pathways. […] Common themes emerge from both datasets, including the importance of angiogenesis in Castleman disease, which is consistent with the vascular histopathology. The involvement of the complement pathway in Castleman disease raises the question of whether this could be a therapeutic target, especially in iMCD patients suffering from thrombotic micro-angiopathy and renal failure. Clearly, follicular dendritic cells play an important role in the pathogenesis of both UCD and MCD.

• #29

  https://penntoday.upenn.edu/news/researchers-discover-key-mechanism-cytokine-storm-castleman-disease

  When Castleman Disease patients have a flare of their symptoms, they experience a cytokine storm inside their bodiesa hyper-response from the immune system that can cause a fever, organ failure, and even death. […] Now researchers at the Perelman School of Medicine say they know whats happening at the cellular level of the immune system when these cytokine storms occur, and the answer not only informs future potential Castleman therapies but may also provide new insight into why similar events take place in COVID-19 patients. […] With iMCD, just as with COVID-19, it is the bodys hyper-response thats deadly rather than the disease itself, and this study gives us new clues about why the immune cells are out of control and what we can do to rein them in, says the studys senior author David C. Fajgenbaum.

• #30 Azthena logo with the word Azthena

  http://www.news-medical.net/news/20250411/Understanding-the-complex-spectrum-of-Castleman-disease.aspx

  Castleman disease (CD) is a rare, non-clonal lymphoproliferative disorder that manifests with a wide range of histologic and clinical features. […] Clonal cytogenetic abnormalities suggest a possible neoplastic origin in HV-CD, involving follicular dendritic cells. Key mutations in UCD include PDGFRB N666S, while iMCD is associated with mutations in NCOA4, SETD1A, and DNMT3A, among others. Dysregulation of genes involved in immune response, angiogenesis (e.g., CXCL13), and oxidative phosphorylation is noted, highlighting diverse molecular landscapes. […] Future studies focused on molecular pathogenesis may help refine the diagnosis and therapeutic strategies for CD and its related disorders.

• #31 Characteristics of Castleman’s Disease

  https://www.targetedonc.com/view/characteristics-of-castlemans-disease

  For the other cases of Castleman’s disease that are not related to the virus, we tend to call those idiopathic multicentric Castleman’s disease or disease that we don’t really know what the etiology is. For those, there’s an increasing understanding of some of the factors that may contribute. For instance, we know that there are promoter polymorphisms for the IL-6 gene that lead to constitutive overexpression of IL-6 protein. Patients have either constant production of IL-6 or an exaggerated response to producing IL-6 when they should only produce a little bit of it. So, that again is an overproduction of IL-6 from a genetic polymorphism. […] So, I guess, in my mind, I think about cases where IL6 is overexpressed because of a virus and we know that’s human herpesvirus-8, but there may be others. We know that there are genetic polymorphisms that lead to too much IL-6 production, and I would imagine that as we learn more about this disease and learn more about the IL-6 pathway, there may be other factors downstream of the receptor signaling within cell signaling pathways that could be mutated and lead to the same phenotype of IL-6 overexpression.

• #32

  https://www.jci.org/articles/view/131332

  Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. […] The etiologic trigger for iMCD remains unknown. However, excessive signaling from the proinflammatory cytokine IL-6 appears to play a role in the pathogenesis and symptomatology of the disease. […] Identification of the role of excessive IL-6 signaling in the pathogenesis of iMCD led to the development of novel iMCD therapies targeting IL-6. […] While IL-6 blockade represented a significant breakthrough in iMCD treatment, a substantial portion of patients with iMCD remain refractory to therapy with siltuximab or tocilizumab. This suggests that additional pathways may underlie iMCD pathogenesis and be important targets for future iMCD therapies.

• #33

  https://haematologica.org/article/view/haematol.2022.280902

  Overall, the present findings suggest potential alternative pathways, which can be targeted in non-responders to therapy against IL-6 by using anti-complement agents, anti-CXC13 monoclonal antibodies and molecules that bind VEGF and PGF. Other research has identified m-TOR and the JAK-STAT pathway as potential therapeutic targets.

• #34 CASE REPORT: Retroperitoneal Castleman Disease – American Urological Association

  https://auanews.net/issues/articles/2022/november-2022/case-report-retroperitoneal-castleman-disease

  Wing et al found that the upregulated expression of IL-6 and VEGF is more likely to occur in patients with multicentric Castleman disease. […] GSK3β- and CCR6-positive megakaryocytes of the bone marrow may be potential factors that activate multiple pathological processes of multicentric Castleman disease. […] Nevertheless, current studies are only based on a small number of cases, and we still lack a deep understanding of Castleman disease. Only by establishing a worldwide sample bank of Castleman disease as well as integrating traditional methods and modern new technology platforms can we truly explore the essence of Castleman disease.

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