scholarly journals Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 318-325 ◽  
Author(s):  
David C. Fajgenbaum
Keyword(s):  
Lymph Node ◽  
Signaling Pathways ◽  
Human Herpesvirus ◽  
Cell Types ◽  
Evidence Base ◽  
Multiple Organ ◽  
Castleman Disease ◽  
Proteomic Profiling ◽  
Durable Response ◽  
Multicentric Castleman Disease

Abstract Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.

scholarly journals Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease

Blood ◽  
2018 ◽  
Vol 132 (22) ◽  
pp. 2323-2330 ◽  
Author(s):  
David C. Fajgenbaum
Keyword(s):  
Lymph Node ◽  
Signaling Pathways ◽  
Human Herpesvirus ◽  
Cell Types ◽  
Evidence Base ◽  
Multiple Organ ◽  
Castleman Disease ◽  
Proteomic Profiling ◽  
Durable Response ◽  
Multicentric Castleman Disease

Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.

scholarly journals Pi3k/Akt/Mtor Pathway Activity Is Increased in Lymph Node Tissue from Idiopathic Multicentric Castleman Disease Patients with Tafro Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1121-1121
Author(s):  
Dustin Shilling ◽  
Dale M Kobrin ◽  
David C Fajgenbaum
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Signaling Pathways ◽  
Germinal Center ◽  
Plasma Cells ◽  
Human Herpesvirus ◽  
Castleman Disease ◽  
Mtor Signaling ◽  
Breast Cancer Patients ◽  
Color Deconvolution

Abstract Castleman disease (CD) describes a group of heterogeneous diseases defined by shared lymph node histopathology, including atrophic or hyperplastic germinal centers, prominent follicular dendritic cells, hypervascularization, polyclonal lymphoproliferation, and/or polytypic plasmacytosis. Unicentric CD (UCD) involves a solitary enlarged lymph node that displays CD histopathology, and patients rarely experience systemic symptoms. In contrast, multicentric CD (MCD) involves multiple regions of enlarged lymph nodes, systemic inflammation, cytopenias, and vital organ dysfunction due to a cytokine storm often including interleukin-6. MCD is caused by uncontrolled infection with Kaposi sarcoma-associated/human herpesvirus-8 (HHV-8) in ~50% of cases. The etiology of the remaining HHV-8-negative MCD cases is idiopathic (iMCD). In iMCD patients, blockade of IL-6 signaling with siltuximab, the only FDA-approved iMCD treatment, induced responses in 34% of cases in the phase II registrational trial. The large proportion of non-responders suggest that alternative pathways are responsible for driving disease pathogenesis in some patients. For these individuals, identification of molecular and cellular abnormalities for therapeutic targeting is urgently needed, particularly for those with the most severe clinical presentations. In fact, a clinical subgroup of iMCD was recently described with a very severe presentation: thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO). We previously reported increased phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling--a central pathway downstream of multiple cell surface receptors, implicated in both autoimmune and oncologic disorders--in a treatment refractory iMCD-TAFRO case that experienced an extended remission on treatment with an mTOR inhibitor. To extend these findings, herein we report immunohistochemistry for phosphorylated ribosomal protein S6 (phospho-S6), a marker of mTOR activation, in lymph node tissue from additional iMCD-TAFRO cases (n=10) and sentinel lymph nodes from breast cancer patients without evidence of metastasis (n=5). Anti-phospho-S6 (Ser235/236, Clone D57.2.2E) was used following standard protocols, and Aperio ImageScope and Image Analysis Toolkit software (color deconvolution v9 algorithm) were used to quantify pixel staining intensity in the germinal center, mantle zone, follicular and interfollicular regions. This analysis identified an increased number of pixels staining weak, medium, and strong for phospho-S6 in the interfollicular region of iMCD-TAFRO cases (p<0.005 for all comparisons) and an increased number of pixels staining weak for phospho-S6 in the germinal center (p<0.05) compared to control cases. Given that T cells are largely represented in the interfollicular region and mTOR signaling is critical to T cell proliferation, we hypothesized that the observed increase in phospho-S6 signal would occur in CD3+ cells. However, co-immunofluorescence assays for phospho-S6 and CD3 (Dako, A0452) across iMCD-TAFRO cases identified 0.08 ± 0.16% (mean ± standard deviation; n = 4 cases) of phospho-S6-positive cells as expressing CD3. In contrast, co-immunofluorescence for phospho-S6 and CD138 (Dako, Clone MI15) revealed 17.89 ± 11.26% of phospho-S6-positive cells as plasma cells. iMCD is considered an IL-6 driven disorder; however, anti-IL-6 therapy is effective in only a portion of cases. Alternative signaling pathways driving CD pathogenesis are poorly understood. This study provides the largest quantification to-date of aberrant PI3K/Akt/mTOR activity in iMCD-TAFRO, the first systematic study demonstrating increased mTOR activation in iMCD-TAFRO, and the first to identify a cell type, plasma cells. These findings are key to advancing our understanding of the pathological cell types and disrupted signaling pathways in iMCD. Disclosures Fajgenbaum: Janssen Pharmaceuticals, Inc.: Research Funding.

scholarly journals Clinical spectrum of POEMS-associated multicentric Castleman disease with renal involvement: a diagnostic challenge

2019 ◽  
Vol 8 (2) ◽  
pp. 21-21
Author(s):  
Caroline Kullmann Ribeiro ◽  
Fernanda Bresciani ◽  
Samile Echeverria Silveira ◽  
Pedro Guilherme Schaefer ◽  
Elvino Guardão Barros ◽  
...  
Keyword(s):  
Renal Function ◽  
Lymph Node ◽  
Plasma Cells ◽  
Clinical Laboratory ◽  
Renal Involvement ◽  
Case Series ◽  
Human Herpesvirus ◽  
Castleman Disease ◽  
Diagnostic Challenge ◽  
Multicentric Castleman Disease

Background: Castleman disease (CD) is a rare and heterogeneous lymphoproliferative disorder with a wide variety of clinical presentations and outcomes. Human herpesvirus-8 (HHV-8) related CD corresponds to the most common subtype of the multicentric Castleman disease (MCD). However, if HHV-8 is negative, POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) associated with MCD or idiopathic MCD are the cause in a subgroup of patients. Considering the rarity of POEMS and MCD association, we herein describe a patient with a typical presentation based on clinical, laboratory and tissue biopsy data. Case Presentation: We report a diabetic patient who presented with asthenia, edema, skin lesions manifested by scarring in chiropodactyls, multiple lymph node enlargement in the neck, armpits and inguinal areas, splenomegaly, severe anemia, thrombocytopenia, and mixed polyneuropathy. Hematuria and proteinuria were detected. The patient developed progressive renal failure requiring dialysis. Renal biopsy showed mesangial expansion with mesangial hypercellularity, and lymphoplasmacytoid cells focally distributed in tubules and interstitium, which were compatible with acute tubulointerstitial nephritis. In immunofluorescence, no deposits of IgG, IgA, IgM, C1q, C3 or fibrinogen were found, and kappa and lambda were also negative. Lymph node biopsy revealed lymphoid tissue with follicular hyperplasia, sinusoidal and medullary infiltration of plasma cells. Immunohistochemistry confirmed positivity for B lymphocytes, T lymphocytes, and plasma cells in sub-capsular and para-follicular areas. The patient was diagnosed as POEMS-associated MCD variant, and chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone was started. The patient did not recover renal function and remained dialysis-dependent. Conclusions: To date, the renal involvement in MCD and POEMS syndrome seems to be uncommon as reported in few case series. Its pathophysiology is not well understood. In the spectrum of MCD, decreased renal function may have impact in patient survival. Early diagnosis and treatment are needed to control the systemic manifestations, and most importantly to avoid chronic organ damage.

Five biopsies, one diagnosis: challenges in idiopathic multicentric Castleman disease

2020 ◽  
Vol 13 (11) ◽  
pp. e236654
Author(s):  
Julie Semenchuk ◽  
Asad Merchant ◽  
Ali Sakhdari ◽  
Vishal Kukreti
Keyword(s):  
Lymph Node ◽  
Kidney Injury ◽  
Lymph Node Biopsy ◽  
Castleman Disease ◽  
Pleuritic Chest Pain ◽  
Multicentric Castleman Disease ◽  
Node Biopsy ◽  
Significant Clinical Improvement ◽  
Night Sweats ◽  
Inflammatory Changes

A previously healthy 29-year-old man initially presented to the hospital with pleuritic chest pain and shortness of breath. Over the next 2 months he developed ongoing fevers and night sweats with recurrent exudative pleural effusions and ascites. He had an extensive infectious and autoimmune workup that was unremarkable. He had an initial lymph node biopsy that showed reactive changes only. He had an acute kidney injury and his renal biopsy revealed thrombotic microangiopathy. His liver biopsy showed non-specific inflammatory changes. His bone marrow biopsy showed megakaryocyte hyperplasia and fibrosis, which raised suspicion for the thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction and organomegaly syndrome subtype of multicentric Castleman disease. This prompted a repeat lymph node biopsy, showing changes consistent with mixed type Castleman disease that fit with his clinical picture. He was initiated on steroids and siltuximab with significant clinical improvement.

Human Herpesvirus Type 8-positive Multicentric Castleman Disease

2016 ◽  
Vol 16 ◽  
pp. S159-S165 ◽  
Author(s):  
Anait L. Melikyan ◽  
Elena K. Egorova ◽  
Hunan L. Julhakyan ◽  
Alla L. Kovrigina ◽  
Valeriy G. Savchenko
Keyword(s):  
Human Herpesvirus ◽  
Castleman Disease ◽  
Herpesvirus Type ◽  
Multicentric Castleman Disease ◽  
Human Herpesvirus Type

Distinct Human and Viral Interleukin-6 Profiles and Other Viral and Immunologic Abnormalities In KSHV-Associated Multicentric Castleman Disease: Relationship with Disease Activity and Individual Disease Manifestations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1573-1573
Author(s):  
Mark N Polizzotto ◽  
Thomas S Uldrick ◽  
Victoria Wang ◽  
Karen Aleman ◽  
Kathleen M Wyvill ◽  
...  
Keyword(s):  
Disease Activity ◽  
Respiratory Symptoms ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Human Herpesvirus ◽  
Castleman Disease ◽  
Multicentric Castleman Disease ◽  
Tnf Α ◽  
Gi Symptoms ◽  
Individual Disease

Abstract Abstract 1573 Background: Multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder characterized by flares of severe inflammatory symptoms, including fever and cachexia, with cytopenias and biochemical abnormalities. In the idiopathic form, its pathogenesis is linked to overproduction of interleukin (IL)-6. A distinct form of MCD is caused by Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus [HHV]-8). KSHV encodes a viral homolog of IL-6, vIL-6, and this has been hypothesized to be central to KSHV-MCD pathogenesis. However, viral and human cytokines have not been examined together in KSHV-MCD, and their contribution to disease activity and symptoms is not known. Methods: Patients with pathologically-proven KSHV-MCD were enrolled on a prospective natural history study incorporating pilot evaluation of novel therapies (NCT00099073). Factors potentially important in pathogenesis were assayed at flare and complete clinical and laboratory remission: KSHV viral load (VL) in peripheral blood mononuclear cells, vIL-6, IL-1β, IL-5, human IL-6 (hIL-6), IL-8, IL-10, IL-12p70, IFN-γ and TNF-α. Paired analyses were performed for each patient comparing initial flare and remission. Associations between cytokines and individual disease manifestations were explored across all flares. Results: 21 patients had at least one flare for analysis (19 [90%] male; med age 44 [range 29–52]). 34 flares were observed (range 1–3 per patient) and followed to remission (20 patients) or death (1). All were HIV infected: CD4 med 252cells/μL (range 24–1319), HIV VL med <48 copies/mL (<48–64,100), 94% receiving antiretrovirals. Clinical symptoms included fever (present in 62%, med 38°C [range 36.1–40.5]); fatigue (91%, med CTC grade 2 [0–3]), gastrointestinal (GI) symptoms (68%, med grade 1 [0–3]) and respiratory symptoms (61%, med grade 1 [0–2]). Laboratory findings included anemia (97%, 9.9g/L [6.8–14.4]), thrombocytopenia (68%, 100×103cells/μL [6–567]), hypoalbuminemia (97%, 2.7g/L [1.2–3.9]) hyponatremia (68%, 133mEg/L [127–143]) and C-reactive protein (CRP) elevation (100%, 87.3g/L [6.3–339.5]). Factors elevated during initial flares were: KSHV VL (med 14,700/106 PBMCs [range 0–3,913,000] P <0.0001 compared with remission); vIL-6 (detected in 48%, <1560pg/mL [<1560-20,500] P= 0.0039); hIL-6 (15.9pg/mL [1.4-171.5] P= 0.0006); IL-10 (449pg/mL [2.8-85,900] P= 0.0007); TNF-α (29.0 pg/ml [7.9–90.8] P= 0.0083) and IL-1β (1.2 pg/ml [0.1–5.7] P= 0.0027). IL-5 was decreased compared with remission (0.6 [0.1–15.4] P= 0.016). Differences were most marked for vIL-6 (undetectable in all remissions), hIL-6 (med increase from remission 520%) and IL-10 (med increase from remission 5000%). KSHV VL was correlated with hIL-6 (R = 0.68, P= 0.001) and IL-10 (R=0.82, P= 0.001) across all flares and remissions; other correlations were weaker. There was also a strong association between KSHV VL and vIL-6 (P= 0.001 by Jonckheere-Terpstra). For hIL-6 and vIL-6 only, we observed distinct profiles across flares: vIL-6 elevation only (2 flares, 6%), hIL-6 only (17 flares, 50%), and hIL-6 with vIL-6 (13 flares, 38%). In 2 flares (6%), neither vIL-6 nor hIL-6 were detected at onset, but in both hIL-6 alone soon became elevated. In contrast, KSHV VL, IL-10, TNF-α and IL-1β were consistently elevated during flares. Compared with hIL-6-only flares, hIL-6 with vIL-6 flares exhibited significantly higher CRP (P =0.0009); worse hyponatremia (P =0.02); higher KSHV VL (P =0.016) and IL-10 (P= 0.012); and lower IL-5 (P= 0.009). In linear/logistic regression models of disease manifestations with cytokines, best predictors were: GI symptoms, respiratory symptoms, temperature, platelet count: hIL-6 alone; hemoglobin: hIL-6 and vIL-6; sodium: hIL-6, vIL-6 and IL-10; albumin: IL-1β and vIL-6. Conclusions: This prospective analysis shows for the first time that vIL-6 and hIL-6 can independently or together lead to flares of KSHV-MCD. It shows novel associations of KSHV-MCD flares with IL-1β and TNF-α elevation and IL-5 depression while confirming associations with KSHV VL and IL-10. It further suggests that vIL-6 and hIL-6 may jointly contribute to the severity of some symptoms during flares. As vIL-6 can signal independently of the ligand-binding IL-6 receptor-a, these findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. Disclosures: No relevant conflicts of interest to declare.

Polynesian Variant Of Idiopathic Multicentric Castleman Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5127-5127 ◽  
Author(s):  
Shaun Zhai ◽  
David Simpson
Keyword(s):  
Patient Group ◽  
Chemotherapeutic Agents ◽  
Castleman Disease ◽  
Controlled Study ◽  
Time Interval ◽  
High Morbidity ◽  
Durable Response ◽  
Multicentric Castleman Disease ◽  
Study Results ◽  
The Mean

Abstract Multicentric Castleman Disease (MCD) is an uncommon non-clonal lymphoproliferative disease that traditionally has high morbidity and carries a poor prognosis, with median survival of 26-30 months. There has been growing interest in using interleukin-6 (IL-6) as a therapeutic target due to its role in the pathogenesis of MCD. In our practice, we noted a high number of Polynesian patients with idiopathic MCD (iMCD) and their prognosis appeared good. We therefore carried out a retrospective review. Via email survey, laboratory audit and our local database we identified 13 patients with MCD. Twelve patients were HIV and HHV8 negative hence classified as having iMCD; one patient was positive for HIV and HHV8. Of the twelve patients with iMCD (five females, seven males), the median age at diagnosis was 53 (41 - 70). Eleven patients had plasma cell variant; one patient’s MCD subtype was not available. 83.3% (10 of 12 patients) were of Polynesian decent: New Zealand Maori (4), Samoan (3), and Niuean (3). Polynesian subjects had fewer general symptoms compared to literature: weight loss 40%, fever 20%;  Skin lesions were observed in 60%, 60% had splenomegaly and 40% had polyarthrialgia related to MCD. There is a recognized association between autoimmune disease and MCD. In our series, 6 of the 12 patients had some form of autoantibodies, including antinuclear antibodies, extractable nuclear antibodies and anti-cardiolipin antibodies; however only 2 patients had confirmed autoimmune diseases, with Grave’s disease in one and concurrent autoimmune haemolytic anaemia and coeliac disease in another patient. The median baseline gammaglobulin (IgG) was 61g/L (12- 96), C-reactive protein (CRP) was 105mg/L (39 - 219) and hemoglobin (Hb) was 89g/L (50 - 118), excluding one Polynesian patient who was an outlier with a CRP of 1 and Hb of 140. We traced pre-diagnosis electronic records of biochemical markers, such as total protein and total globulin levels, an indirect marker for hypergammaglobulinaemia. We could not find a normal value amongst the Polynesian patient group prior to the diagnosis, abnormalities were noted up to 6 years pre-diagnosis. Despite the biochemical derangement of most patients, performance status was high and 80% of the Polynesian patients remained at work. The mean duration of disease after tissue diagnosis was 5.3 years whereas the mean duration of biochemical evidence of disease presence was 9.2 years. Various therapies including corticosteroid (dexamethasone or prednisone), Rituximab and chemotherapeutic agents were used with mixed but mostly non-durable response until 2009 when those needing treatment were given targeted treatment to block IL-6 with Tocilizumab (6) or Siltuximab (2 in a randomized double-blind placebo controlled study; results will be presented separately). Tocilizumab was administered as an intravenous infusion (at 8mg/kg) in a 3-4 weekly cycle. We used CRP as a measure of the response to treatment. By aiming for a low CRP (i.e. less than 20mg/L) rather than a normal CRP value, at the end of each cycle, we were able to increase the time interval between treatment cycles and therefore rationalize treatment frequency. The median duration of therapy was 19 months during which we saw normalization of Hb in 6/6 of patients, their median hemoglobins increasing from 87g/L (69 - 140) to 133g/L (118 - 157). There were significant improvement of IgG from 65g/L (42 - 96) to 32g/L (17 - 59); CRP from 86mg/L (39 - 160) to 4mg/L (1 - 23). Treatment was stopped in 2/6 patients with subsequent relapse, and response to tocilizumab retreatment. There were three deaths in the entire patient group, only 1/10 Polynesian, and all three patients died before IL-6 specific therapy became available. Because most patients had high levels of IgG, we reviewed all patients tested at North Shore Hospital in the past 3 years with a polyclonal increase of IgG>35g/l and identified 3 further patients, all Polynesian, with blood test consistent with iMCD. Clinical follow-up on these patients was not available. Our review demonstrates a disproportionately large group of Polynesians with iMCD, with distinctively favourable disease outcome. iMCD shows promising response to IL-6 targeted therapy. Based on the chronicity of the IgG elevation and the genetic association, we speculate that the up-regulation of IL-6 could be related to a defect in IL-6 regulation. Similar clinical cases have also been described in Japan. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Kaposi sarcoma–associated herpesvirus/human herpesvirus 8–associated lymphoproliferative disorders

Blood ◽  
2019 ◽  
Vol 133 (11) ◽  
pp. 1186-1190 ◽  
Author(s):  
Eric Oksenhendler ◽  
David Boutboul ◽  
Lionel Galicier
Keyword(s):  
B Cells ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
Kaposi Sarcoma ◽  
Castleman Disease ◽  
Lymphoproliferative Disorders ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Multicentric Castleman Disease ◽  
Infected Cells

Abstract Kaposi sarcoma–associated herpesvirus/human herpesvirus 8 is associated with multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL). In MCD, infected B cells, although polyclonal, express a monotypic immunoglobulin Mλ phenotype, probably through editing toward λ light chain in mature B cells. They are considered to originate from pre–germinal center (GC) naive B cells. Both viral and human interleukin-6 contribute to the plasmacytic differentiation of these cells, and viral replication can be observed in some infected cells. PEL cells are clonal B cells considered as GC/post-GC B cells. One can also hypothesize that they originate from the same infected naive B cells and that additional factors could be responsible for their peculiar phenotype.

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