Scientists at the CSTL published the first ever consensus of iMCD diagnosis guidelines found here. Our ongoing natural history research powered by our ACCELERATE database will allow us to test and improve these guidelines further.

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The cause of hyper-activation of the immune system in iMCD is still unknown. One of the main hypotheses is that an infectious agent, such as a virus or bacteria, triggers the immune system. Our lab is using multiple methods to study lymph node tissue of iMCD patients in order to search for the DNA of viruses, fungi, and bacteria.

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Proteomic quantification of serum samples is allowing us to biochemically characterize the heterogeneity of iMCD and how it fits with other related diseases such as rheumatoid arthritis and Hodgkin lymphoma. Serum analytes may also lead to the development of algorithms that predict which patients would respond to specific treatments (such as IL-6 blockade). Furthermore, serum proteins may signal the hyperactivation of certain biochemical pathways and elucidate them as novel therapeutic targets.

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Human herpesvirus (HHV)-8-negative, idiopathic multicentric Castleman disease (iMCD) is a deadly hematologic illness involving progressive flares of systemic inflammation, polyclonal lymphoproliferation, and multiple organ system dysfunction. Approximately 600-1000 individuals of all ages are diagnosed annually in the USA; 35% die within 5 years. Poor outcomes are related to the limited mechanistic understanding of iMCD. The etiology, dysregulated signaling pathway, and cell type in iMCD are completely unknown. A family with germline FAS mutations in a patient with iMCD and one with UCD has been reported, however very limited research has been performed into genetic risk factors and/or pathogenic variants

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We know that CD is a heterogeneous group of disorders involving systemic inflammation and polyclonal lymphoproliferation, and it is important to note that there are no clonal cell populations that are visible microscopically and no evidence of spreading or “metastasis,” which is often the case with somatically-mutated/clonal malignancies. Nevertheless, given the clinico-pathologic similarities between iMCD and disorders like Hodgkin lymphoma and angioimmunoblastic T-cell lymphoma, the field has long hypothesized that a rare population of somatically mutated clonal cells may be involved in UCD and iMCD pathogenesis. Recently, somatic mutations have been described in a couple studies of unclear/poor quality in patients with UCD and iMCD, suggesting a potential role for somatically mutated cells in pathogenesis.

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In iMCD we still don't know which immune cells or pathways are activated. This study looks for the activated immune cells and cellular pathways. We are examining iMCD lymph node tissue using multiple cutting-edge technologies, such as TCRb sequencing, BCR sequencing, flow cytometry, Whole Exome Sequencing, CyTOF, MIBI, CODEX, and/or single-cell RNASeq. These new technologies will investigate dozens and hundreds of markers to help determine the active cell types and cellular pathways.

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Idiopathic multicentric Castleman disease (iMCD) is a heterogeneous cytokine storm disorder that involves systemic inflammation, multicentric lymphadenopathy with characteristic histopathology, and life-threatening multiple organ dysfunction. Patients can present with a range of symptoms from thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), reticulin myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO) to thrombocytosis, hypergammaglobulinemia, and plasmacytosis (iMCD-IPL); patients not falling into either group are considered iMCD-NOS. Though the etiology of iMCD is unknown, the proinflammatory cytokine interleukin-6 (IL-6) drives disease pathogenesis in a portion of patients. Unfortunately, two-thirds of patients do not respond to anti-IL-6 therapy, the only FDA-approved treatment, and limited treatments exist beyond anti-IL-6 therapy due to poor understanding of pathogenesis. The molecular mechansims of iMCD, particularly within the three clinical subtypes and compared to clinco-pathologically overlapping inflammatory disorders has not been elucidated. Here, we report our findings characterizing quantitative gene expression data using multiple platforms on lymph node tissue from iMCD, pathologically related disorders, and normal controls. The transcriptome of iMCD-TAFRO lymph node tissue identified a number of significantly altered genes involved in angiogenesis, cell proliferation, and orchestration of multiple facets of the humoral and innate immune response. Gene expression data revealed shared upregulation of multiple genes across clinical subtypes of iMCD, supporting a role for shared pathologic mechanisms across iMCD subtypes.

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Neutrophil extracellular traps (NETs) are net-like structures composed of DNA-histone complexes that are released by activated neutrophils, usually in response to bacteria, fungi, or viruses. NETs can be induced by auto-antibodies, and NETs are capable of inducing potent IFN-I production by plasmacytoid dendritic cells and thus a strong IFN-I response in other cells. Increasing evidence suggests that NETs play an important role in autoimmunity including SLE and RA. The purpose of this study is to determine if NETs play a role in the pathogenesis/etiology of iMCD and to gain an initial indication of the potential role of neutrophils in the inflammatory/immune response in iMCD.

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Castleman Disease (CD) is a rare, atypical lymphoproliferative disorder with significant morbidity and mortality and a poorly understood pathophysiology. Defined by a shared lymph node (LN) histology, CD encompasses a wide range of clinical presentations from unifocal adenopathy with mild symptoms (unicentric CD, UCD) to multifocal adenopathy with a systemic inflammatory cytokine storm driving multi-organ dysfunction (multicentric CD, MCD). MCD can be further divided into human herpesvirus (HHV)-8-associated MCD and HHV-8-negative/idiopathic MCD (iMCD). Disease etiology, pathophysiology, including the identity of the pathogenic cells and transcriptional programs, remains largely unknown. Thus, a fundamental question in CD is whether an etiological mechanism of iMCD is an infectious disease, an inflammatory disease, or an autoimmune disease. In this study, we hypothesized that autoantibodies may be driving iMCD pathology in at least a subset of iMCD patients.

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