Project description:Castleman disease (CD) is a rare hematologic disorder involving inflamed lymph nodes and distinct histological features. Unicentric Castleman disease (UCD) and idiopathic multicentric Castleman disease (iMCD) are of particular interest as their etiologies are poorly understood and treatment options are limited. As iMCD patients, and occasionally UCD patients, also present with a cytokine storm, we sought to investigate if the cytokine release from iMCD and UCD subtypes have pathogenic origins as observed in human herpesvirus 8 MCD (HHV-8-MCD). To identify potential active viruses that may be contributing to immune system dysregulation in Castleman Disease tissues we conducted bulk RNA sequencing on FFPE preserved lymph node tissue from patients with various phenotypes including Idiopathic multicentric Castleman disease (n = 9), systemic lupus erythematosus (n =3), diffuse large B cell lymphoma (n =5), and reactive lymph nodes with inconclusive pathology (n = 7).
Project description:Castleman disease is polyclonal lymphoproliferative disorder characterized by unicentric or multicentric lymphadenopathy with characteristic histomorphologic features, in addition to variable inflammatory symptomatology. The molecular mechanisms and etiologies of unicentric Castleman disease (UCD) and idiopathic multicentric Castleman disease (iMCD) are poorly understood, and identification of targetable disease mediators remains an unmet clinical need. We performed whole exome sequencing on lymph node biopsies from patients with UCD and iMCD; and compared the transcriptomic profile to that of benign control lymph nodes. We identified significantly upregulated genes in UCD (443), iMCD (316) or both disease subtypes (51); in addition to downregulated genes in UCD (321), iMCD (105) or both (10). The transcriptomes of UCD and iMCD showed enrichment and upregulation of elements of the complement cascade. By immunohistochemistry, C4d deposits indicative of complement activation were present in UCD and iMCD mostly within abnormally regressed germinal centers, but also in association with plasma cell clusters, endothelial cells and stroma cells proliferations. Other enriched gene sets included collagen organization, S1P3 pathway and VEGFR pathway in UCD; and humoral response, oxidative phosphorylation and proteosome in iMCD. Analysis of cytokine transcripts showed upregulation of CXCL13 but not IL-6 in UCD and iMCD. Among angiogenic mediators, the VEGFR1 ligand placental growth factor (PGF) was upregulated in both disease subtypes. We hereby report for the first time the whole lymph node transcriptome of UCD and iMCD, underscoring findings that could aid in the discovery of targetable disease mediators.
Project description:Idiopathic Multicentric Castleman Disease (iMCD) is a rare IL-6-driven hematological disorder characterized by systemic lymphadenopathy, elevated immunoglobulin levels, and prominent plasmacytosis in the bone marrow and lymph nodes. Here, we present an unusual occurrence of iMCD in identical twins. Using single cell sequencing, we identified nodal endothelial cells and fibroblastic reticular cells as the source of IL-6 signals. An “inflammatory” peripheral monocytosis enriched for the expression of S100A family genes was evident in both twins, as well as a group of monocytes expressing cytotoxic gene signatures in the affected twin with milder clinical manifestations.
Project description:Gene expression profiling of biopsied human lymph node (LN) tissue comparing each patient sample against mobilised peripheral blood stem cells (PBSC), the reference channel Evaluate whether gene expression microarray can diagnose lymph node biopsies as reactive or as one of three main types of lymphoma: classical Hodgkin’s lymphoma (cHL), diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL).
Project description:The aim of the current study is to identify genes that show differential expression within the gastric lymph node of parasite resistant and susceptible sheep. For this we exploited parasite-naïve Blackface lambs with diversity in their predicted genetic resistance to T. circumcincta, which were trickle-infected with L3 larvae to mimic natural infection. This regime resulted in lambs with a spectrum of resistance as assessed by adult worm counts, faecal egg counts and IgA levels. Gastric lymph node tissue was used for transcription profiling of resistant and susceptible lambs to identify genes and physiological pathways associated with the differential activation of the immune response linked to the different disease outcomes.
Project description:Gene expression profiling of biopsied human lymph node (LN) tissue comparing each patient sample against mobilised peripheral blood stem cells (PBSC), the reference channel Evaluate whether gene expression microarray can diagnose lymph node biopsies as reactive or as one of three main types of lymphoma: classical Hodgkin’s lymphoma (cHL), diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL). Two condition experiment, LN vs mobilised PBSC, 116 cases assayed, 1 replicate per array