Increased mTOR activation in idiopathic multicentric Castleman disease

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for nonresponders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported 3 anti-IL-6 nonresponders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N = 26) compared with control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and readouts of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared with Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Gene set enrichment analysis of serum proteomic data from iMCD patients (n = 88) and controls (n = 42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T cells from iMCD remission samples compared with healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT03933904).

Download Full-text

Increased mTORC2 Pathway Activation in Lymph Nodes of Imcd-Tafro

Blood ◽

10.1182/blood-2021-146821 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4316-4316

Author(s):

Alexis D Phillips ◽

Joseph K Kakkis ◽

Patricia Y Tsao ◽

Sheila K Pierson ◽

David C Fajgenbaum

Keyword(s):

Lymph Nodes ◽

Therapeutic Target ◽

Study Drug ◽

Cell Types ◽

Castleman Disease ◽

Sustained Remission ◽

Multicentric Castleman Disease ◽

Pathway Activation ◽

Life Threatening ◽

Normal Controls

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving polyclonal lymphoproliferation and organ dysfunction due to excessive cytokine production, including interleukin-6 (IL-6). Anti-IL-6 therapy is recommended first-line and effective in 34-45% of patients. mTOR, which functions through mTORC1 and mTORC2, is a recently-discovered therapeutic target. The mTOR inhibitor sirolimus, which preferentially inhibits mTORC1, has led to sustained remission in a small cohort of anti-IL-6 refractory iMCD patients with thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO). However, sirolimus has not shown uniform effect, potentially due to its limited mTORC2 inhibition. To investigate mTORC2 activation in iMCD, we quantified the mTORC2 effector protein pNDRG1 by immunohistochemistry of lymph node tissue from iMCD-TAFRO (N=6) patients and iMCD patients not meeting TAFRO criteria (iMCD-NOS; N=8) (Table 1) as well as autoimmune lymphoproliferative syndrome (ALPS) (N=6), Hodgkin lymphoma (positive controls, N=8), and metastasis-free sentinel lymph nodes (normal controls, N=8). In iMCD-TAFRO, pNDRG1 expression was elevated in the interfollicular space (IF) (P=0.005), germinal centers (GC) (P=0.002), and mantle zones (MZ) (P=0.007) relative to normal controls (Figure 1A). pNDRG1 staining was increased in the IF (P=0.005) of iMCD-NOS relative to normal controls and there was no difference in the GC (P=0.59) and the MZ (P=0.30) (Figure 1B). Next, we compared pNDRG1 expression in iMCD-TAFRO and iMCD-NOS to ALPS, an mTOR-driven, sirolimus-responsive lymphoproliferative disorder.Our results revealed increased pNDRG1 staining in iMCD-TAFRO GC relative to ALPS (P=0.02) (Figure 1C). There were no differences in pNDRG1 expression between iMCD-NOS and ALPS in any region (Figure 1C). Notably, the strongly positive pNDRG1 cells had spindle-shaped morphology resembling stromal cells (Figure 1H). These results suggest increased mTORC2 activity in iMCD and that dual mTORC1/mTORC2 inhibitors may be a rational therapeutic approach for anti-IL-6 treatment refractory patients. Further studies are needed to confirm this finding, uncover cell types showing increased mTORC2 expression, and investigate therapeutic approaches. Figure 1 Figure 1. Disclosures Fajgenbaum: EUSA Pharma: Research Funding; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'; Pfizer: Other: Study drug for clinical trial of sirolimus.

Download Full-text

A novel mouse model expressing human forms for complement receptors CR1 and CR2

10.1101/2019.12.23.887489 ◽

2019 ◽

Author(s):

Harriet M. Jackson ◽

Kate E. Foley ◽

Rita O’Rourke ◽

Timothy M. Stearns ◽

Dina Fathalla ◽

...

Keyword(s):

Mouse Model ◽

Lupus Erythematosus ◽

Transcriptional Profiling ◽

Enrichment Analysis ◽

Cell Number ◽

Gene Set Enrichment Analysis ◽

Human Populations ◽

Complement Cascade ◽

Complement Receptors ◽

Human Complement

AbstractThe complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer’s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known. To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to as CR1long and CR1short) are replicated within this mouse model, along with a CR1 knockout allele (CR1KO). Transcriptional profiling of spleens and brains identifies genes and pathways differentially expressed between mice homozygous for either CR1long, CR1short or CR1KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated by CR1long, but not CR1short or CR1KO. Therefore, this mouse model provides a novel tool for determining the relationship between human-relevant CR1 alleles and disease.Summary StatementWe present the creation and validation of a novel mouse model that expresses human forms of complement cascade regulators CR1 and CR2.

Download Full-text

A novel mouse model expressing human forms for complement receptors CR1 and CR2

BMC Genetics ◽

10.1186/s12863-020-00893-9 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Harriet M. Jackson ◽

Kate E. Foley ◽

Rita O’Rourke ◽

Timothy M. Stearns ◽

Dina Fathalla ◽

...

Keyword(s):

Mouse Model ◽

Lupus Erythematosus ◽

Transcriptional Profiling ◽

Enrichment Analysis ◽

Cell Number ◽

Gene Set Enrichment Analysis ◽

Human Populations ◽

Complement Cascade ◽

Complement Receptors ◽

Human Complement

Abstract Background The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer’s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known. Results To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to here as CR1long and CR1short) can be replicated within this mouse model, along with a CR1 knockout allele (CR1KO). Transcriptional profiling of spleens and brains identified genes and pathways differentially expressed between mice homozygous for either CR1long, CR1short or CR1KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated by CR1long, but not CR1short or CR1KO. Conclusion The B6.CR2CR1 mouse model provides a novel tool for determining the relationship between human-relevant CR1 alleles and disease.

Download Full-text

Effects of IRF5 Lupus Risk Haplotype on Pathways Predicted to Influence B Cell Functions

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/594056 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Joel M. Guthridge ◽

Daniel N. Clark ◽

Amanda Templeton ◽

Nicolas Dominguez ◽

Rufei Lu ◽

...

Keyword(s):

B Cell ◽

Lupus Erythematosus ◽

Enrichment Analysis ◽

Cell Receptor ◽

Gene Set Enrichment Analysis ◽

Interferon Response ◽

Risk Haplotype ◽

Interferon Signature ◽

Cell Functions ◽

Gene Sets

Both genetic and environmental interactions affect systemic lupus erythematosus (SLE) development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5) gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by theIRF5risk haplotype confirmed significant correlation with the interferon pathway, Toll-like receptor pathway, and the B-cell receptor pathway. SLE patients with theIRF5risk haplotype have a heightened interferon signature, even in an unstimulated state (P=0.011), while patients with theIRF5protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE.

Download Full-text

Ongoing Symptoms and Reduced Health Measures in Unicentric Castleman Disease Patients Despite Perceived-to-be Curative Surgical Excision

Blood ◽

10.1182/blood-2021-153756 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2709-2709

Author(s):

Freda R Coren ◽

Mateo Sarmiento Bustamante ◽

Sheila K Pierson ◽

David C Fajgenbaum

Keyword(s):

Lymph Nodes ◽

General Health ◽

Castleman Disease ◽

Index Score ◽

Health Index ◽

Poor General Health ◽

Multicentric Castleman Disease ◽

Health Measures ◽

Night Sweats ◽

Separate Cohort

Abstract Unicentric Castleman disease (UCD) is one of several subtypes of Castleman disease that share characteristic histopathology. While UCD involves one region of enlarged lymph nodes (LN) and milder symptoms, idiopathic multicentric CD (iMCD) involves multiple regions of enlarged lymph nodes and cytokine-driven organ dysfunction. UCD symptoms can occur due to compression of neighboring structures or inflammatory cytokine production. Complete excision of the enlarged LN is reported in the literature to be curative in 84-96% of UCD patients. However, many UCD patients describe persistence or worsening of symptoms post excision despite normal laboratory values and absence of measurable disease. To better characterize and describe the experience of individuals diagnosed with UCD, we administered surveys to UCD patients to capture information about general quality of life (QOL), specific health measures, and ongoing UCD symptoms. All patients enrolled in the ACCELERATE Natural History registry who either self-reported a UCD diagnosis or were suspected to have a UCD diagnosis were invited to participate in the Rand36-item Short Form survey, the EQ-5D-5L, the MCD Symptom Score survey, all of which are validated instruments, as well as an additional form regarding ongoing symptoms. Among the 107 UCD patients invited to participate, 51 (48%) responded. Descriptive analyses were conducted on all 51 respondents with a self-reported UCD diagnosis. Subsequently, a subset consisting of 25 respondents, who had been reviewed by a panel of physicians that confirmed a UCD diagnosis (confirmed subcohort, CS), was analyzed. Mean (SD) EQ-5D-5L health index score (100 being perfect health, 0 being worst health imaginable) of the 51 patients was 67.6 (19.9), compared to a representative sample of the US population whose score was 80.4. Patients reported having poor health over the prior 4 weeks, with low scores indicating high levels of fatigue (38.8) and poor general health (47.7). These are notable and comparable to scores for fatigue (52.2) and general health (57.0) among a separate cohort of patients with diabetes, hypertension, coronary heart disease, and/or depression. Strikingly, 57% of patients reported continuation of symptoms post-LN excision, with an additional 16% being unsure. Only 29% reported complete symptom resolution, with the remainder reporting partial resolution (29%), stable disease (20%), worsening disease (12%), or unsure (10%). Nearly all 51 respondents underwent their LN-excision >1 year prior (93%). Fatigue (61%) and night sweats (39%) were most commonly reported in patients with continued symptoms. In fact, 27 patients (53%) reported ongoing symptoms on the day of survey completion with 93% of those patients reporting fatigue that day. Of note, sub-group analyses of the CS revealed similar findings, with a potential trend towards slightly better overall health with mean (SD) health index score 72.6 (14.5), fatigue (44%) and night sweats (36%), and ongoing symptoms reported in 40%. Of the patients in the CS, all had a complete resection, with 3 demonstrating subsequent lymphadenopathy in new regions ranging from 6 months to 5 years after their initial excision. Overall, these data suggest that UCD patients who have had resection of disease continue to experience symptoms that affect QOL. Patients reported lower QOL than a representative national average, as well as health measures comparable to a separate cohort of individuals with chronic health conditions. Of note, the full cohort of self-reported individuals consistently reported lower scores compared to the subset of patients with confirmed UCD (not statistically tested). Of the 26 non-confirmed cases, 8 did not achieve criteria to meet UCD and 18 have not yet been reviewed by our physician panel. A different undiagnosed disorder may be the root cause of symptoms in a portion of these patients and others may be experiencing symptoms due to a co-occurring disorder. These results may be confounded by reporting bias and may not be representative of the full UCD population. Nevertheless, these data suggest that perceived-to-be curative excision does not result in symptom-free outcomes in a substantial proportion of patients and that symptom management may be required beyond excision. Future work is needed to correlate these findings with clinical, laboratory, and experimental data to further elucidate mechanisms and treatment options. Disclosures Fajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'.

Download Full-text

A review of digital cytometry methods: estimating the relative abundance of cell types in a bulk of cells

Briefings in Bioinformatics ◽

10.1093/bib/bbaa219 ◽

2020 ◽

Cited By ~ 2

Author(s):

Trang Le ◽

Rachel A Aronow ◽

Arkadz Kirshtein ◽

Leili Shahriyari

Keyword(s):

Gene Expression ◽

Gene Expression Profile ◽

Expression Profile ◽

Single Cells ◽

Enrichment Analysis ◽

Cell Types ◽

Gene Set Enrichment Analysis ◽

Single Sample ◽

Batch Correction ◽

Signature Matrix

Abstract Due to the high cost of flow and mass cytometry, there has been a recent surge in the development of computational methods for estimating the relative distributions of cell types from the gene expression profile of a bulk of cells. Here, we review the five common ‘digital cytometry’ methods: deconvolution of RNA-Seq, cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), CIBERSORTx, single sample gene set enrichment analysis and single-sample scoring of molecular phenotypes deconvolution method. The results show that CIBERSORTx B-mode, which uses batch correction to adjust the gene expression profile of the bulk of cells (‘mixture data’) to eliminate possible cross-platform variations between the mixture data and the gene expression data of single cells (‘signature matrix’), outperforms other methods, especially when signature matrix and mixture data come from different platforms. However, in our tests, CIBERSORTx S-mode, which uses batch correction for adjusting the signature matrix instead of mixture data, did not perform better than the original CIBERSORT method, which does not use any batch correction method. This result suggests the need for further investigations into how to utilize batch correction in deconvolution methods.

Download Full-text

Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease

Blood Advances ◽

10.1182/bloodadvances.2020004016 ◽

2021 ◽

Vol 5 (17) ◽

pp. 3445-3456

Author(s):

Sheila K. Pierson ◽

Sushila Shenoy ◽

Ana B. Oromendia ◽

Alexander M. Gorzewski ◽

Ruth-Anne Langan Pai ◽

...

Keyword(s):

Therapeutic Target ◽

Immunoglobulin E ◽

Multiorgan Failure ◽

Human Herpesvirus ◽

Castleman Disease ◽

Janus Kinase ◽

Multicentric Castleman Disease ◽

Hematologic Disorder ◽

Established Disease ◽

Response Biomarkers

Abstract Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti–IL-6 therapy, siltuximab, is the only US Food and Drug Administration–approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8–associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.

Download Full-text

Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer

BMC Cancer ◽

10.1186/s12885-021-07995-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jingyi Chen ◽

Yuxuan Song ◽

Mei Li ◽

Yu Zhang ◽

Tingru Lin ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Target Genes ◽

Immune Cell ◽

Pearson Correlation ◽

Enrichment Analysis ◽

Cell Types ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cerna Network

Abstract Background Competing endogenous RNA (ceRNA) represents a class of RNAs (e.g., long noncoding RNAs [lncRNAs]) with microRNA (miRNA) binding sites, which can competitively bind miRNA and inhibit its regulation of target genes. Increasing evidence has underscored the involvement of dysregulated ceRNA networks in the occurrence and progression of colorectal cancer (CRC). The purpose of this study was to construct a ceRNA network related to the prognosis of CRC and further explore the potential mechanisms that affect this prognosis. Methods RNA-Seq and miRNA-Seq data from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed lncRNAs (DElncRNAs), microRNAs (DEmiRNAs), and mRNAs (DEmRNAs), and a prognosis-related ceRNA network was constructed based on DElncRNA survival analysis. Subsequently, pathway enrichment, Pearson correlation, and Gene Set Enrichment Analysis (GSEA) were performed to determine the function of the genes in the ceRNA network. Gene Expression Profiling Interactive Analysis (GEPIA) and immunohistochemistry (IHC) were also used to validate differential gene expression. Finally, the correlation between lncRNA and immune cell infiltration in the tumor microenvironment was evaluated based on the CIBERSORT algorithm. Results A prognostic ceRNA network was constructed with eleven key survival-related DElncRNAs (MIR4435-2HG, NKILA, AFAP1-AS1, ELFN1-AS1, AC005520.2, AC245884.8, AL354836.1, AL355987.4, AL591845.1, LINC02038, and AC104823.1), 54 DEmiRNAs, and 308 DEmRNAs. The MIR4435-2HG- and ELFN1-AS1-associated ceRNA subnetworks affected and regulated the expression of the COL5A2, LOX, OSBPL3, PLAU, VCAN, SRM, and E2F1 target genes and were found to be related to prognosis and tumor-infiltrating immune cell types. Conclusions MIR4435-2HG and ELFN1-AS1 are associated with prognosis and tumor-infiltrating immune cell types and could represent potential prognostic biomarkers or therapeutic targets in colorectal carcinoma.

Download Full-text

A kinase-independent role for CDK8 in BCR-ABL1+ leukemia

Nature Communications ◽

10.1038/s41467-019-12656-x ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Ingeborg Menzl ◽

Tinghu Zhang ◽

Angelika Berger-Becvar ◽

Reinhard Grausenburger ◽

Gerwin Heller ◽

...

Keyword(s):

Drug Targets ◽

Enrichment Analysis ◽

Mtor Inhibitors ◽

Gene Set Enrichment Analysis ◽

Leukemic Cells ◽

Mtor Inhibition ◽

Cyclin Dependent Kinases ◽

Highly Sensitive ◽

Transcriptional Changes ◽

Human Leukemic Cells

Abstract Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. We provide evidence that CDK8 has a key role in B-ALL. Loss of CDK8 in leukemia mouse models significantly enhances disease latency and prevents disease maintenance. Loss of CDK8 is associated with pronounced transcriptional changes, whereas inhibiting CDK8 kinase activity has minimal effects. Gene set enrichment analysis suggests that the mTOR signaling pathway is deregulated in CDK8-deficient cells and, accordingly, these cells are highly sensitive to mTOR inhibitors. Analysis of large cohorts of human ALL and AML patients reveals a significant correlation between the level of CDK8 and of mTOR pathway members. We have synthesized a small molecule YKL-06-101 that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. We propose that simultaneous CDK8 degradation and mTOR inhibition might represent a potential therapeutic strategy for the treatment of ALL patients.

Download Full-text

Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease

Blood ◽

10.1182/blood-2018-05-848671 ◽

2018 ◽

Vol 132 (22) ◽

pp. 2323-2330 ◽

Cited By ~ 20

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.

Download Full-text