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Correspondence to Author: Zrits van Mhee, 

Zrits van Mhee, University of Arkansas for Medical Sciences.

Introduction: Two germ line mutations that may contribute to the development of iMCD are described by Chan et al. Each twin had heterozygous mutations in the tumor necrosis factor receptor-associated factor (TRAF) gene and homozygous mutations in the nuclear receptor cooperator 4 (NCOA4) gene. You et al. previously reported variants in NCOA4 in 5 out of 22 patients (23%) with iMCD.2. Even though You et al. classified those variants as probably somatic, their unique approach of using external patient controls for somatic variant calling and the variant allele frequency of roughly 50% in each case imply that those variants in that study are most likely germ line heterozygous variants. This route can also be triggered by interleukin-6 (IL-6), and it has been proposed that the interaction between androgen receptor-associated proteins such NCOA4 and MAPK may improve it.Two TRAF mutations have been connected to aberrant immunity, higher risk for B-cell malignancies, enhanced inflammatory response, and B-cell dysregulation and hyperactivity. The fact that the two twins’ clinical phenotype and the development of iMCD did not occur at the same time raises interesting possibilities about the interaction of unknown environmental triggers with a genetic background.
Many hematologic conditions with comparable lymph node histological characteristics are together referred to as Castleman disease (CD). In general, CD can be classified as either unicentric or multicentric based on the degree of lymphadenopathy. Human herpes virus type 8 (HHV8) is the primary cause of many multicentric CD cases; it usually occurs in the context of immunosuppression (HHV8- associated multicentric CD); nevertheless, in some cases, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin abnormalities) syndrome (POEMS syndrome–associated multicentric CD) coexists with immunosuppression. Nevertheless, no cause is found in about 50% of instances; these patients are now classified as having iMCD. The cytokine-driven inflammatory syndrome linked to iMCD, which frequently involves IL-6, is responsible for fevers, sweats at night, and other constitutional symptoms. It also causes abnormalities in laboratory tests, including high levels of C-reactive protein, erythrocyte sedimentation rate, and hypergammaglobulinemia. Organ dysfunction, including renal failure, or even death, may occur in extreme circumstances. Lately, Under the direction of the Castleman Disease Collaborative Network (CDCN), an expert group has made progress in developing international consensus criteria for the diagnosis of Castleman.3. Similar to this, the CDCN has developed worldwide consensus treatment guidelines, according to which siltuximab monoclonal antibody therapy is advised as the first line of treatment for neutralizing the cytokine IL-6.

Citation:

Zrits van Mhee. New perspectives on the origins of Castleman illness.. The American Journal of Hematology 2024.