Idiopathic Multicentric Castleman Disease : TAFRO Lymph Nodes Demonstrate Increased phospho-4EBP1 Expression Compared to Controls
Srkalovic, Maya B.
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Castleman Disease (CD) is a devastating, rare disease involving systemic inflammation and characteristic features of the enlarged lymph nodes. CD includes many different subtypes, one of which is idiopathic multicentric CD (iMCD). There are several symptoms associated with iMCD including: multiple regions of enlarged lymph nodes, fluid accumulation, fevers, and enlarged liver and spleen. iMCD has no known cause, and treatment options are currently insufficient. Siltuximab is the only FDA approved treatment for iMCD, and was found to be successful in 33% of patients. The other 67% of patients still do not have an effective treatment. Recent research data has implicated P13K/Akt/mTOR pathway activation as a possible driver of iMCD pathogenesis. Expression of one marker of this pathway, phosphorylated S6 (pS6), has been previously studied in iMCD lymph nodes. However, it is possible the phosphorylation of S6 could occur through an mTOR-independent pathway, so other markers needed to be studied. To investigate PI3K/Akt/mTOR pathway through an alternate marker, phosphorylated eukaryotic translation initiation factor 4E-binding protein (4E-BP1) was studied. Phospho-4E-BP1 (p4EBP1) is a marker that is parallel to and independent of pS6. Immunohistochemistry was performed on iMCD and control lymph nodes to detect expression of p4E-BP1. Analysis of the lymph nodes were done by region, since each region of the lymph node contains different cell types and immunological functions. The regions were the germinal center, mantle zone, follicle, and the interfollicular zone. It was hypothesized that the interfollicular zone of the iMCD lymph nodes would express higher levels of p4E-BP1 than the controls based on previous results from pS6. We determined that the interfollicular zone expressed higher levels of p4E-BP1 in iMCD lymph nodes. This finding further supports that there is increased PI3K/Akt/mTOR pathway activation in iMCD, which has important implications for iMCD diagnosis and treatment.