Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening hematologic illness involving uncontrolled systemic inflammation due to unknown causes. Hallmark features of iMCD include multiple enlarged lymph nodes with characteristic histopathology, polyclonal lymphoproliferation, and the release of pro-inflammatory cytokines including interleukin-6 (IL-6) that can lead to multi-organ dysfunction and death. The only FDA-approved drug for iMCD, siltuximab, blocks IL-6 and is effective in treating a portion of patients suggesting other key cytokines may contribute to iMCD pathogenesis.

To uncover other potential pathogenic mediators, we analyzed 1,178 serum analytes in the blood of iMCD patients (n=88) compared to healthy donors (n=42) and other inflammatory disease controls, including rheumatoid arthritis (n=20), Hodgkin lymphoma (n=20), and HHV-8-associated multicentric Castleman disease (n=20). We discovered evidence of elevated activity of interferon gamma (IFNγ), a pro-inflammatory cytokine critical for innate and adaptive immunity. Included among the top most up-regulated cytokines and chemokines in iMCD compared to healthy donors were several IFNγ-inducible proteins such as interleukin-18 binding protein (IL-18BP) and chemokines CXCL9 and CXCL11 that are well defined markers of IFNγ activity. These markers are considered to be more robust indicators of IFNγ activity than circulating levels of IFNγ due to the often locally acting and complicated nature of IFNγ signaling. Expression of IL-18BP was also significantly up-regulated in iMCD compared to rheumatoid arthritis and Hodgkin lymphoma. These data suggest that increased IFNγ signaling may contribute to the cytokine storm in iMCD, potentially unlocking a new mechanistic regulator of disease.

To determine if IL-6, the only cytokine known to be involved in iMCD pathogenesis, influenced the expression of IFNγ-induced proteins, we quantified IL-18BP in iMCD patients before and after IL-6 blockade with siltuximab (n=52). We discovered that expression of IL-18BP was associated with response to treatment: expression of IL-18BP decreased in iMCD patients who improved with IL-6 inhibition whereas levels of IL-18BP remained elevated among non-responders. These data indicated that IL-18BP levels and thus IFNγ activity could serve as potential indicators of treatment response. Furthermore, these data show that IL-18BP levels in iMCD can be either IL-6 dependent or independent suggesting that IFNγ signaling is a major pathway involved in iMCD and a novel therapeutic target.

The clinical presentation of iMCD is similar to that of hemophagocytic lymphohistiocytosis (HLH), a cytokine-storm disorder resulting from the over production of IFNγ that can be treated with IFNγ inhibition. In addition, both inflammatory disorders are associated with an increase in cell populations that produce IFNγ, including activated CD8 T cells and NK cells. Given the similarities between iMCD and HLH, we compared the expression of the IFNγ-induced protein, IL-18BP, in iMCD to a previously published dataset that included serum from patients with macrophage activated syndrome (MAS), a subtype of HLH associated with autoimmune disorders. We discovered comparable levels of IL-18BP between iMCD and MAS further indicating that similar to HLH, high levels of IFNγ activity are characteristic of iMCD and may play a mechanistic role in disease pathogenesis.

Finally, previously published single-cell RNA sequencing data from our group showed that IFNγ signaling was up-regulated in every circulating cell population profiled in iMCD during active disease suggesting that IFNγ signaling is activated in immune cells in the blood, likely from high levels of IFNγ. Herein, we present evidence that increased IFNγ activity is characteristic of iMCD and propose IFNγ signaling as an underappreciated pathway and key mechanism underlying iMCD and potential therapeutic target.

Fajgenbaum:EUSA Pharma: Consultancy, Research Funding.

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Asterisk with author names denotes non-ASH members.

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