Cryptococcosis in a sarcoidosis patient with impaired response to IL-2

Abstract

Introduction: The incidence of Cryptococcus infections (CI) is increased in sarcoidosis (Bernard et al. QJM 2013;106). There is no explanation for this increased risk of opportunistic infections in sarcoidosis.

Methods: We present the results of a whole exome sequencing (WES) of a patient with a history of sarcoidosis and CI at the age of 18. The sarcoidosis begun with lung and mediastinal involvement rapidly improving under corticosteroids (CS). The patient presented deep lymphopenia which intriguingly did not respond to CS. Seven months later, he developed neuro meningeal CI.

Results: In the WES study, variants were considered to be relevant if their minor allele frequency was under 0.01. Pathogenicity was determined in silico with Sift and Polyphenv2. We found a pathogenic variant of FER which encodes a STAT3 regulating kinase and CARMIL2 which regulates Rac1, a major negative regulator of autophagy, and interleukin-2 (IL-2) pathway. Our patient presented impaired T-cell proliferation to phytohemagglutinin and/or IL-2 although IL-2R was normally expressed among T cells. He was unresponding to rhIL-2 suggesting an intracellular pathway deficiency. FER regulates IL-2 through STAT3 which activates IL-2 promoter. Moreover, CARMIL2 deficiency is associated with immunodeficiency in humans (Schober et al. Nat Commun 2017;8). Finally, CARMIL2 interacts with CD28, a co-signaling element in T cells, which function could be impaired in sarcoidosis patients.

Conclusion: We speculate that IL-2 axis dysregulation through the accumulation of pathogenic variants in IL-2 regulating genes is responsible for our patient immunodeficiency. This provides clues to understand the subjacent immunosuppression in sarcoidosis.