Impaired RASGRF1/ERK–mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians

Abstract

Hypomorphic CARD9 deficiency caused by p.Y91H results in adult-onset disease with variable penetrance and expressivity. Our findings establish the CARD9/RASGRF1/ERK/GM-CSF axis as critical to the pathophysiology of sCNSc.

Immunity against fungi

“…In this cohort, mutant CARD9 was impaired in its ability to complex with RASGRF1, but not with BCL10 and MALT1 (165). The mechanism by which these cytokines bypass the CARD9-dependent immune defect in this cohort and the generalizability of this protection in other CARD9-deficient patients remain to be elucidated.…”

30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology

“…Therefore, it is still controversial whether the NF-κB signaling defect in the CARD9 deficient patient cells is CBM-dependent or not. Moreover, CARD9-deficient cells showed blunted GMCSF responses mediated by the ERK signaling pathway, reminiscent of defects in neutrophil killing and recruitment defects reported in CARD9 deficient patients (Gavino et al, 2016). CARD9 deficient patients also have decreased Th17 T cells, which are crucial for controlling mucosal, but not systemic candidiasis (Glocker et al, 2009).…”

Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals

“…Cerebrospinal fluid (CSF) analysis typically reveals a mononuclear cell (lymphocytes and/or mononuclear cells) predominance; eosinophil pleocytosis but no neutrophil pleocytosis in most cases; high protein concentration; and hypoglycorrhachia. Three cases of C. albicans osteomyelitis [56,61,64], two of which were associated with endophthalmitis, one case of intra-abdominal (liver and mesenteric lymph nodes) candidiasis [57], and two cases of severe Candida colitis [52] have also been reported (Table 2). Three of the 16 patients died [22].…”

“…The existence of this pathway was subsequently confirmed in humans, as, following zymosan stimulation, CARD9-deficient PBMCs display lower levels of ERK activation and, consequently, impaired granulocyte-monocyte colony-stimulating factor (GM-CSF) production (Figure 2). The success of adjuvant GM-CSF therapy in CARD9-deficient patients with Candida CNS disease refractory to antifungal therapy [61,85] also provides support for the biological relevance of this pathway. Furthermore, it has been shown that CARD9-deficient neutrophils have impaired responses to C. albicans , in terms of both their capacity to migrate towards foci of fungal infection [56], and in their management of fungi under specific conditions in vitro [59,86,87].…”

“…Similarly, despite the maintenance of anti- Aspergillus effector functions (phagocytosis and killing) or normal neutrophil-intrinsic chemotactic functions, it has been suggested that extrapulmonary aspergillosis results from impaired CARD9-dependant neutrophil recruitment to sites of infection [56,57]. Likewise, the blunted pro-inflammatory responses of patients’ PBMCs, as shown for C. albicans , Exophiala spp., P. verrucosa , and A. fumigatus [22,52,57,59,61,70,71,85], probably contribute to the impaired neutrophilic response and weaken inherent mechanisms of fungal control. Finally, the impaired or normal production of IL-17, measured ex vivo or in vitro after PMA/ionomycin or fungal stimulation, suggests that CARD9 may be important, but not critical, for Th17-cell differentiation, accounting for the incomplete penetrance for CMC in CARD9 deficiency.…”