Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults

Abstract

• Inherited CARD9 deficiency (OMIM #212050) is an AR PID due to mutations that may be present in a homozygous or compound heterozygous state. • CARD9 is expressed principally in myeloid cells and transduces signals downstream from CLR activation by fungal ligands. • Endogenous mutant CARD9 levels differ between alleles (from full-length normal protein to an absence of normal protein). • The functional impacts of CARD9 mutations involve impaired cytokine production in response to fungal ligands, impaired neutrophil killing and/or recruitment to infection sites, and defects of Th17 immunity. • The key clinical manifestations in patients are fungal infections, including CMC, invasive (in the CNS in particular) Candida infections, extensive/deep dermatophytosis, subcutaneous and invasive phaeohyphomycosis, and extrapulmonary aspergillosis. • The clinical penetrance of CARD9 deficiency is complete, but penetrance is incomplete for each of the fungi concerned. • Age at onset is highly heterogeneous, ranging from childhood to adulthood for the same fungal disease. • All patients with unexplained IFD should be tested for CARD9 mutations. Familial screening and genetic counseling should be proposed. • The treatment of patients with CARD9 mutations is empirical and based on antifungal therapies and the surgical removal of fungal masses. Patients with persistent/relapsing Candida infections of the CNS could be considered for adjuvant GM-CSF/G-CSF therapy. The potential value of HSCT for CARD9-deficient patients remains unclear.

Fungi Enter the Stage of Colon Carcinogenesis

“…Card9deficient mice are susceptible to diverse fungal infections, such as those of Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. In humans, CARD9 deficiency causes mostly Candida infections, although one recent study reported Ascomycete infection (Corvilain et al, 2018). The fungal b-glucans and a-mannans are recognized by the C-type lectin receptors Dectin-1, Dectin-2, Dectin-3, and Mincle (Zhu et al, 2013).…”

Phaeohyphomycosis

“…12 Mutations of CARD9 lead to impaired cytokine production after stimulation of immune cells with various fungal ligands, impaired recruitment of neutrophils to the site of infection, and impairment of interleukin-17 immunity. 13 More mutations are likely to be found in patients who develop invasive fungal infections, and more research in the field of immunology is needed to understand the specific immunodeficiency they impart.…”

Hematopoietic Stem Cell Transplantation in CARD9 Deficiency: Knight in Shining Armor?

“…In this Issue of the Journal of Clinical Immunology, Queiroz-Telles et al report the first successful use of hematopoietic stem cell transplantation (HSCT) in two unrelated patients with autosomal recessive Caspase Recruitment Domain 9 (CARD9) deficiency suffering from recurrent and ongoing invasive dermatophytosis [1]. Autosomal recessive (CARD9) deficiency (OMIM 212050) has recently been extensively reviewed in this journal [2]. In brief, the condition underlies life-threatening invasive infections by ascomycete fungi typically including invasive and superficial dermatophytosis, invasive phaeohyphomycosis, but also invasive Candida (especially central nervous system infection), and extrapulmonary aspergillosis, in otherwise healthy individuals.…”

“…It is however expressed in monocytes and engages in the B cell lymphoma (BCL)-CARD-mucosa-associated lymphoid tissue lymphoma (MALT)-signaling complex downstream of C-type lectin receptors leading to activation of canonical NF-kB and mitogen-activated protein kinase (MAPK) pathway in response to fungal components. Pro-inflammatory cytokine and chemokine responses to various fungal ligands are impaired in CARD9-deficient patients' peripheral blood mononuclear cells (PBMCs), monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells, and impaired Th17 immunity was reported in some but not all studied patients [2]. In two patients with invasive extrapulmonary aspergillosis, CARD9-deficient neutrophils killed Aspergillus effectively but did not accumulate at sites of infection, parallel to observations made in Candida infection of the central nervous system [3].…”