Defects Involving Other Pattern-Recognition Signaling Pathways with Increased Susceptibility to Fungal Infections
Chronic mucocutaneous candidiasis is a common complication affecting patients with APECED due to mutation in the transcription factor AIRE138 and those with autosomal dominant HIES due to mutations in the transcription factor STAT3.146 Genetic evaluation of a large consanguineous family in which four members had recurrent mucocutaneous candidiasis and two additional members had died of invasive candidiasis of the brain.225A Homozygosity mapping identified a region within chromosome 9 that encompassed CARD9 encoding the caspase recruitment domain-containing protein 9. Affected members of this family had a homozygous point mutation in CARD9, resulting in a premature termination codon. CARD9 is recruited by Dectin-1, a transmembrane pattern-recognition receptor that senses the beta-glucan component of fungal cell walls, and together with other cytoplasmatic proteins, forms an intracellular signaling complex that leads to the nuclear import of NFkB and the induction of key cytokines including IL-1, IL-6, IL-23, and the generation of IL-17 cells, which are required to control antifungal immune responses.
Mendelian Susceptibility to Mycobacterial Disease
The IL-12/IFN- axis is essential for controlling mycobacterial infections. Following phagocytosis of mycobacteria, macrophages secrete IL-12, a heterodimer composed of IL-12p40 and IL-12p70. IL-12 binds to the heterodimeric IL-12R (composed of IL12R1 and IL-12R2 chains) expressed by Th1 and NK cells. This results in activation of the JAK-STAT4 pathway and ultimately in the production of IFN-, which binds to its receptor (comprising IFN-R1 and IFN-R2 chains) on the surface of macrophages, triggering a signalling cascade that involves the transcription factor STAT1 and induction of IFN–responsive genes that are essential to contain the infection and kill the mycobacteria. A variety of defects along this pathway have been shown to account for mendelian susceptibility to mycobacterial disease in humans.60,226 The basis for increased susceptibility to mycobacterial disease in patients with NEMO deficiency was discussed above in the section “X-Linked Anhydrotic Ectodermal Dysplasia with Immunodeficiency.”
Autosomal recessive IL-12p40 deficiency is the only genetically-determined cytokine deficiency known in humans. Affected patients are at increased risk of severe infections due to bacillus Calmette-Guerin and environmental mycobacteria, but Salmonella, Nocardia, and Mycobacterium tuberculosis infections have also been reported.227 The clinical course is variable, but approximately 40 percent of the IL-12p40-deficient patients have died prematurely of infections. Treatment with antibiotics and IFN- is indicated.
Autosomal recessive IL-12R1 deficiency is characterized by infections with mycobacteria of low virulence and Salmonella species. However, infections with M. tuberculosis have also been reported.228 Unlike salmonellosis, mycobacterial infections tend not to recur and the overall prognosis is good. In most cases, IL-12R1 expression on the cell surface is absent, and in vitro IFN- production in response to IL-12 is abrogated. Treatment with appropriate antibiotics and IFN- is effective.
IFN-R1 and IFN-R2 Deficiencies
The genetic and biochemical pathophysiology of IFN-R1 and IFN-R2 deficiencies are remarkably complex. Autosomal recessive forms are most often associated with mutations that abrogate cell surface expression of IFN-R1 or result in the expression of receptors that do not bind IFN-. Partial autosomal recessive deficiency is the result of hypomorphic mutations, with residual IFN- binding and signaling. Dominant partial forms reflect the presence of heterozygous mutations in the cytoplasmic tail of IFN-R1, allowing the expression of mutant molecules on the cell surface (often in increased density due to defective receptor shedding) which are unable to mediate signal transduction.229
The severity of the clinical features reflects the nature of the biochemical defect.230 Patients with complete deficiency develop severe infections with environmental mycobacteria infections early in life, with lack of granuloma formation.230 Osteomyelitis caused by bacillus Calmette-Guerin or by environmental mycobacteria has been reported in several patients with dominant partial IFN-R1 deficiency.
Treatment of partial deficiency should be based on careful identification and typing of the mycobacterial strains and appropriate antimicrobial therapy; addition of IFN- may be useful. Recessive forms are resistant to medical treatment. Although allogeneic hematopoietic stem cell transplantation has been attempted,231 a high rate of graft failure has been observed as a consequence of the inhibitory effect of high levels of circulating IFN-.232