Immunodeficiency 51

A number sign (#) is used with this entry because of evidence that immunodeficiency-51 (IMD51) is caused by homozygous mutation in the IL17RA gene (605461) on chromosome 22q11.

Description

Immunodeficiency-51 is an autosomal recessive primary immune deficiency that is usually characterized by onset of chronic mucocutaneous candidiasis in the first years of life. Most patients also show recurrent Staphylococcal skin infections, and may show increased susceptibility to chronic bacterial respiratory infections. Patient cells show a lack of cellular responses to stimulation with certain IL17 isoforms, including IL17A (603149), IL17F (606496), IL17A/F, and IL17E (IL25; 605658) (summary by Levy et al., 2016).

Clinical Features

Puel et al. (2011) investigated a French child, born to first-cousin parents of Moroccan descent, who presented with Candida albicans dermatitis during the neonatal period and displayed Staphylococcus aureus dermatitis at 5 months of age. Known causes of chronic mucocutaneous candidiasis (CMC) were excluded clinically and genetically and the lack of any phenotype other than CMC led to a diagnosis of autosomal recessive CMC.

Levy et al. (2016) reported 20 patients from 11 families with IMD51. The families had various ethnic origins, including Turkey, Japan, Saudi Arabia, Algeria, and Argentina, and most were consanguineous. All patients showed chronic mucocutaneous candidiasis affecting the skin, scalp, mucosal sites, or nails before 6 months of age. Fourteen patients also had recurrent Staphylococcal skin infections by the same age; these infections included abscesses, folliculitis, furunculosis, and crusted pustules. Eight children had other recurrent infections including otitis, sinusitis, bronchitis, and lobar pneumonia. None had features of autoimmune endocrinopathy. Detailed phenotyping of lymphocyte subsets from patients from 3 families showed no abnormalities.

Inheritance

The transmission pattern of IMD51 in the families reported by Levy et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

Puel et al. (2011) found that a French child of Moroccan descent with autosomal recessive CMC was homozygous for a nonsense mutation in the IL17RA gene (605461.0001). Consistent with autosomal recessive inheritance, the parents and sibs were heterozygous for this mutation. The mutation was not identified in 1,065 healthy controls. The IL17RA protein was not detected on the surface of fibroblasts, peripheral blood monocytes, or CD4+ T cells, CD8+ T cells, and monocytes from the patient. Investigation of the cells showed that the patient with CMCD displayed autosomal recessive complete IL17RA deficiency with a lack of cellular responses to at least 3 IL17 cytokine dimers, IL17A (603149), IL17F (606496), and IL17A-IL17F, in fibroblasts and leukocytes.

In 20 patients from 11 families with IMD51, Levy et al. (2016) identified 11 different homozygous mutations in the IL17RA gene (see, e.g., 605461.0002-605461.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All of the mutations were frameshift, nonsense, or splice site mutations, predicted to result in a loss of function, except for 1 missense mutation (D387N; 605461.0003), which was demonstrated in vitro to result in a loss of function. Cells derived from several patients with truncating mutations showed complete loss of IL17RA surface expression on fibroblasts and monocytes, and patient cells showed a lack of cellular responses to stimulation with certain IL17 isoforms, including IL17A, IL17F, IL17A/F, and IL17E. The findings demonstrated the importance of IL17RA for mucocutaneous immunity.

Animal Model

Tan et al. (2006) noted that mice lacking Il17ra have reduced resistance to bacterial and fungal infections.

Kudva et al. (2011) found that mice lacking Il17a, Il17f, Il17ra, or Il22 (605330), all of which are components of Th17 immunity, had impaired clearance of Staphylococcus aureus. Deletion of Il22 did not diminish neutrophil recruitment. Wildtype mice challenged with influenza A and then by S. aureus had increased inflammation and decreased clearance of both pathogens, accompanied by greater production of type I IFN (e.g., IFNA1; 147660) and type II IFN (i.e., IFNG; 147570) in lung, compared with mice infected with virus alone. Coinfection with influenza A substantially decreased Il17, Il22, and Il23 production after S. aureus infection in a type II IFN-independent and type I IFN-dependent manner. Overexpression of Il23 in coinfected mice rescued induction of Il17 and Il22 and markedly improved bacterial clearance. Kudva et al. (2011) concluded that type I IFNs induced by influenza A infection inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.