Immunodeficiency 39

A number sign (#) is used with this entry because of evidence that immunodeficiency-39 (IMD39) is caused by compound heterozygous mutation in the IRF7 gene (605047) on chromosome 11p15. One such family has been reported.

Clinical Features

Ciancanelli et al. (2015) reported a French girl, born of unrelated parents, who developed life-threatening acute respiratory distress during infection with H1N1 influenza A at age 2.5 years. She had no detectable immunologic abnormalities suggesting any T- or B-cell defects, and had a normal vaccination response to typical childhood immunizations. She also had laboratory evidence of antibodies against other viruses, including cytomegalovirus, varicella zoster, respiratory syncytial virus, adenovirus, and parainfluenza viruses 1, 2, and 3, but had no other clinical viral infections at age 7 years. The patient's parents were unaffected.

Inheritance

The transmission pattern of IMD39 in the family reported by Ciancanelli et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a 7-year-old French girl with immunodeficiency-39 manifest as life-threatening H1N1 influenza A infection, Ciancanelli et al. (2015) identified compound heterozygous mutations in the IRF7 gene (F410V, 605047.0001 and Q421X, 605047.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. In vitro studies and studies of patient cells showed impaired type I and type III interferon responses to influenza virus, as well as increased virus replication.

Animal Model

Honda et al. (2005) generated mice deficient in Irf7 by targeted disruption. Using Irf7-null mice, they showed that the transcription factor IRF7 is essential for the induction of IFN-alpha (see 147660)/beta (see 147640) genes via the virus-activated, MYD88 (602170)-independent pathway and the toll-like receptor (TLR)-activated, MYD88-dependent pathway. Viral induction of Myd88-independent Ifn-alpha/beta genes is severely impaired in Irf7-null fibroblasts. Irf7-null mice were consistently more vulnerable than Myd88-null mice to viral infection, and this correlated with marked decrease in serum interferon levels, indicating the importance of the IRF7-dependent induction of systemic interferon responses for innate antiviral immunity. Furthermore, robust induction of interferon production by activation of the Tlr9 (605474) subfamily in plasmacytoid dendritic cells was entirely dependent on Irf7, and this Myd88-Irf7 pathway governed the induction of CD8(+) T-cell responses. Honda et al. (2005) concluded that all elements of interferon responses, whether the systemic production of interferon in innate immunity or the local action of interferon from plasmacytoid dendritic cells in adaptive immunity, are controlled by IRF7.