Irak4 Deficiency

A number sign (#) is used with this entry because IRAK4 deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding interleukin-1 receptor-associated kinase-4 (IRAK4; 606883).

Description

IRAK4 deficiency is an autosomal recessive primary immunodeficiency that impairs Toll (see TLR4; 603030)/IL1R (see IL1R1; 147810) immunity, except for the TLR3 (603029)- and TLR4-interferon-alpha (IFNA; 147660)/beta (IFNB; 147640) pathways (Ku et al., 2007).

Clinical Features

Haraguchi et al. (1998) described a 3-year-old female with interleukin-12 (see IL12B, 161561) deficiency associated with recurrent episodes of pneumococcal pneumonia with sepsis and other infections in the absence of fevers. She was the product of an incestuous relationship. The patient's peripheral blood mononuclear cells (PBMCs) exhibited normal proliferative responses to antigens. Immune responses, including in vivo production of antibodies to diphtheria, tetanus, or pneumococcal antigens, were normal. Immunoglobulin levels and B-cell and T-cell phenotypes were also normal. In contrast, IL12 p70 heterodimer production was undetectable by using supernatants of the patient's stimulated PBMCs when compared with control cells treated similarly. Although present, IFNG (147570) was reduced. The addition of recombinant IFNG to control cells enhanced the production of IL12 up to 6-fold. In contrast, IL12 was undetectable in supernatants of the patient's cells in the presence of recombinant IFNG. The IL12 p40 subunit (IL12B) mRNA by using the patient's PBMCs after stimulation with Staphylococcus aureus or lipopolysaccharide was also undetectable by RT-PCR when compared with control cells. Production of IL2 (147680), IL6 (147620), tumor necrosis factor-alpha (191160), or IFNG of the patient's PBMCs after appropriate stimulation was observed. This patient was thought to have either a defect in the signaling pathways for the activation of IL12B gene expression or an abnormality in IL12B itself.

Picard et al. (2003) described 3 unrelated children, including the child originally reported by Haraguchi et al. (1998), with recurrent infections and poor inflammatory response in whom extracellular, pyogenic bacteria were the only microorganisms responsible for infection. Gram-positive Streptococcus pneumoniae and Staphylococcus aureus were the most frequently found and were the only pathogens identified in 2 patients. Infections began early in life but became less frequent with age, and the patients were well with no treatment at ages 6, 11, and 7 years. All known primary immunodeficiencies were excluded. In particular, the patients had normal serum antibody titers against protein and polysaccharide antigens, including those from S. pneumoniae. However, 1 of the 3 patients had been shown not to respond to lipopolysaccharide (LPS) or S. aureus (Haraguchi et al., 1998). None of the patients' monocytes responded to LPS; however, they responded normally to TNF-alpha (191160). The patients did not respond to IL1-beta (147720), IL18 (600953), or any of the TLR1-6 (see 601194) or TLR9 (605474) ligands, as assessed by activation of NF-kappa-B (see 164011) and p38-MAPK (600289) and induction of IL1-beta, IL6, IL12, TNF-alpha, and IFNG.

In a follow-up of the patients reported by Picard et al. (2003), Day et al. (2004) found that 2 continued to do well, but 1, an 8-year-old girl, was unable to sustain antibody responses to polysaccharide or protein antigens or to a neoantigen-bacteriophage. She continued to have recurring bacterial and fungal infections, eventually requiring intravenous immunoglobulin therapy. They recommended testing for IRAK4 deficiency in patients with recurrent bacterial and fungal infections without sustained antibody response to immunization.

Ku et al. (2007) tested TLR responses of whole blood and individual leukocyte subsets in 28 patients with IRAK4 deficiency and found that only the TLR3 agonist poly(I:C) could induce production of 11 non-IFN cytokines. The TLR4 agonist, LPS, could induce some responses in myeloid dendritic cells and monocyte-derived dendritic cells. Most patients suffered from invasive and often recurrent pneumococcal disease, but other infections, except for severe staphylococcal disease, were rare. Nearly half of the patients died. Death occurred only in patients 8 years old and younger, and invasive disease occurred only in those 14 years old and younger. Ku et al. (2007) concluded that IRAK4-dependent TLRs and IL1Rs are vital for childhood immunity to pyogenic bacteria, particularly S. pneumoniae, but they are not essential for protective immunity to most infections.

Hoarau et al. (2007) investigated a 14-year-old French boy of healthy, unrelated patients with IRAK4 deficiency characterized by recurrent infections, osteomyelitis, and cellulitis beginning at age 15 days. Apart from elevated C-reactive protein (CRP; 123260) and very low polymorphonuclear neutrophil (PMN) numbers, his immunologic status was normal. Hoarau et al. (2007) found that the patient was compound heterozygous for 2 mutations in the IRAK4 gene (see 606883.0006 and 606883.0007). Stimulation of the patient's PMNs with TLR agonists revealed the absence of IRAK1 (300283) phosphorylation and impaired PMN responses. However, responses to the TLR9 agonist CpG were normal, except for cytokine production. Impairment of TLR9 responses was observed after pretreatment with PI3K (see 601232) inhibitors. Hoarau et al. (2007) proposed that there may be an alternative TLR9 pathway leading to PI3K activation independently of the classical MYD88 (602170)-IRAK4 pathway. They suggested that this alternative pathway may play a role in control of infections by microorganisms other than pyogenic bacteria in patients with IRAK4 deficiency.

Molecular Genetics

Picard et al. (2003) found that all 3 patients with pyogenic bacterial infections were homozygous for a mutation in the IRAK4 gene (see 606883.0001-606883.0002) and that in each case the mutations were associated with complete deficiency for the kinase.

Pathogenesis

By studying responses to the TLR4 ligand, LPS, and to the bacterial chemoattractant, fMLP, in PMNs from 1 patient with IRAK4 deficiency and 3 patients with NEMO (300248) deficiency causing X-linked hyper-IgM immunodeficiency with ectodermal dysplasia (300291), Singh et al. (2009) demonstrated reduced or absent superoxide production after impaired priming and activation of the oligomeric neutrophil NADPH oxidase (NOX; see 300481). The response was particularly weak or absent in IRAK4-deficient PMNs. NEMO-deficient PMNs had a phenotype intermediate between IRAK4-deficient PMNs and normal PMNs. Decreased LPS- and fMLP-induced phosphorylation of p38 (MAPK14; 600289) was observed in both deficiencies. Singh et al. (2009) proposed that decreased activation of NOX may contribute to increased risk of infection in patients with IRAK4 deficiency or NEMO deficiency.