Heritable defects of the human TLR signalling pathways

Abstract

Recently, three human primary immunodeficiencies associated with impaired TLR signalling were described. Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), either X-linked recessive or autosomal dominant, is caused by hypomorphic mutations in NEMO or hypermorphic mutation in IKBA, respectively, both involved in nuclear factor-κB (NF-κB) activation. These patients present with abnormal development of ectoderm-derived structures and suffer from a broad spectrum of infectious diseases. In vitro studies of the patients' cells showed an impaired, but not abolished, NF-κB activation in response to a large set of stimuli, including TLR agonists. More recently, patients with autosomal recessive amorphic mutations in IRAK4 have been reported, presenting no developmental defect and a more restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive. In vitro studies carried out with these patients' cells showed a specific impairment of the Toll—interleukin-1 receptor (TIR)—interleukin-1 receptor associated kinase (IRAK) signalling pathway. NF-κB- and mitogen activated protein kinase (MAPK) pathways are impaired in response to all TIR agonists tested. These data, therefore, suggest that TLRs play a critical role in host defence against pyogenic bacteria, but may be dispensable or redundant for immunity to most other infectious agents in humans.

Keywords

Human TLR signalling heritable defects NEMO IKBA IRAK4 anhidrotic ectodermal dysplasia

References

Lemaitre B. The road to Toll. Nat Rev Immunol 2004;, 4: 521—527.

Beutler B. , Rietschel ET Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol 2003; 3: 169—176.

Poltorak A. , He X. , Smirnova I. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282: 2085—2088.

Takeda K. , Kaisho T. , Akira S. Toll-like receptors. Annu Rev Immunol 2003 ; 21: 335—376.

Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling . Nature 2004; 430: 257—263.

O'Neill LA Signal transduction pathways activated by the IL-1 receptor/Toll-like receptor superfamily. Curr Top Microbiol Immunol 2002 ; 270: 47—61.

Akira S. , Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4: 499—511.

Beutler B. , Du X. , Hoebe K. From phenomenon to phenotype and from phenotype to gene: forward genetics and the problem of sepsis. J Infect Dis 2003 ; 187: S321—S326.

Netea MG , van der Graaf C. , Van der Meer JW , Kullberg BJ Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system. J Leukoc Biol 2004; 75: 749—755.

10.

Qureshi ST , Medzhitov R. Toll-like receptors and their role in experimental models of microbial infection . Genes Immun 2003; 4: 87—94.

11.

Casanova JL , Abel L. The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol 2004; 4: 55—66.

12.

Ku CL , Yang K. , Bustamante J. et al. Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol Rev 2005; 203: 10—20.

13.

Courtois G. , Smahi A. , Reichenbach J. et al. A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest 2003; 112: 1108—1115.

14.

Janssen R. , van Wengen A. , Hoeve MA et al. The same IκBα mutation in two related individuals leads to completely different clinical syndromes. J Exp Med 2004; 200: 559—568.

15.

Abinun M. , Spickett G. , Appleton AL , Flood T. , Cant AJ Anhidrotic ectodermal dysplasia associated with specific antibody deficiency . Eur J Pediatr 1996; 155: 146—147.

16.

Carrol ED , Gennery AR , Flood TJ , Spickett GP , Abinun M. Anhidrotic ectodermal dysplasia and immunodeficiency: the role of NEMO. Arch Dis Child 2003; 88: 340—341.

17.

von Bernuth H. , Puel A. , Ku C. -L et al. Septicaemia without sepsis: inherited disorders of NF-κB-mediated inflammation. Clin Infect Dis 2005; In press.

18.

Puel A. , Picard C. , Ku CL , Smahi A. , Casanova JL Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol 2004; 16: 34—41.

19.

Ghosh S. , Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109: S81—S96.

20.

Orange JS , Levy O. , Brodeur SR et al. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol 2004; 114: 650—656.

21.

Niehues T. , Reichenbach J. , Neubert J. et al. Nuclear factor kappaB essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia. J Allergy Clin Immunol 2004; 114: 1456—1462.

22.

Picard C. , Puel A. , Bustamante J. , Ku CL , Casanova JL

Primary immunodeficiencies associated with pneumococcal disease. Curr Opin

Allergy Clin Immunol 2003; 3: 451—459.

23.

Jain A. , Ma CA , Liu S. , Brown M. , Cohen J. , Strober W. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2001; 2: 223—228.

24.

Doffinger R. , Smahi A. , Bessia C. et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 2001; 27: 277—285.

25.

Dupuis-Girod S. , Corradini N. , Hadj-Rabia S. et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics 2002; 109: e97.

26.

Orange JS , Brodeur SR , Jain A. et al. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J Clin Invest 2002; 109: 1501—1509.

27.

Nishikomori R. , Akutagawa H. , Maruyama K. et al. X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival. Blood 2004; 103: 4565—4572.

28.

Picard C. , Puel A. , Bonnet M. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency . Science 2003; 299: 2076—2079.

29.

Medvedev AE , Lentschat A. , Kuhns DB et al. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 2003; 198: 521—531.

30.

Enders A. , Pannicke U. , Berner R. et al. Two siblings with lethal pneumococcal meningitis in a family with a mutation in interleukin-1 receptor-associated kinase 4. J Pediatr 2004; 145: 698—700.

31.

Chapel H. , Puel A. , von Bernuth H. , Picard C. , Casanova JL Shigella sonnei meningitis in a 10-year-old girl due to IRAK-4 deficiency — first association with a primary immune deficiency. Clin Infect Dis 2005; 40: 1227—1231.

32.

Currie AJ , Davidson DJ , Reid GS et al. Primary immunodeficiency to pneumococcal infection due to a defect in Toll-like receptor signaling. J Pediatr 2004; 144: 512—518.

33.

Day N. , Tangsinmankong N. , Ochs H. et al. Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses. J Pediatr 2004; 144: 524—526.