Toll-like receptor signaling defects

What every physician needs to know:

This chapter discusses Toll-like receptor signaling defects (interleukin-1 receptor-associated kinase 4 [IRAK-4], myeloid differentiation primary response gene [88] [MYD88], NF-kappa-B essential modulator [NEMO]).

Signal transduction both to generate and to perpetuate inflammation requires the activation of nuclear factor kappa B (NFkB). Therefore, defects along this pathway lead to impaired inflammation and consequently, an increased susceptibility to infection. IRAK4, MYD88, and NEMO deficiencies have overlapping but somewhat distinct features.

Are you sure your patient has a toll-like receptor signaling defect? What should you expect to find?

Recurrent infection is the hallmark of IRAK4/MYD88 defects. Typically, infections are meningeal or disseminated and severe. They are usually due to encapsulated organisms (Streptococcus pneumoniae,Staphylococcus aureus, Neisseria meningitidis, Pseudomonas aeruginosa) as well as salmonella species. Patients present with a striking paucity of fever and inflammation. However, infections can be more limited, such as lymphadenopathy or osteomyelitis or visceral abscesses. The patients are not especially susceptible to viruses or fungi or mycobacteria. IRAK4 and MYD88 deficiencies are essentially phenocopies of each other, with very little to discriminate between them. They do not have morphologic or somatic features.

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In contrast, patients with NEMO deficiency may have all the features of IRAK4/MYD88 deficiency (infection susceptibility, paucity of inflammation) but they also have susceptibility to viruses such as CMV and mycobacteria. Because NEMO is an X-linked gene that acts at the convergence of signaling for a variety of pathways, these patients are boys who often have defects in ectodermal formation as well, such as widely gapped or missing teeth, abnormal hair whorls, and abnormal sweating because of impaired sweat glands. However, the morphologic aspects of NEMO deficiency are inconsistent. Patients may also have impaired immunoglobulin production.

Beware of other conditions that can mimic a toll-like receptor signaling defect:

Any of the immunodeficiencies that lead to infections by encapsulated bacteria can look like IRAK4/MYD88 deficiency. However, the paucity of inflammatory response and the relatively normal values for immunoglobulins and white cells should suggest this disease. Conversely, low immunoglobulins or leukopenia suggest other etiologies, and one should search for a cause of agammaglobulinemia or neutropenia.

NEMO can be mimicked by many other infection susceptibility syndromes. Other syndromes that can cause disseminated mycobacterial disease include defects in the interferon gamma/IL-12 (interleukin 12 receptor)pathway, defects in GATA2, and advanced HIV infection. However, the occurrence of both severe infections from encapsulated organisms and mycobacterial infections in the same boy, should always prompt a thorough search for NEMO deficiency.

Which individuals are most at risk for developing toll-like receptor signaling defects:

IRAK4/MYD88 deficiency are autosomal recessive, so they are favored by consanguinity. However, compound heterozygotes do occur.

NEMO deficiency is an X-linked recessive disease, so only boys develop full disease and mothers are carriers. In boys, most of the NEMO mutations are hypomorphic, that is, they retain some residual function but cause the syndrome of NEMO deficiency or ectodermal dysplasia with immunodeficiency. However, since females are X chromosome expression mosaics because of lyonization, they can get a condition called incontinentia pigmenti. Incontinentia pigmenti is caused by inflammation of the NEMO deficient skin or visceral cells with subsequent scarring. This can cause inflammatory lesions in the skin or brain in particular, causing rashes or seizures, respectively.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The decision to seek diagnosis of IRAK4/MYD88 deficiency or NEMO deficiency is driven by the spectrum of infections and the clinical symptoms. Severe infections with encapsulated bacteria with inappropriately low fever or inflammatory marker response should cause one to consider these diseases in the differential. There are no specific confirmatory lab tests short of gene sequencing.

For NEMO deficiency, the spectrum of infection is wider, including viruses and mycobacteria with associated physical findings in the teeth, hair, and sweat glands. NEMO deficiency can also be associated with hypogammaglobulinemia of immunoglobulin G with concomitant elevation of immunoglobulin M, reflecting impaired B cell immunoglobulin class switching. However, these are inconsistent findings.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of toll-like receptor signaling defects?

None in particular. NEMO patients may have hypodontia or widely gapped or misshapen teeth (peg or conical teeth), but these are also seen on physical exam.

If you decide the patient has a toll-like receptor signaling defect, what therapies should you initiate immediately?

One should treat infections when they are present. If a patient has IRAK4/MYD88 deficiency and is not on prophylaxis, they should take antibiotics immediately upon developing a febrile illness, such as an intravenous cephalosporin. Prophylaxis is sensible and given by many experts but not absolute. Some NEMO patients need immune globulin replacement.

More definitive therapies?

IRAK4/MYD88 are probably best treated with antibiotic prophylaxis (penicillin derivatives or cotrimoxazole), aggressive vaccination for S. pneumoniae, Haemophilus influenzaeand N. meningitidis and in some cases with immune globulin.

NEMO deficiency is best managed with prophylactic antibiotics, including prophylaxis against nontuberculous mycobacteria with azithromycin or clarithromycin. Aggressive vaccination is less effective in NEMO deficiency because of the underlying defect in antibody production. Therefore, for those with antibody impairment, immune globulin replacement is indicated.

The role of bone marrow transplantation is controversial. Because NEMO deficiency is expressed in cells beyond the hematopoietic system, bone marrow transplantation creates a chimeric situation in which the leukocytes are properly responsive to microbial signals but somatic cells, such as enterocytes, are not. This can lead to serious inflammatory bowel disease after transplantation.

What other therapies are helpful for reducing complications?

Antibiotic prophylaxis, vaccination, and immune globulin replacement as indicated.

What should you tell the patient and the family about prognosis?

IRAK4/MYD88 are unusual in that the severity of the disease gets less with age. After early adolescence, patients with IRAK4/MYD88 deficiency develop many fewer infections and may lead normal lives. The reasons for this apparent acquisition of immunity are unclear, but children who survive to age 14 apparently do fine. In the absence of specific therapy, the survival to age 14 is only about 50%, but with therapy and close follow up, it is quite high. Since these are recessive disorders, the risk of vertical disease transmission is low.

NEMO deficiency does not seem to have the same age-related amelioration as IRAK4/MYD88. These patients remain at risk for infections, although their exposure to the environment and their compliance with therapy certainly improve with age. Long term prognosis is not fully appreciated yet, but there are certainly patients in their forties who are well. All NEMO deficient patient daughters will be carriers of the gene and are potentially at risk for incontinentia pigmenti.

"What if" scenarios.

The paucity of symptoms can lull patients and doctors into a false sense of security. Pneumocystis jiroveci can also occur in NEMO deficiency and should be included in the differential diagnosis of diffuse infiltrates in this disease.


Extracellular signals are transmitted through a variety of surface receptors, including the toll-like receptors (TLR) as well as cytokine receptors, such as the IL-1 (interleukin 12) receptor). IRAK4 and MYD88 mediate signaling through all the TLR except toll-like receptor 3 (TLR3), as well as the IL-1 receptor. These signals converge on NEMO, which facilitates the inactivation of the inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NK-kB) [IkB], the protein that holds NFkB latent in the cytoplasm. With IkB inactivation NFkB is released and facilitates inflammatory responses including fever, leukocytosis, and the acute phase reaction. Therefore, defects in these proteins block inflammatory signals impairing myeloid and downstream responses.

NEMO sits further downstream of the above receptors, and also supports signals from the critical B cell class switch receptor, CD40, as well as the ectodermal development receptor ectodysplasin. Therefore, defects at the level of NEMO lead to problems with inflammation, similar to those of IRAK4/MYD88, as well as problems with immunoglobulin class switching and ectoderm formation.

What other clinical manifestations may help me to diagnose toll-like receptor signaling defects?

In the history of patients with IRAK4/MYD88 deficiency, queries about the extent and severity of infection and the extent of fever can be helpful.

For NEMO deficiency, questions about dental history can be important.

Patients with IRAK4/MYD88 have no distinguishing findings on physical exam. NEMO deficiency may be associated with abnormal hair whorls, and gapped, missing or misshapen teeth.

What other additional laboratory studies may be ordered?

Acute phase reactants during infections. In NEMO deficiency, it is critical to search for mycobacterial infection as a cause of fever, malaise, adenopathy, anemia, or organomegaly.

What’s the evidence?

Picard, C, von Bernuth, H, Ghandil, P. “Clinical features and outcome of patients with IRAK-4 and MyD88 Deficiency”. Medicine. vol. 89. 2010. pp. 403-425. [A global compendium of all known cases with detailed immunophenotyping and outcomes.]

Hanson, EP, Monaco-Shawver, L, Solt, LA. “Hypomorphic nuclear factor-kB =essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity”. J Acad Clin Immunol. vol. 122. 2008. pp. 1169-1177. [A comprehensive analysis of the various mutations and their in vitro functions as well as phenotypes.]

Permaul, P, Narla, A, Hornick, JL, Pai, SY. “Allogeneic hematopoietic stem cell transplantation for X-linked ectodermal dysplasia and immunodeficiency: case report and review of outcomes”. Immunol Res. vol. 44. 2009. pp. 89-98. [A review of the bone marrow transplants done so far in NEMO deficiency.]