ImmunologyTier 1Medical Sciences concept

NF-kB pathway defects (NEMO) and immunodeficiency

Core concept

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TLR / IL-1R / TNFR / CD40 / TCR / BCR / EDA receptor

-> IKK complex = IKK-alpha + IKK-beta + NEMO (IKK-gamma, the regulatory subunit)
-> phosphorylates IkB-alpha -> ubiquitinated and degraded
-> NF-kB released, enters nucleus
-> inflammatory cytokines, antimicrobial peptides, survival genes
-> and ectodermal appendage development (via EDA/EDAR)

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NEMO is encoded by IKBKG on Xq28 -> X-linked
The ectodermal features are not incidental - the same pathway builds sweat glands, hair follicles and teeth, which is why the immunodeficiency comes with a recognisable face

X-linked anhidrotic/hypohidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)

Feature	Detail
Ectodermal	Absent or reduced sweating -> unexplained recurrent hyperpyrexia, sparse fine hair, conical/peg-shaped or absent teeth, frontal bossing, periorbital wrinkling, dry skin
Immunological	Pyogenic infection - Strep pneumoniae, Staph aureus, Haemophilus; atypical mycobacteria; poor anti-polysaccharide antibody response; often raised IgM with low IgG (hyper-IgM-like); impaired NK function
Other	Colitis, osteopetrosis and lymphoedema in specific alleles

Incontinentia pigmenti = the same gene (IKBKG), complete loss of function, in females - X-linked dominant, male-lethal; blaschkoid vesicular -> verrucous -> hyperpigmented -> atrophic skin stages
IkB-alpha gain-of-function (NFKBIA) - autosomal dominant EDA-ID; the inhibitor cannot be degraded, so NF-kB is permanently off
Related NF-kB pathway defects
- NFKB1 haploinsufficiency - the commonest monogenic cause of CVID-like disease in Europeans
- NFKB2 - CVID with central adrenal insufficiency (DAVID syndrome)
- IRAK4 and MyD88 deficiency - upstream of NF-kB; invasive pneumococcal and staphylococcal disease with a strikingly ABSENT inflammatory response (normal CRP, no fever); risk falls markedly after childhood

Hypohidrosis presenting as recurrent unexplained fever in an infant with abnormal teeth and hair -> examine the sweat pores and count the teeth before ordering immunology
Investigations: immunoglobulins with IgG subclasses, specific antibody responses to polysaccharide (pneumococcal) and protein (tetanus) antigens, lymphocyte subsets, NK function, then IKBKG sequencing (technically difficult - pseudogene)
Management: immunoglobulin replacement, antibiotic prophylaxis, prompt treatment of infection, avoid heat stress and monitor for hyperthermia, dental prosthetics
- HSCT in severe disease, though ectodermal features are not corrected
A normal CRP does not exclude invasive bacterial infection in IRAK4/MyD88 deficiency - the pathway that makes CRP is the one that is broken

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