Immunodeficiencies with Selective Susceptibility to Pathogens
Although classical forms of primary immune deficiency disease are characterized by susceptibility to a broad range of pathogens, several disorders have been identified with selective susceptibility to certain microorganisms. Some of these diseases (e.g., mendelian susceptibility to herpes simplex encephalitis or to pyogenic infections, especially S. pneumoniae) are a result of defects of innate immunity, in particular toll-like receptor (TLR) signaling. Others (mendelian susceptibility to mycobacterial disease) involve defects of the IL-12/IFN- axis at the interface of innate and adaptive immunity. Susceptibility to recurrent meningitis caused by Neisseria meningitidis is discussed under “Genetically Determined Deficiencies of the Complement System”.
Immunodeficiencies with Impaired Signaling through Toll-Like Receptors
TLRs are transmembrane proteins expressed on a variety of cell types that recognize pathogen-associated molecular patterns, such as lipopolysaccharide derived from Gram-negative bacteria, lipopeptide, double-stranded RNA that is generated during viral replication, viral single-stranded RNA, viral cytosine phosphate guanine DNA moieties and flagellin. Most TLRs are expressed at the cell surface, however TLRs 7, 8, and 9 are expressed on the membrane of endosomal vesicles.
Binding of pathogen-associated molecular patterns to TLRs induces characteristic intracellular signalling. The classical pathway of TLR activation involves the adaptor molecules MyD88 (myeloid differentiation factor 88) and toll-interleukin 1 receptor domain-containing adaptor protein, and the intracellular kinases IL-1 receptor-associated kinase (IRAK)-4 and IRAK-1, ultimately resulting in the nuclear transfer of NF-B and the production of inflammatory cytokines (IL-1, IL-6, tumor necrosis factor-, IL-12). TLRs 3, 7, 8, and 9 activate an alternative pathway that involves other adaptor molecules, such as toll-interleukin 1 receptor domain-containing adaptor-inducing IFN- (TRIF), TRIF-related adaptor molecule, and the UNC-93B protein, and ultimately results in the induction of type 1 interferons (IFN-/). Deficiencies of IRAK-4, MyD88, TLR3, and UNC-93B have been identified in humans, and are associated with two distinct phenotypes.
TLR-Signaling Defects with Increased Susceptibility to Herpes Simplex Virus Encephalitis
Two unrelated patients with herpes simplex virus encephalitis (HSE) from consanguineous families were found to carry homozygous mutations in the UNC-93B1 gene.218 Blood mononuclear cells from these patients failed to produce IFN-, -, and – in response to TLR3, TLR7, TLR8, and TLR9 agonists.
Heterozygous, dominant-negative mutations of TLR3 have also been identified in patients with recurrent HSE.219 Because TLR3 recognizes double-stranded RNA and is normally expressed in CNS resident cells, TLR3 mutations impair the response of these cells to actively replicating herpes simplex virus-1. Because cellular responsiveness to type 1 IFN is intact in both UNC-93B– and in TLR3-deficient patients, the use of IFN- along with acyclovir should be considered to treat HSE in these patients.219
HSE may also be a result of null mutations of STAT1, a transcription factor that is activated upon interaction of type 1 IFN with their receptors, and is critical for the induction of IFN-responsive genes. Because STAT1 is also involved in the response to IFN-, patients with null STAT1 mutations are also at risk for mycobacterial disease.220
TLR-Signaling Defects with Increased Susceptibility to Pyogenic Infections
IRAK-4 and MyD88 deficiencies are characterized by recurrent and invasive pyogenic bacterial infections, particularly from S. pneumoniae and S. aureus.221,222 These infections are common especially during the first years of life (when lethality rate can be as high as 50%), but their frequency tends to decline with age.223 Fever and systemic inflammatory responses are absent or unusually modest, reflecting poor induction of inflammatory cytokines and reduced response through the IL-1R. Failure to sustain antibody responses to T-cell–dependent and T-cell–independent antigens has been reported in patients with IRAK-4 deficiency.224 Diagnosis can be suspected based on the infection history associated with poor inflammatory responses. Defective shedding of CD62L from the surface of granulocytes upon addition of TLR agonists can be used as a flow cytometry-based screening assay.225
Use of antimicrobic prophylaxis is important to prevent invasive pyogenic infections, especially in childhood. Substitution therapy with immunoglobulins may be beneficial in patients with impaired antibody responses.