Page 530 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Immunodeficiencies at the Interface of Innate

and Adaptive Immunity

Jacinta Bustamante, Shen-Ying Zhang, Bertrand Boisson, Michael Ciancanelli,
Emmanuelle Jouanguy, Stéphanie Dupuis-Boisson, Anne Puel, Capucine Picard,
Jean-Laurent Casanova

In the last 20 years, new primary immunodeficiencies (PIDs) initially thought to be rare, but they have since been diagnosed
affecting the immunity mediated by interferon (IFN)- γ, IFN- in about 800 patients around the world (see Table 36.1).
α/β-λ, Toll and interleukin-1 receptor (TIR) domain nuclear
factor (NF)-κB, Toll-like receptor (TLR)-3 pathway, and inter-
leukin (IL)-17 have been identified. Some of these genetic defects MENDELIAN SUSCEPTIBILITY TO
are “conventional” PIDs, associated with a broad range of MYCOBACTERIAL DISEASE: GENETIC
infections, but others provide a molecular explanation for severe DISORDERS OF THE IFN-γ CIRCUIT
pediatric infectious diseases previously thought to be idiopathic
(Table 36.1). These “nonconventional” PIDs may be associated Genetic disorders of the IFN-γ circuit are associated with a
with severe and/or recurrent infections caused by a single family selective susceptibility to weakly pathogenic mycobacteria, such
of microorganisms, a situation strongly contrasting with that as environmental mycobacteria (EM) and/or Bacille Calmette-
for “conventional” PIDs. Standard immunological explorations Guérin (BCG) vaccines, and Salmonella (MSMD, Online
21
are generally normal in these patients, whether they are susceptible mendelian Inheritance in Man [OMIM]: 209950) (Fig. 36.1).
to one or many infectious agents. Despite the lack of a clear These PIDs are caused by mutations in 10 genes involved in
immunological abnormality, infections in these patients are IFN-γ–mediated immunity: IFNGR1 and IFNGR2, encoding the
typically severe, and often fatal. This chapter is devoted to the two chains of the receptor for IFN-γ, a pleiotropic cytokine
description of these PIDs. They include disorders of the IFN-γ secreted by natural killer (NK) and T cells; STAT1, encoding a
circuit associated with the syndrome of mendelian susceptibility transcription factor essential to the IFN-γR signaling pathway;
1,2
to mycobacterial disease (MSMD). Combined disorders of IL12B, encoding the p40 subunit of IL-12 and IL-23, IFN-γ–
IFN-γ- and IFN-α/β-λ-mediated immunity are associated with induced cytokines secreted by macrophages and dendritic cells
mycobacterial and viral diseases. We also describe genetic defects (DCs); IL12RB1, encoding the β 1 chain of the receptor for IL-12
3-9
affecting primarily the TLR-3 pathway. The predominant and IL-23, which is expressed on NK and T cells; NEMO, encoding
infectious phenotype of patients with these defects is herpes NF-κB essential modulator (NEMO), which is involved in the
simplex virus (HSV)-1 encephalitis (HSE) in childhood. We CD40-dependent induction of IL-12; IRF8, encoding an IFN
discovered the first genetic defect associated with severe isolated regulatory factor inducible by IFN-γ; TYK2, which is involved
10
influenza, and mutation of IRF7. We describe four PIDs associ- in IL-12–dependent IFN-γ immunity; and ISG15, encoding an
1,2
ated with impaired signaling downstream from or via the TIR IFN-γ-inducing molecule that acts in synergy with IL-12. The
canonical pathway as a result of mutations of IRAK4, MYD88, MSMD-causing mutations in CYBB affect the respiratory burst
22
NEMO, and NFKBIA. 11-15 Mutations of NEMO and NFKBIA selectively in macrophages. Some mutations of STAT1 and most
also impair the alternative, Toll/IL-1R homologous region (TIR) mutations of NEMO are associated with a much broader range
domain–containing adapter-inducing IFN-β (TRIF)–dependent of infectious diseases (see below), and complete interferon regula-
16
pathway. The principal infectious phenotype of patients with tory factor-8 (IRF8) deficiency is associated with a lack of circulat-
any of these defects is the occurrence of pyogenic bacterial ing monocytes and DCs, and severe clinical disease, mimicking
infections. Finally, we have described a new group of defects combined immunodeficiency (CID). 1,23,24 The molecular and
affecting IL-17 pathways and conferring predisposition to chronic clinical features of MSMD have been reviewed elsewhere. 1
mucocutaneous candidiasis (CMC). 17-20 All these disorders were
Complete IFN-γR1 and IFN-γR2 Deficiencies
KEY CONCEPTS Autosomal recessive (AR) complete IFN-γ receptor 1 (IFN-γR1)
deficiency (OMIM 107470) is caused by recessive null IFNGR1
• New primary immunodeficiencies (PIDs) should be sought in patients mutations precluding the expression of IFN-γR1 on the cell
with unexplained infectious diseases. surface or the recognition of its ligand, IFN-γ, by surface-expressed
• Children with severe infectious diseases should be repeatedly receptors. Affected patients fail to respond to IFN-γ and have
investigated for known and unknown immunodeficiency conditions. high serum concentrations of IFN-γ after infection. Mutations
1
• The exploration of idiopathic infections leads to the discovery of new
PIDs and to a better understanding of immunity to pathogens. of the IFNGR2 gene encoding IFN-γR2 lead to a complete loss
of cellular responsiveness to IFN-γ because of a lack of receptor
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