Page 537 - Clinical Immunology_ Principles and Practice ( PDFDrive )

516 ParT fOur Immunological Deficiencies

to consanguineous Saudi parents, suffered from HSE at the age fibroblasts from both patients displayed normal IFN responses
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of 2 years. A homozygous nonsense mutation, R141X, was to the TLR3-independent agonists and viruses tested. AD TBK1
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identified as the cause of her AR TRIF deficiency. Another patient, deficiency, therefore, confers narrow, partial cellular phenotypes,
with AD TRIF deficiency, of mixed European descent (French, probably accounting for the narrow clinical phenotype of
Portuguese, and Swiss), suffered from HSE at the age of 21 months. these patients, which is limited to HSE. The two patients with
A heterozygous missense mutation, S186L, led to AD TRIF TBK1 deficiency suffered from HSE at the ages of 7 years and
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deficiency in this girl. . The two patients with TRIF deficiency 11 months, respectively. During subsequent follow-up over a
have displayed no other unusually severe infectious diseases period of years, they have suffered no other unusual infectious
during follow-up to date. The TLR3 signaling pathway was found diseases, including viral diseases, in the absence of prophylaxis.
to be impaired in cells from patients with both AR and AD TRIF As in other HSE patients with genetic deficiencies of the TLR3
deficiencies, whereas the TRIF-dependent TLR4 pathway was pathway, treatment with recombinant IFN-α, in parallel with
affected only in patients with AR TRIF deficiency. Interestingly, acyclovir, may be considered in patients with TBK1 deficiency
abnormally weak responses to stimulation of the DExD/H-box and HSE.
helicase pathway have been observed in both AR and AD TRIF-
deficient fibroblasts. These results demonstrate the importance IRF3 Deficiency
of TRIF for the TLR3-dependent production of antiviral IFNs IRF3 is a transcription factor that controls multiple IFN-inducing
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in the CNS during primary infection with HSV-1. However, pathways, including the TLR3 pathway, which can be triggered
they also suggest that the TRIF-dependent TLR4 and, probably, by dsRNA, and the pathways triggered by other RNA and DNA
the DExD/H-box helicase pathways, are largely redundant in sensors. IRF3 is normally activated by TBK1 and/or IKKε kinases.
host defense in humans. A missense IRF3 mutation has been identified in a 15-year-old
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patient with HSE. The resulting mutant IRF3 protein could not
TRAF3 Deficiency activate transcription and was dominant through haploinsuf-
A French patient with AD TRAF3 deficiency and HSE has recently ficiency. In heterozygous cells, haploinsufficiency for IRF3 impairs
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been identified. The de novo germline heterozygous missense the induction of antiviral IFN-α/β in leukocytes following
mutation in this patient is loss-of-expression, loss-of-function, stimulation with various agonists. Moreover, the induction of
and dominant-negative. Fibroblasts from the patient displayed IFN-β in fibroblasts stimulated with poly(I:C), which mimics
impaired responses to TLR3 agonist stimulation, in terms of viral dsRNA and activates TLR3, was also impaired. Finally, IFN-β
IFN-β and -λ production. Various TRAF3-dependent pathways induction by HSV1 was impaired in fibroblasts. Overall, consistent
were impaired in the patient’s cells, including the IFN-α/β-, and with the key role of IRF3 in inducing IFN-α/β, a profound,
IFN-λ–inducing and TNF-R–responsive pathways. However, broad cellular phenotype was observed in patients with AD IRF3
there was sufficient residual TRAF3-dependent signaling for most deficiency. Despite the broad impact of AD IRF3 deficiency, in
defects to remain clinically silent. By contrast, the impaired TLR3 terms of both the pathways and cell types affected, its clinical
response was symptomatic and caused HSE, implying that the phenotype in the single patient identified to date is surprisingly
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TLR3 pathway is critically dependent on TRAF3 and essential narrow, restricted to HSE. Moreover, clinical penetrance is
for immunity to HSV-1 in the CNS. The first clinical signs of incomplete, as a heterozygous relative of the patient is healthy.
HSE in the patient with TRAF3 deficiency appeared at the age Overall, the discovery of IRF3 deficiency in a patient with HSE
of 4 years. The patient with TRAF3 deficiency and HSE described suggests that IRF3 is a key component in TLR3-dependent,
here is now 18 years old and has otherwise remained healthy IFN-mediated, CNS-intrinsic immunity to HSV-1. It also adds
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with no prophylaxis. She shows normal resistance to other weight to the emerging notion that impaired TLR3-IFN immunity
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infectious diseases, including viral diseases, in particular. We can underlie HSE of childhood, suggesting that IFN treatment
cannot yet exclude the possibility that other forms of human may be beneficial to patients. 9
TRAF3 deficiency are involved in other human diseases, including
viral diseases, but TRAF3 deficiency should be sought in other IRF7 Deficiency
children with HSE. AR complete IRF7 deficiency was identified, in 2015, as the first
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genetic etiology of severe isolated influenza (OMIM 616345).
TBK1 Deficiency A 30-month-old girl born to nonconsanguineous French parents
The identification of AD TBK1 deficiency as a new genetic was admitted to intensive care for 3 weeks and required respiratory
etiology of isolated childhood HSE was probably the greatest support for 10 days because of pandemic H1N1 (pH1N1) 2009
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surprise to come out of human studies to date. TBK1 is a kinase influenza A virus (IAV)–induced acute respiratory distress
at the crossroads of multiple IFN-inducing signaling pathways, syndrome. This patient carries compound heterozygous mutations,
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including those mediated by TLR3, cytosolic double-stranded RNA p.F410V and p.Q421X, in IRF7, encoding IRF7. Each of her
(dsRNA) sensors, and dsDNA sensors. Two unrelated children parents has a single heterozygous mutation, and neither has any
with HSE were found to carry different heterozygous missense significant infectious disease history. IRF7 is required for the
mutations in the gene encoding TBK1. Both mutations underlie production and amplification of the antiviral type I (IFN-α/β)
a phenotype that is dominant, but presumably by different and III (IFN-λ) IFNs. The patient’s fibroblasts displayed impaired
mechanisms: negative dominance (G159A) and haplotype insuf- IFN-β and IFN-λ1 production in response to various stimuli,
ficiency (D50A). A defect in poly(I:C)–induced TLR3 responses including IAV. Consequently, IAV replication resulted in titers
was detected only in fibroblasts from the patient carrying the 100 times higher in the patient’s fibroblasts than in fibroblasts
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dominant-negative TBK1 mutation. Nevertheless, levels of viral from a healthy donor. Furthermore, type I IFN production was
replication and cell death caused by two TLR3-dependent viruses abolished in the patient’s plasmacytoid DCs, a cell type that
(HSV-1 and VSV) were high in fibroblasts from both patients. normally produces constitutively high levels of IRF7 and, therefore,
However, the peripheral blood mononuclear cells (PBMCs) and large amounts of type I IFN. Moreover, pulmonary epithelial