Page 535 - Clinical Immunology_ Principles and Practice ( PDFDrive )

514 ParT fOur Immunological Deficiencies

and possibly antiviral treatment directed against herpes viruses
NEMO and CYBB Deficiencies should be administered without interruption, and HSCT should
An X-linked recessive (XR) form of MSMD (XR-MSMD) (OMIM be considered for these patients. Vaccination with live BCG is
300248) was discovered in three unrelated kindreds. This condition contraindicated. Partial, as opposed to complete, AR STAT1
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was caused by two neighboring mutations (E315A and R319Q) deficiency has also been described in three unrelated kindreds.
in NEMO. 1,37 These two missense mutations, which affect two These patients suffered from mild mycobacterial and viral diseases.
neighboring residues in the leucine zipper domain that normally Their responses to IFN-γ and IFN-α were impaired, but not
form a salt bridge, were entirely responsible for impairment of abolished, in terms of GAF- and ISGF3-mediated immunity. AR
the CD40-triggered induction of IL-12 production by monocyte- complete and partial STAT1 deficiencies constitute an innate
derived cells following stimulation with CD40L-expressing T immunodeficiency, ranging from lethal to moderate clinical
cells. Four maternally related male patients from two successive disease, and a diagnosis of STAT1 deficiency should be considered
generations presented M. avium infection only, and the other two, in infants and children with infectious diseases, particularly (but
unrelated patients presented only mycobacterial disease. These not exclusively) if mycobacterial and viral in nature. 24
patients had a purely mycobacterial infectious phenotype, with
no sign of anhidrotic ectodermal dysplasia (EDA). 1,37 GENETIC DISORDERS OF THE TLR3–IFN-α, IFN-β,
A second form of XR MSMD has been reported (OMIM AND IFN-λ PATHWAY
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300645) in seven patients from two unrelated French families.
The CYBB or gp91 phox mutations identified in these patients were This group of genetic disorders leads to impaired TLR3 signaling
previously unknown and affect the transmembrane domain and and susceptibility to HSE in childhood. The affected patients bear
an extracellular loop. CYBB encodes the major component of mutations of TLR3, UNC93B1, TRIF, TRAF3, TBK1, or IRF3
the nicotinamide adenine dinucleotide phosphate (NADPH) (Fig. 36.4). The TLR3 signaling pathway is mediated exclusively
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oxidase complex. Mutations in any of the genes encoding by the TRIF adapter and leads to activation of the transcription
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molecules from this complex generally result in chronic granu- factors IRF3 and NF-κB (see Fig. 36.4). TRIF recruits TNF
lomatous disease (CGD). However, unlike the cells of patients receptor–associated factor 6 (TRAF6) and activates TAK1 for
with CGD, neutrophils, monocytes, and monocyte-derived NF-κB activation. TRIF also recruits a signaling complex involving
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dendritic cells (MDDCs) from these seven patients with XR TBK1 and IKKε via TRAF3 for IRF3 activation. This signaling
MSMD displayed perfectly normal levels of NADPH oxidase pathway induces the production of type I and type III IFNs and
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activity. These patients produce only small amounts of neu- inflammatory cytokines and is important in antiviral immunity.
trophil and monocyte gp91 phox protein, but normal amounts of UNC-93B is a 12-transmembrane domain protein present in
cytochrome b 558 . However, monocyte-derived macrophages and the ER that delivers the nucleotide-sensing receptors TLR3, -7,
EBV-B cells display much more profound defects of gp91 phox -8, and -9 from the ER to endolysosomes. TRAF-3, TBK1, and
expression, resulting in impaired cytochrome b 558 assembly and IRF3 have functions downstream from multiple tumor necrosis
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low levels of NADPH oxidase activity. Thus NADPH oxidase factor (TNF) receptors and the receptors inducing IFN-α, -β,
activity in human macrophages is a crucial effector mechanism and -λ production, including TLR3.
for protective immunity to tuberculous mycobacteria. None of
the seven patients suffered from any other infectious diseases. TLR3 Deficiency
These patients are all adults and are currently well. Vaccination AD and AR forms of TLR3 deficiency caused by heterozygous,
with live BCG is contraindicated in patients with these deficiencies. compound heterozygous, or homozygous mutations of TLR3
4,8
None of the patients described, to date, has had prophylactic were first identified in 2007 (OMIM 613002). Six patients from
treatment. Infections can be treated with multiple antibiotics. 1 six unrelated kindreds have been reported, and each of these
patients developed childhood HSE as a result of AR or AD,
INHERITED DISORDERS OF IFN-γ– AND complete or partial TLR3 deficiency. There is a high degree of
IFN-α/β–MEDIATED IMMUNITY allelic heterogeneity, with three AD partial defects resulting from
negative dominance or haploinsufficiency, and two AR defects
AR Complete and Partial STAT1 Deficiency resulting from complete or partial deficiency. Some subsets of
Nine children from six unrelated kindreds with AR complete blood leukocytes (MDDCs, NK cells, and CD8 T cells) from
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STAT1 deficiency (OMIM 600555) have also been identified patients with TLR3 deficiency have an impaired response to
8,40
(unpublished data). These patients carried homozygous mutations stimulation with TLR3 agonist. The fibroblasts of the patients
that completely abolished cellular responses to both IFN-γ and produce low levels of the antiviral molecules IFN-β/-λ in response
IFN-α/β. Responses to IL-27 and IL-29 (IFN-λ) were abolished, to TLR3 agonist and HSV-1, leading to higher levels of viral
potentially accounting for the susceptibility of these children to replication and virus-induced cell death than for healthy control
bacteria and viruses, respectively. All patients had disseminated cells. Only one child from each of the kindreds identified
BCG disease. One patient died from recurrent encephalitis caused developed HSE. The patients with TLR3 deficiency developed
by HSV, a second died from an undocumented illness thought HSE upon primary infection with HSV-1 during childhood. Four
to be of viral origin, and a third died 3 months after HSCT, from (66%) of the six patients with TLR3 deficiency had at least one
EBV-induced lymphoproliferative disorder. The principal causes late relapse of HSE, whereas relapse generally occurs in only
8
of death in children with AR complete STAT1 deficiency are about 10% of HSE patients. All patients with HSC who had
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viral diseases or disseminated infection with BCG (unpublished TLR3 deficiency were exposed to other viruses during many
data). The outcome of viral illnesses in children with AR complete years of follow-up, as shown by the positive serological results
STAT1 deficiency suggests that the STAT1-dependent response obtained for other herpes viruses, with no subsequent acute
8
to human IFN-α/β is necessary for viral immunity. The patients events. None of the other individuals from the six kindreds
with AR complete STAT-1 deficiency had multiple, severe, early- with dominant or homozygous hypomorphic TLR3 mutations
onset viral infections. Multiple antibiotics against mycobacteria developed HSE despite serologically documented HSV-1 infection.