Page 1255 - Williams Hematology ( PDFDrive )

1230 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1231

IMMUNODEFICIENCIES WITH patients with null STAT1 mutations are also at risk for mycobacterial
288
disease.
SELECTIVE SUSCEPTIBILITY TO
PATHOGENS Other Immunodeficiencies with Increased Susceptibility to
Viral Infections
Although classical forms of PIDD are characterized by susceptibility Mutations of STAT2, leading to impaired response to IFN-α and
to a broad range of pathogens, several disorders have been identified IFN-β predispose to severe viral infections, including disseminated
with selective susceptibility to certain microorganisms. Some of these vaccine-strain measles. 289
diseases (e.g., mendelian susceptibility to herpes simplex virus enceph- Skin warts caused by HPV infection are the hallmark of epider-
alitis [HSE] or to pyogenic infections, especially S. pneumoniae) are the modysplasia verruciformis. This disease is caused by mutations of the
result of defects of innate immunity, in particular TLR signaling. Others EVER1 and EVER2 genes. There is an increased risk of squamous cell
290
(mendelian susceptibility to mycobacterial disease) involve defects of carcinoma.
the IL-12/IFN-γ axis at the interface of innate and adaptive immunity.
Susceptibility to recurrent meningitis caused by Neisseria meningitidis is
discussed in “Genetically Determined Deficiencies of the Complement Toll-Like Receptor Signaling Defects with Increased Suscepti-
System” below. bility to Pyogenic Infections
IRAK-4 and MyD88 deficiencies are characterized by recurrent and
invasive pyogenic bacterial infections, particularly from S. pneumoniae
IMMUNODEFICIENCIES WITH IMPAIRED and S. aureus. 123,291,292 These infections are common especially during
SIGNALING THROUGH TOLL-LIKE RECEPTORS the first years of life (when lethality rate can be as high as 50 percent),
293
TLRs are transmembrane proteins (Chap. 17) expressed on a variety of but their frequency tends to decline with age. Fever and systemic
cell types that recognize pathogen-associated molecular patterns, such inflammatory responses are absent or unusually modest, reflecting poor
as lipopolysaccharide derived from Gram-negative bacteria, lipopep- induction of inflammatory cytokines and reduced response through the
tide, double-stranded RNA that is generated during viral replication, IL-1R.
viral single-stranded RNA, viral cytosine phosphate guanine DNA Use of antimicrobic prophylaxis is important to prevent invasive
moieties, and flagellin. Although most TLRs are expressed at the cell pyogenic infections, especially in childhood. Substitution therapy with
surface, TLRs 7, 8, and 9 are expressed on the membrane of endosomal immunoglobulins may be beneficial in patients with impaired antibody
vesicles. 280 responses.
The recognition of pathogen-associated molecular patterns by
TLRs induces characteristic intracellular signaling. The classical path- Defects Involving Other Pattern-Recognition Signaling
280
way of TLR activation involves the adaptor molecules MyD88 (myeloid Pathways with Increased Susceptibility to Fungal Infections
differentiation factor 88) and toll–IL-1R domain-containing adaptor Several inborn errors of immunity have unraveled key mechanisms of
protein (TIRAP), and the intracellular kinases IL-1R–associated kinase defense against Candida. Chronic mucocutaneous candidiasis (CMC) is
(IRAK)-4 and IRAK-1, ultimately resulting in the nuclear transfer of a common complication affecting patients with APECED; it results from
177
NF-κB and the production of inflammatory cytokines (IL-1, IL-6, a mutation in the transcription factor AIRE. CMC also affects those
TNF-α, IL-12). TLRs 3, 7, 8, and 9 activate an alternative pathway that with AD-HIES; in this case, it is a result of mutations in the transcrip-
190
involves other adaptor molecules, such as TRIF, TRAF3, and the UNC- tion factor STAT3. Autoantibodies to IL-17 are a common feature of
93B protein, and ultimately results in the induction of type 1 interfer- APECED, 181,294 and Th17 differentiation is impaired in HIES because of
ons (IFN-α/β). Deficiencies of IRAK-4, MyD88, TLR3, and UNC-93B STAT3 mutations. The Th17 cytokines IL-17A, IL-17F, and IL-22 induce
have been identified in humans, and are associated with two distinct the synthesis of chemokines that recruit neutrophils, and promote
phenotypes. production of antimicrobial peptides from epithelial cells, thereby
playing a key role in mucocutaneous resistance to Candida spp.
Heterozygous, dominant negative mutations in IL17F gene, and bial-
Toll-Like Receptor Signaling Defects with Increased Suscepti- lelic loss-of-function mutations in the IL-17RA gene (encoding for the
bility to Herpes Simplex Virus Encephalitis α chain of IL-17 receptor) have been linked with CMC. Furthermore,
295
296
Selective susceptibility to HSE is associated with monogenic disorders mutations of the ACT1 gene (that encodes for an adaptor molecule
that affect TLR3, 281,282 or components of the TLR3 signaling pathway, that interacts with IL-17R) and gain-of-function STAT1 mutations
170
including UNC-93B, TRAF3, TRIF, and TBK1. The disease impairing Th17 immunity are associated with CMC.
285
286
283
284
reflects a CNS-intrinsic defect of neurons and oligodendrocytes to pro- Mutations of the CARD9 gene have been identified in patients with
duce type 1 IFN in response to herpes simplex virus (HSV). 287 CMC or disseminated candidiasis, including infection of the brain.
297
Because TLR3 recognizes double-stranded RNA and is normally CARD9 is recruited by Dectin-1, a transmembrane pattern-recogni-
expressed in CNS-resident cells, mutations of TLR3 or other compo- tion receptor that senses the β-glucan component of fungal cell walls,
nents of the TLR3-dependent signaling pathway impair the response of and together with other cytoplasmic proteins, forms an intracellular
these cells to actively replicating HSV-1. Because cellular responsiveness signaling complex that leads to the nuclear import of NF-κB and the
to type 1 IFN is intact in both UNC-93B–deficient and TLR3-deficient induction of key cytokines including IL-1, IL-6, IL-23, and the gener-
patients, the use of IFN-α along with acyclovir should be considered to ation of IL-17 cells, which are required to control antifungal immune
treat HSE in these patients. 281,287 responses. However, invasive fungal infections in CARD9 deficiency
HSE may also be a result of null mutations of STAT1, a transcrip- are not restricted to Candida, but also include other species, such as
298
tion factor that is activated upon interaction of type 1 IFN with their Exophiala, an environmental black yeast with low virulence. Granulo-
receptors, and is critical for the induction of IFN-responsive genes. cyte macrophage-colony stimulating factor (GM-CSF) therapy resulting
However, these patients are also prone to other severe viral infections. in complete clinical remission has been reported in one CARD9-
Furthermore, because STAT1 is also involved in the response to IFN-γ, deficient patient with relapsing albicans meningoencephalitis. 299

Kaushansky_chapter 80_p1211-1238.indd 1230 9/18/15 10:02 AM