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

MENDELIAN SUSCEPTIBILITY TO antimicrobial therapy; addition of IFN-γ may be useful in patients with
MYCOBACTERIAL DISEASE AD mutations in IFN-γR1 who are able to express reduced amounts
of normal IFN-γR1 on the cell surface. Recessive forms are resistant to
The IL-12/IFN-γ axis is essential for controlling mycobacterial infec- medical treatment. Although allogeneic HSCT may be curative, a high
tions. Following phagocytosis of mycobacteria, macrophages secrete rate of graft failure has been observed as a consequence of the inhibi-
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IL-12, a heterodimer composed of IL-12p40 and IL-12p70. IL-12 binds tory effect of high levels of circulating IFN-γ. 309
to the heterodimeric IL-12R (composed of IL12Rβ and IL-12Rβ
1
2
chains) expressed by Th1 and NK cells. This results in activation of the
JAK-STAT4 pathway, and ultimately in the production of IFN-γ, which GATA2
binds to its receptor (comprising IFN-γR1 and IFN-γR2 chains) on the The syndrome of monocytopenia, B-cell and NK-cell lymphopenia
surface of macrophages, triggering a signaling cascade that involves the associated with mycobacterial, fungal and viral infections, also called
transcription factor STAT1 and induction of IFN-γ-responsive genes MonoMAC syndrome or familial myelodysplasia/leukemia with
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that are essential to contain the infection and kill the mycobacteria. lymphedema (Emberger) syndrome was first described in 2010. One
A variety of defects along this pathway have been shown to account year later, heterozygous mutations in GATA2 resulting in haploinsuf-
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for mendelian susceptibility to mycobacterial disease (MSMD) in ficiency were identified as the molecular defect causing MonoMAC
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humans. The basis for increased susceptibility to mycobacterial dis- and Emberger syndrome. 312,313
ease in patients with NEMO deficiency was discussed in “X-Linked GATA2 plays a role in the early development of lymphatics and
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Anhydrotic Ectodermal Dysplasia with Immunodeficiency Caused by their valves, explaining the connection with Emberger syndrome. The
Mutations in Nuclear Factor-κB Essential Modulator” above. transcription of GATA2 occurs in early and undifferentiated hemato-
poietic cells, but also in somatic cells. Because of its progression to
IL-12p40 Deficiency myelodysplastic syndrome or acute myeloid leukemia, mortality can
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Affected patients are at increased risk of childhood infections because be as high as 28 percent. HSCT has successfully reversed clinical
of BCG and Salmonella; Candida infections have also been reported. symptoms. 315
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Recurrence of Salmonella infection is common. IL-12p40 can asso-
ciate with IL-12p70 to form the IL-12 heterodimer, or with IL-23p19 STAT1 Deficiency
subunit to form IL-23. Consequently, patients with IL-12p40 deficiency Complete STAT1 deficiency causes increased susceptibility to viral
have defects in both IL-12 and in IL-23–dependent immunity, with the infections and to mycobacterial disease with a severe clinical course
latter causing a Th17 deficiency. The clinical course is variable, with and early death. 288
some genetically affected siblings being asymptomatic, but approxi- Dominant partial STAT1 deficiency is caused by a heterozygous
mately 32 percent of symptomatic IL-12p40–deficient patients die pre- mutation that allows formation of the IFN-α/β-dependent ISGF3 tran-
maturely of infections. Treatment with antimicrobial drugs and IFN-γ scription factor, but abrogates expression of the γ-activating factor,
301
has been tried with variable results. which is composed of STAT1 homodimers. Affected individuals have
either a mild clinical course, characterized by selective susceptibility to
IL-12Rβ Deficiency mycobacterial infections, or are asymptomatic. 316
1
Autosomal recessive IL-12Rβ deficiency is characterized by infections Partial autosomal recessive STAT1 deficiency is associated with
1
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with mycobacteria of low virulence and Salmonella species. However, impaired, but not abrogated, IFN-α/β and IFN-γ signaling, and occur-
infections with Mycobacterium tuberculosis, Cryptococcus, and dissem- rence of severe, but curable, intracellular bacterial and viral infections. 317
inated coccidioidomycosis have also been reported. 302–304 Unlike sal- Heterozygous STAT1 gain-of-function mutations result in suscep-
monellosis, mycobacterial infections tend not to recur and the overall tibility to mycobacterial infections, candidiasis, and IPEX-like pheno-
prognosis is good. In most cases, IL-12Rβ expression on the cell surface type (see “Immune Dysregulation, Polyendocrinopathy, Enteropathy,
1
is absent, and in vitro IFN-γ production in response to IL-12 is abro- X-Linked–Like Syndromes” above). 171
gated. Treatment with appropriate antibiotics and IFN-γ is effective.
Other Genetic Disorders with Mendelian Susceptibility to
IFN-γR1 and IFN-γR2 Deficiencies Mycobacterial Disease
The genetic and biochemical pathophysiology of IFN-γR1 and IFN-γR2 Interferon-regulated factor 8 (IRF8) is a transcription factor that reg-
deficiencies are remarkably complex. Autosomal recessive forms are ulates the differentiation of granulocytes and macrophages, and the
most often associated with mutations that abrogate cell surface expres- development of DCs. IRF8 mutations in humans cause MSMD. Two
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sion of IFN-γR1 or result in the expression of receptors that do not bind variants of the disease have been described: an autosomal recessive form
IFN-γ. Partial autosomal recessive deficiency is the result of hypomor- characterized by extreme leukocytosis (up to 98 × 10 /L cells), marked
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305
phic mutations, with residual IFN-γ binding and signaling. Domi- expansion of lymphocytes and granulocytes, and absence of monocytes,
nant partial forms reflect the presence of heterozygous mutations in the myeloid DCs, and plasmacytoid DCs; and an AD variant, in which
cytoplasmic tail of IFN-γR1, allowing the expression of mutant mole- monocytes and DCs are present, but there is selective loss of IL-
+
cules on the cell surface (often in increased density because of defective 12–producing CD1c DCs. The clinical phenotype of autosomal reces-
receptor shedding) which are unable to mediate signal transduction. 306 sive IRF8 deficiency is more severe, with early onset, failure to thrive,
The severity of the clinical features reflects the nature of the bio- and disseminated BCG. HSCT is curative. The AD variant of the disease
307
chemical defect. Patients with complete deficiency develop severe is characterized by disseminated but curable BCG infection.
infections with environmental mycobacteria infections early in life, The interferon stimulated gene 15 (ISG15) protein is an IFN-
with lack of granuloma formation. Osteomyelitis caused by BCG or by α/β-inducible, ubiquitin-like protein involved in ISGylation, but can
environmental mycobacteria has been reported in several patients with be also secreted by granulocytes and act upon T and NK lymphocytes,
dominant partial IFN-γR1 deficiency. inducing IFN-γ production. Inherited ISG15 deficiency causes severe
Treatment of partial deficiency should be based on careful iden- MSMD, with disseminated BCG infection, which is responsive to
tification and typing of the mycobacterial strains and appropriate antimycobacterial treatment. 319

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