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1222 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1223

CONGENITAL ALOPECIA AND ABSENCE OF Cd25 Deficiency
THYMUS CD25 (IL-2 receptor α chain) was found to be deficient in three infants
from two unrelated families. Clinical features resemble those of both
Mutations of the FOXN1 gene, encoding for a transcription factor that IPEX and SCID. CD25-deficient infants presented with severe chronic
plays a critical role in development of thymic epithelial cells, causes diarrhea, villous atrophy and autoimmune hepatitis at an early age. 164,165
thymic aplasia, associated with congenital alopecia, nail dystrophy, and Early onset insulin-dependent diabetes was observed in one patient;
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a severe neural tube defect. This phenotype is the equivalent of the all presented with eczema and developed autoantibodies, hepatosple-
mouse nude/SCID phenotype. Successful outcome has been reported nomegaly, lymphadenopathy, and lymphocytic infiltrates in the lung,
after thymic transplantation. 160 gut, and liver. However, CD25-deficient patients suffered from infec-
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tious complications more commonly observed in patients with SCID,
including recurrent CMV pneumonitis, persistent thrush, and EBV
PRIMARY IMMUNODEFICIENCY infection. One patient was treated successfully with HSCT. 164
DISORDERS PRESENTING AS STAT5B Deficiency

AUTOIMMUNE DISEASES The transcription factor STAT5B is activated/phosphorylated in
response to growth hormone and the cytokines IL-2, IL-7, IL-15 and
The concept of a link between immune dysregulation and autoimmu- IFN-γ, and promotes the transcription of nonimmune and immune
nity has been strengthened by the discovery of distinct single-gene genes. STAT5B plays a crucial role in the transcription of insulin-like
defects resulting in unusual susceptibility to autoimmune diseases. The growth factor 1 (IGF-1), which is required for in utero and postnatal
three representative syndromes in this category include (1) IPEX, (2) growth. In addition, STAT5B is required for the transcription of IL-2Rα,
autoimmune polyendocrinopathy, candidiasis, and ectodermal dys- a crucial component of the IL-2 receptor necessary for induction of
trophy (APECED), and (3) the autoimmune lymphoproliferative syn- FOXP3, which programs the development of Tregs in the thymus.
drome (ALPS). The clinical phenotype of homozygous STAT5B deficiency reflects
these molecular observations. Affected patients suffer from intrauter-
IMMUNE DYSREGULATION, ine and postnatal growth failure from lack of IGF-1 resulting in growth
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POLYENDOCRINOPATHY, ENTEROPATHY, hormone insensitivity. Moderate T and NK cell lymphopenia may
be the cause of susceptibility to viral infections. Importantly,
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X-LINKED SYNDROME STAT5B-deficient patients have reduced numbers of Tregs with low
Clinical Findings FOXP3 expression, and decreased suppressor function. As a result of
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The most prominent IPEX symptoms include early onset diarrhea sec- abnormal Treg homeostasis, STAT5B-deficient patients have immune
ondary to autoimmune enteropathy, eczematous dermatitis, multiple dysfunction and multiple autoimmune problems, including arthritis,
endocrinopathies including early onset insulin-dependent type 1 diabe- lymphocytic interstitial pneumonia, severe eczema, autoimmune thy-
tes mellitus, thyroiditis, and, rarely, adrenal insufficiency. Autoimmune roiditis, and idiopathic thrombocytopenic purpura. 169
hemolytic anemia, thrombocytopenia, and neutropenia are common
complications. Eczema is the most frequent pathology of the skin, but STAT1 Gain-of-Function Mutations
erythematous, psoriasiform dermatitis, and alopecia universalis have been Heterozygous mutations in STAT1 were recently identified in patients
reported. Autoimmune hepatitis is present in 20 percent of IPEX patients. with chronic mucocutaneous candidiasis. These mutations were
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Lymphadenopathy and hepatosplenomegaly are less common. Loss of within the coiled-coil and DNA-binding domains, leading to hyper-
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small bowel villi and lymphocytic infiltrates in the intestinal mucosa, the phosphorylation of STAT1 in response to cytokines such as IFN-γ.
pancreas, thyroid, lung, and liver are commonly observed. Immunologic Screening of a cohort of patients with IPEX-like symptoms who also had
abnormalities include elevated serum IgA and IgE concentrations and the mucocutaneous fungal infections revealed heterozygous STAT1 gain of
absence of CD4 CD25 FOXP3 regulatory T cells. function mutations. The clinical characteristics included enteropathy
+
+
+
IPEX is caused by mutations in the FOXP3 gene located in the with villous atrophy, type I diabetes, thyroiditis, eczema, short stature,
+
centromeric region of the X chromosome. The transcription factor vascular aneurysms and viral infections. FOXP3 Treg numbers were
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FOXP3 binds to more than 700 promotors and acts as a transcriptional within the normal range, and showed normal suppressive function.
repressor of the IL-2, IL-4, and IFN-γ promoters by interfering with the It has been hypothesized that effector cells may be less responsive to
cytokine regulator, NFAT (nuclear factor of activated T cells). FOXP3 suppression as a result of excessive STAT1 activity.
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plays a crucial role in the generation of T-regulatory cells (Tregs) in the
thymus. STAT3 Gain-of-Function Mutations
A Finnish-British consortium discovered heterozygous gain-of-function
Treatment mutations in several patients with short stature, polyendocrinopathy
Immunosuppressive drugs such as cyclosporine, tacrolimus, sirolimus, including type 1 diabetes starting at a very young age (in utero or before
and glucocorticoids provide temporary remission. Allogeneic HSCT 3 weeks of age). The clinical phenotype included the presence of multi-
can cure this disease. 163 ple autoantibodies, celiac disease or autoimmune enteropathy, eczema,
thyroiditis, arthritis, autoimmune cytopenias and large granular lym-
IMMUNE DYSREGULATION, phocytic (LGL) leukemia in one in five patients. Except for eczema,
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POLYENDOCRINOPATHY, ENTEROPATHY, none of the patients with STAT3 gain-of-function mutations had the
X-LINKED–LIKE SYNDROMES clinical features of autosomal dominant (AD) hyperimmunoglobulin E
syndrome (HIES) as a result of heterozygous dominant negative STAT3
An IPEX-like phenotype has been associated with mutations in a num- mutations, although the mutations, all missense, were located in the
ber of genes, including CD25, STAT5B, STAT1 (gain-of-function muta- same domains (DNA binding, SH3 [Src homology 3], and transactiva-
tions) STAT3 (gain-of-function) and ITCH/AIP4. tion) as those observed in AD-HIES. When studied for STAT3 activity

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