Page 832 - Hematology_ Basic Principles and Practice ( PDFDrive )

718 Part VI Non-Malignant Leukocytes

diabetes. Other autoimmune manifestations (hepatitis, ovarian Cytotoxic T Lymphocyte Antigen 4 Deficiency
failure) are also common. Hyposplenism has been reported in one
study. Candidiasis may reflect elevated levels of antibodies to IL-17 Cytotoxic T lymphocyte antigen 4 (CTLA4) is a surface molecule
and IL-22, which play an important role in the defense against expressed by conventional and regulatory T cells. It competes with
Candida spp. CD28 for binding to CD80/CD86 molecules expressed by antigen-
Management of patients with APECED is based on regular presenting cells. However, in contrast to CD28, CTLA4 delivers a
follow-up and search for autoantibodies, which should be repeated suppressive signal that limits T-cell activation. Heterozygous loss-of-
every 6 months. Hormone-replacement therapy is indicated for the function mutations of CTLA4 cause a condition characterized by
endocrinopathies. Aggressive management and prevention of candi- lymphoid infiltrates in the lung, gastrointestinal tract, and the brain
diasis is important to avoid persistent or recurrent infections that may (simulating lymphoma), autoimmune cytopenias, hypogammaglobu-
favor development of squamous cell carcinoma. linemia, lymphopenia, accumulation of activated T cells, and
decreased Treg cell function. The disease is inherited as an autosomal
Immune Dysregulation Polyendocrinopathy Enteropathy dominant trait with incomplete penetrance. Treatment is based on
use of CTLA4-Ig (abatacept) and sirolimus. HCT may be considered
X-Linked Syndrome in severe cases.

Immune dysregulation polyendocrinopathy enteropathy X-linked
(IPEX) is an X-linked disorder of systemic autoimmunity. Males with Lipopolysaccharide Responsive Beige-Like Anchor
IPEX syndrome present early in life with skin rash, intractable watery Protein Deficiency
diarrhea, insulin-dependent diabetes mellitus, lymphadenopathy,
splenomegaly, and failure to thrive. Other autoimmune manifesta- Deficiency of the lipopolysaccharide responsive beige-like anchor
tions include thyroid disease, nephropathy, cytopenias, and vasculitis. protein (LRBA) is inherited as an autosomal recessive trait and causes
In addition, patients with IPEX show elevated levels of IgE. a combined immunodeficiency with prominent immune dysregula-
IPEX is caused by mutations of the FOXP3 gene, which encodes tion affecting mostly the gastrointestinal tract (with severe chronic
for a transcription factor that plays a critical role in the development diarrhea and failure to thrive) and the lungs. Autoimmune cytopenias
and function of regulatory T (Treg) lymphocytes. These cells have are also common. Typical immunological abnormalities include
+
suppressive functions; they have a distinctive phenotype (CD4 hypogammaglobulinemia and a variable degree of lymphopenia, with
+
+
hi
CD25 FOXP3 ) and normally represent 5% to 15% of CD4 cir- increased proportion of activated T cells. The disease shares some
culating lymphocytes. Most patients with IPEX lack Treg cells; acti- clinical and immunologic manifestation similarities with CTLA4
vated self-reactive T lymphocytes infiltrate target tissues and secrete deficiency. Indeed, LRBA binds to CTLA4 and allows endosomal
cytokines, causing tissue damage. trafficking of the latter to the cell membrane. In the absence of LRBA,
IPEX has a severe prognosis. Death often occurs within the first CTLA4 is targeted to the lysosomal compartment where it is
few years of life due to severe malabsorption, failure to thrive, meta- degraded. Consistent with this, Treg cells from patients with LRBA
bolic derangement, or because of severe infections secondary to deficiency have low levels of expression of CTLA4 and FOXP3, and
immune suppression. Use of immunosuppressive drugs (steroids, the actual number and function of Treg lymphocytes are impaired.
sirolimus, tacrolimus, rituximab) is necessary to treat the disease. Treatment with CTLA4-Ig (alone or in combination with sirolimus)
However, the only definitive treatment is allogeneic HCT. Mixed may be beneficial.
chimerism is sufficient to control the disease; therefore, reduced-
intensity conditioning has been used with good results.
Defects of Calcium Flux
CD25 and STAT5B Deficiencies T lymphocyte activation and homeostasis depend on calcium mobi-
lization. In particular, TCR-induced activation results in release of
2+
2+
IL-2 plays an important role in T lymphocyte proliferation and in Ca from the endoplasmic reticulum stores, followed by Ca entry
2+
immune homeostasis. Upon binding to the high-affinity IL-2 recep- through the Ca release-activated channels (CRAC) located in the
tor, IL-2 promotes phosphorylation and nuclear translocation of the cell membrane. Mutations of STIM1 (which encodes for a sensor of
transcription factor signal transducer and activator of transcription endoplasmic reticulum calcium stores) and of ORAI1 (which encodes
(STAT)5, which drives expression of IL-2 target genes, including for CRAC) cause severe immunodeficiency in which T-lymphocyte
FOXP3. Autosomal recessive mutations of the IL2RA (CD25) gene, generation in the thymus is not affected, but peripheral T cells are
which encodes for the α chain of the IL-2 receptor, cause a disease functionally impaired. Autoimmunity and nonprogressive myopathy
that is associated with IPEX-like manifestations (lymphadenopathy, are distinguishing features of these disorders.
hepatosplenomegaly, autoimmune cytopenias, inflammatory bowel
disease) and increased susceptibility to severe viral infections. The
number of circulating T cells may be normal or slightly reduced, and Autoimmune Lymphoproliferative Syndrome
in vitro proliferative response to mitogens is decreased. The patients’
T cells produce reduced amounts of the immunosuppressive cytokine Interaction between Fas (CD95) on activated T and B lymphocytes,
IL-10 upon in vitro activation. HCT represents the only definitive and Fas ligand (FASLG) on activated T cells triggers the extrinsic
treatment. pathway to activation of the caspase cascade, culminating in apopto-
Autosomal recessive mutations of the STAT5B gene cause a syn- sis. In addition, cellular stress (including cytokine deprivation) may
drome characterized by autoimmunity (especially cytopenias and activate the intrinsic pathway of apoptosis, leading to disruption of
autoimmune hepatitis), eczema, severe and/or recurrent infections, mitochondrial membrane permeability, release of cytochrome c,
lymphocytic interstitial pneumonia, and growth hormone (GH)- activation of caspase 9 and apoptosis. Defects of Fas- or mitochondrial-
insensitive dwarfism. The latter reflects the critical role played by dependent apoptosis are responsible for autoimmune lymphoprolif-
STAT5 in the cellular response to GH. Affected patients have a low erative syndrome (ALPS), characterized by early-onset, chronic (>6
number of circulating T and NK lymphocytes and Treg cells, and in months), nonmalignant lymphoproliferation, autoimmunity, and
vitro proliferative responses to mitogens are reduced. In contrast, IgG increased risk of lymphoma.
levels are often elevated. Aggressive treatment of infections, use of The majority of patients with ALPS carry heterozygous dominant-
immunosuppressive drugs to treat autoimmune manifestations, and negative mutations in the FAS (CD95, TNFRSF6) gene (ALPS-FAS).
regular monitoring of pulmonary function are the mainstay of Somatic mutations of the FAS gene are the second most common
treatment. cause of the disease (ALPS-sFAS). More rarely, ALPS is caused by