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Chapter 51 Congenital Disorders of Lymphocyte Function 719

mutations of the FASLG gene (ALPS-FASLG), of caspase 8, caspase containing lytic granules are transported and dock and fuse with
10, Fas-associated death domain (FADD) protein, or by somatic acti- the cell membrane, permitting release of cytotoxic proteins into the
vating mutations of N-RAS or K-RAS. Finally, autosomal recessive target cells.
deficiency of protein kinase C (PRKCD), which plays an important
role in regulating cell survival and apoptosis, also causes an ALPS-like
disease with B-cell lymphoproliferative disease. Hemophagocytic Lymphohistiocytosis
Lymphoproliferation, manifesting as lymphadenopathy, spleno-
megaly, or hepatomegaly, is the most common clinical manifesta- Defects in the intracellular transport and release of cytolytic gran-
tion, with a trend toward progressive remission in adulthood. More ules are responsible for various forms of familial HLH, including
than 70% of ALPS patients develop autoimmune disease—most deficiency of Munc13-4 (required to prime vesicles), syntaxin 11
commonly immune cytopenias, less frequently organ-specific and Munc18-2 (both of which promote vesicle fusion with the cell
autoimmunity. There is an increased risk of malignancies, especially membrane), and perforin. In these disorders, infections (mostly
EBV-associated non-Hodgkin lymphoma. Patients with PRKCD caused by viruses) trigger an uncontrolled immune response mediated
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deficiency often present SLE-like manifestations, with nephropathy by CD8 T lymphocytes and NK cells that secrete large amounts of
and antiphospholipid antibody syndrome. IFN-γ, which activates macrophages. Fever, liver, and spleen enlarge-
An immunologic signature of ALPS is the increased number of ment, lymphadenopathy, profound cytopenias, hypoalbuminemia,
DN circulating T lymphocytes that express the αβ form of the TCR, coagulopathy, high levels of ferritin and triglycerides, and immune
but do not express CD4 or CD8 molecules. There is defective in activation (with increased levels of soluble CD25) characterize these
vitro apoptosis of lymphocytes through the Fas-mediated or intrinsic acute episodes, which may lead to multiple-organ failure and death.
pathway (depending on the genetic variant). Elevated levels of soluble The diagnosis of these familial forms of HLH is facilitated by flow
Fas ligand, vitamin B12, and IL-10, Hypergammaglobulinemia, and cytometric analysis of surface expression of CD107a (a protein
anti-phospholipid antibodies are often present in patients with ALPS- normally contained in endosomal vesicles) upon in vitro activation
FAS. By contrast, patients with PRKCD deficiency have low levels of cytotoxic T cells and NK cells. Defective expression of CD107a
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of IgG and an increased proportion of CD5 B cells. Patients with is observed in patients with Munc13-4, Munc18-2, and syntaxin 11
caspase 8 deficiency, FADD deficiency, and PRKCD deficiency have deficiencies. By contrast, this test is normal in patients with perforin
recurrent infections. The number of DN T cells may be normal in deficiency, in which reduced or absent expression of perforin can be
patients with NRAS or KRAS mutations. easily demonstrated by flow cytometry.
Treatment is based on immunosuppression (with steroids, ritux-
imab, mycophenolate mofetil, or sirolimus) and surveillance against
lymphoma. Splenectomy may improve cytopenias; however, relapse HLH Associated With Pigmentary Dilution Disorders
of autoimmunity has been observed in 50% of the splenectomized
patients. Furthermore, severe, invasive bacterial infections have been Typical features of HLH are also observed in some pigmentary dilu-
reported in 30% of splenectomized patients, and the mortality rate tion disorders. In particular, Chediak-Higashi syndrome (CHS) is an
for invasive bacterial infection after splenectomy is as high as 13.3%. autosomal recessive disease due to mutations of the LYST gene, which
encodes for a protein involved in the sorting of proteins to secre-
tory endosomes. This defect affects not only cytotoxic lymphocytes
Other Conditions With Immune Dysregulation (accounting for FHL-like clinical features), but also melanocytes (that
are unable to transfer melanin to keratinocytes and other epithelial
Gain-of-function mutations of the STAT1 gene cause a variable cells) and peripheral neurons. Clinical features of CHS include partial
clinical phenotype ranging from chronic mucocutaneous candidiasis albinism (with silvery hair), progressive peripheral neuropathy, recur-
to increased occurrence of viral, fungal, and bacterial infections, to rent bacterial infections, and mild tendency to bleeding. Neutropenia
autoimmunity. is often present and may cause bacterial infections. Giant lysosomes
Gain-of-function mutations of the STAT3 gene cause increased can be identified in circulating leukocytes.
STAT3 signaling and enhanced Th17 differentiation, with lympho- Griscelli syndrome type 2 (GS2) is caused by mutations of the
proliferation and solid-organ autoimmunity. The number of Treg RAB27A gene, which encodes for a protein involved in docking of
cells is reduced. secretory granules of cytotoxic lymphocytes and melanocytes to the
Deficiency of ITCH, an E3 ubiquitin ligase that regulates cell membrane. Accordingly, patients with GS2 present with HLH
activation of phospholipase Cγ1 (PLCγ1), causes multiple auto- and hypopigmentation. The diagnosis is facilitated by the demonstra-
immune manifestations (enteropathy, thyroiditis, type 1 diabetes, tion of large clumps of pigment distributed irregularly along the hair
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hepatitis), interstitial lung disease, dysmorphic features, and devel- shaft, and by reduced expression of CD107a on the surface of CD8
opmental delay. and NK lymphocytes upon in vitro activation.
Defects of IL-10 and IL-10R are responsible for very early onset Hermansky-Pudlak syndrome type 2 is an autosomal recessive
inflammatory bowel disease. disorder caused by mutations of the AP3B1 gene, which encodes
Mutations of the tripeptidyl-peptidase II (TPP2) gene cause severe for the β component of the AP-3 complex, involved in sorting of
autoimmune hemolytic anemia, variable lymphoproliferation, and transmembrane proteins to secretory lysosomes. Clinical manifes-
recurrent infections. Accelerated senescence of lymphoid cells and tations include partial albinism, nystagmus, prolonged bleeding,
hypergammaglobulinemia are observed. recurrent bacterial and viral infections, and increased risk of HLH.
Pigmentary abnormalities, neutropenia, platelet dysfunction (with
absence of dense granules and reduced platelet aggregation), and
DEFECTS OF CELL-MEDIATED CYTOTOXICITY defective cytotoxic activity account for the clinical manifestations
of the disease.
Mechanisms of immune defense against viral infections are largely Irrespective of the nature of the genetic defect, HLH therapy is
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dependent on responses mediated by CD8 cytotoxic T lymphocytes based on the prompt and aggressive treatment of underlying infec-
(CTLs) and NK lymphocytes. Multimers of perforin, a protein tions and immunosuppression to curtail macrophage activation.
contained in cytolytic granules, form pores through which CTL Administration of humanized anti-IFN-γ monoclonal antibodies
and NK cells release cytotoxic proteins (granzyme B, granulolysin) may block continuous activation of the immune system and induce
into virus-infected target cells, causing activation of caspases and remission. Ultimately, definitive treatment is based on allogeneic
apoptosis. In resting CTLs and NK lymphocytes, cytotoxic pro- HCT from a matched related or unrelated donor, and the best results
teins are contained in endosomal secretory lytic granules. Follow- are obtained using reduced-intensity conditioning. Mixed chimerism
ing interaction of CTLs or NK cells with the target cell, vesicles is sufficient to correct the immunologic abnormalities.