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1228 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1229

Fulminant infectious mononucleosis is marked by a rapid increase partial oculocutaneous albinism, platelet functional abnormalities, and
of liver enzymes, followed by impaired coagulation, hepatic encephal- neurologic involvement. The disease is caused by mutations in the lys-
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opathy, and signs of hemophagocytic lymphohistiocytosis (HLH), asso- osomal trafficking regulator (LYST) gene. LYST plays an important role
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ciated with a high EBV viral load in the blood and other tissues. B-cell in sorting of lysosomal proteins, and in docking and fusion of lysosomal
lymphomas carry monoclonal immunoglobulin gene rearrangements. vesicles. 228
Patients who develop dysgammaglobulinemia show impaired antibody Patients are susceptible to recurrent pyogenic and viral infections.
responses. Antibody levels to the EBV nuclear antigen usually remain Bruises are common and reflect deficiency of the platelet specific gran-
undetectable, even in patients who survive the acute EBV infection. In ules responsible for secondary aggregation (Chap. 120). Both bacterial
contrast, antibodies to the EBV viral capsid antigen can be low to ele- and viral infections may trigger the life-threatening “accelerated phase”
+
vated. During clinical manifestations of XLP, the proportion of CD8 of the disease, characterized by high fever, hepatosplenomegaly, coagu-
T cells carrying activation markers is increased and the number of lation abnormalities, increase of liver enzymes and bilirubin (with pos-
+
–
memory (CD27 ), and specifically switched memory (CD27 IgD ) sible jaundice), edema, and neurologic symptoms, with seizures, ataxia,
+
B cells, is reduced. NK cell cytotoxicity is usually normal, when mea- cranial nerve palsies, and peripheral neuropathy. 269
sured in a conventional K562 killing assay. However, NK cytolytic activ- Abnormally large granules in lymphocytes, neutrophils, platelets,
ity is markedly reduced in XLP1, when costimulation through CD244 is melanocytes, and neurons represent a morphologic hallmark of the
provided. Flow cytometry can be used to detect a lack of SAP protein disease. Light microscopy examination of hair reveals large and evenly
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expression in circulating T and NK lymphocytes in patients with XLP1. 257 distributed granules of melanin. Reduced NK cytotoxic activity and
XLP2 often manifests with HLH, and EBV is a common trig- prolonged bleeding time are typical findings.
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ger. However, some important differences exist in the phenotype of Treatment requires control of infections, and immunosuppres-
XLP2 versus XLP1. In particular, recurrent splenomegaly often associ- sive intervention during the accelerated phase. Allogeneic HSCT, best
ated with cytopenia and fever is preferentially observed in XLP2, and performed during remission, is the only permanent cure of the immu-
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may represent an attenuated manifestation of HLH. By contrast, lym- nohematologic problems. However, HSCT does not seem to prevent
phoma, a common complication of XLP1, is not frequently observed progressive neurologic involvement. 272
in XLP2. Importantly, severe inflammatory bowel disease (IBD) has
been reported in a significant proportion of patients with XLP2, 258,259 Griscelli Syndrome Type 2
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and in some cases may represent the dominant clinical phenotype. Griscelli syndrome type 2 (GS2) is an autosomal recessive syndrome
Moreover, XLP2 may also manifest as delayed-onset Crohn disease. characterized by immunodeficiency and hypopigmentation, and a vari-
260
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The occurrence of IBD in XLP2 may reflect the notion that the RING able degree of neurologic involvement. The presence of immune defi-
domain of XIAP is required for NOD2 signaling. 261 ciency distinguishes GS2 from Griscelli syndrome type 1 (GS1; marked
A flow-cytometry-based assay can be used to facilitate differential by the association of partial albinism and neurologic involvement) and
diagnosis of XLP1 and XLP2. 262 Griscelli syndrome type 3 (GS3; with isolated hypopigmentation). GS2
is caused by mutations of the RAB27A gene, which encodes for a
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Treatment and Prognosis GTPase involved in intracellular transport of granules.
If untreated, approximately 70 percent of XLP1 patients die within GS2 patients are highly susceptible to recurrent pyogenic infec-
10 years of onset. The mortality rate is particularly high (96 percent) tions and to episodes of “accelerated phase” of the disease, with typi-
in patients who present with fulminant infectious mononucleosis. cal features of HLH. Prominent hypopigmentation is a result of large
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Allogeneic HSCT is the treatment of choice, yielding the best results clumps of melanin in the hair shafts. NK cytotoxicity is defective and
when the transplant is performed early in life, prior to EBV infection. CD107 expression at the cell membrane of NK lymphocytes is impaired
However, transplantation using reduced-intensity conditioning may upon coculture with target cells. Treatment is based on allogeneic
permit correction of the disease in EBV-positive patients with severe HSCT, and promising results have been reported with reduced intensity
organ toxicity. The use of anti-CD20 monoclonal antibody can reduce conditioning. 274
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viral load and improve the clinical status, and anti–TNF-α therapy or
etoposide may be beneficial in patients with active EBV infection and Hermansky-Pudlak Syndrome Type 2
severe systemic inflammatory response. 265–267 Administration of immu- This autosomal recessive disease is characterized by oculocutaneous albi-
noglobulin may reduce the risk of infections, but does not prevent or nism, bleeding tendency, recurrent infections, and moderate to severe
attenuate the symptoms of primary EBV infection. neutropenia (Chap. 120). Bone anomalies (with dysplastic acetabula),
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Similar survival rates have been reported in XLP2 and in XLP1. facial dysmorphisms and development of pulmonary fibrosis are also
However, this figure does not take into account forms of XLP2 that may part of the clinical phenotype. Hermansky-Pudlak type 2 is caused by
present with features other than HLH, and IBD in particular. Sulfasala- mutations of the AP3B1 gene that encode for the β subunit of the AP-3
1
zine, glucocorticoids, 5-amino salicylic acid, and anti-TNF medications endosomal protein, which is required for sorting of lysosomal mem-
have been used in the treatment of IBD in patients with XLP2, however brane proteins to the granules. Missorting of tyrosinase in melanocytes
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the only curative approach is allogeneic HSCT. Use of myeloablative accounts for oculocutaneous albinism. Reduced platelet-dense granules
conditioning is associated with high mortality and toxicity rate, but and impaired platelet degranulation are responsible for increased sus-
good results have been reported with reduced intensity conditioning. 268 ceptibility to bleeding. Absence of AP-3 leads to low intracellular content
of neutrophil elastase in myeloid progenitors causing neutropenia. Even
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CYTOTOXICITY DEFECTS ASSOCIATED WITH though CTL and NK cell cytolytic activity is defective, the risk of pro-
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PIGMENTARY DILUTION DISORDERS gression to HLH is lower than in Chediak-Higashi syndrome or GS2.
Consequently, preemptive use of HSCT is not justified.
Chédiak-Higashi Syndrome Hermansky-Pudlak syndrome type 9 is caused by mutations of the
Chédiak-Higashi syndrome is an autosomal recessive disorder charac- pallidin (PLDN) gene, and is characterized by recurrent infections, par-
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terized by immune dysregulation with impaired cellular cytotoxicity, tial albinism and nystagmus. NK cell cytolytic activity is impaired. 279

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