Page 1253 - Williams Hematology ( PDFDrive )

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

cytolytic granzymes A and B. Different genetic defects can affect various Treatment and Prognosis
steps in the formation, intracellular transport, and delivery of cytolytic Without treatment, FHL is usually rapidly fatal. Treatment of active
granules, 228,229 and result in different defects of cell-mediated cytotoxic- disease should focus on controlling or eliminating possible triggers
ity, that include various forms of familial hemophagocytic lymphohisti- (infections in particular), blocking T-cell activation, and stopping the
ocytosis (FHL), Chédiak-Higashi syndrome, Griscelli syndrome type II, hyperinflammatory cytokine response. To this purpose, antimicrobi-
and Hermansky-Pudlak syndrome type II. Overall, these disorders are als, etoposide, immune suppression (antithymocyte globulin), cyclo-
characterized by increased susceptibility to severe viral infections that sporine, and dexamethasone are commonly used. 239,241 Alemtuzumab
in some cases is associated with defects of hair and skin pigmentation, has shown some efficacy in controlling etoposide-resistant forms.
242
and neurologic problems. Dysregulation in CTL and NK homeostasis, However, relapses are common in FHL. Patients should be monitored
with increased production of inflammatory cytokines and accumula- carefully for reactivation of the disease, especially in the central ner-
tion of activated lymphocytes, characterizes the two genetic variants of vous system. Administration of anti–IFN-γ monoclonal antibody has
X-linked lymphoproliferative syndrome (XLP1 and XLP2). given interesting results in animal model of the disease, and is cur-
243
rently being tested in a clinical trial. Permanent cure for FHL can be
only provided by allogeneic HSCT. A higher success rate is obtained
FAMILIAL HEMOPHAGOCYTIC when HLA-matched related or unrelated donors are available. Use
LYMPHOHISTIOCYTOSIS of myeloablative conditioning regimen is associated with high trans-

FHL includes a group of genetically heterogeneous conditions that are plantation-related mortality. Considering that partial chimerism is
enough to achieve disease control, reduced intensity condition-
244
characterized by the uncontrolled proliferation of activated lympho- ing is being increasingly used, with promising results. Outcome
245
cytes and histiocytes that secrete large amounts of proinflammatory of HSCT is worse if the disease is not in remission at the time of
cytokines. This results in life-threatening manifestations, characterized transplantation.
by fever, hepatosplenomegaly, marrow infiltration and pancytopenia,
and severe neurologic manifestations (Chap. 71).
There are at least five different forms of FHL, four of which X-LINKED LYMPHOPROLIFERATIVE DISEASE
have been defined at the molecular level. FHL2 is caused by muta-
tions of the PRF1 gene, which encodes perforin. FHL3 is caused by Definition and History
230
mutations in UNC13D, also known as Munc13–4. FHL4 is caused In 1975, Purtilo described a family in which numerous males in mul-
231
by defects of the STX11 gene, that encodes syntaxin 11, whereas tiple generations presented with fulminant infectious mononucleosis,
232
FHL5 is a result of mutations of the STXBP2 gene, that encodes for lymphoma, or hypogammaglobulinemia after primary EBV infection.
246
233
Munc18–2, a protein that interacts with STX11. Each of these XLP1 is caused by mutations in the SH2D1A gene 247,248 that encodes an
defects interferes with a specific step of the cytolytic machinery, and adaptor protein (SLAM [signaling lymphocyte activation molecule]-
ultimately causes inefficient pathogen clearance, uncontrolled activa- associated protein [SAP]) involved in T- and NK-cell signaling. Thus,
249
tion of CTLs, and release of IFN-γ and other inflammatory cytokines, defects of SAP drastically affect both T- and NK-mediated cytotoxic-
resulting in recruitment and activation of macrophages, and inhibi- ity. 250–252 SAP also plays an important role in germinal center formation
tion of hematopoiesis. and antibody production by modulating development and function of
follicular helper T cells. Finally, SAP is required for the development
253
of iNKT cells, which are immunoregulatory cells that are involved in the
Clinical and Laboratory Features responses to pathogens and cancer cells. In the absence of SAP, EBV
254
In approximately 85 percent of the cases, FHL becomes clinically evi- and other virus infections result in dysregulated immune responses,
234
dent within the first year of life, but late presentations may occur in because of persistent antigenic stimulation that leads to hyperactive
patients with hypomorphic mutations. 235–237 High fever, severe hepa- cytotoxic T lymphocytes and macrophages, with increased production
tosplenomegaly, lymphadenopathy, hemorrhagic manifestations as a of IFN-γ.
result of thrombocytopenia, and edema are common. Neurologic symp- However, not all males with X-linked lymphoproliferative syn-
toms, including seizures and decreased level of consciousness, may lead drome (XLP) features have mutations in SH2D1A and mutations in
to long-term disability. 238 another X-chromosome–associated gene (XIAP; X-linked inhibitor of
239
The FHL diagnostic guidelines were updated in 2007. Anemia apoptosis, also known as BIRC4) have been identified, resulting in
255
and thrombocytopenia are early signs followed by increased serum XLP2.
levels of triglycerides, bilirubin, liver enzymes, ferritin, and coagula-
tion abnormalities. Hemophagocytosis can be observed in the marrow, Clinical and Laboratory Features
lymph nodes, and cerebrospinal fluid, which often shows abundant Although lymphoproliferative disease is observed in both XLP1 and
mononuclear cells and increased proteins, even in the absence of overt XLP2, there are some important differences in the disease phenotype.
neurologic symptoms. Immunologic findings include persistently Most often, XLP1 becomes clinically manifest following EBV infection
impaired cytolytic activity of NK cells and elevated levels of inflamma- in childhood, although later presentations are possible. Fulminant infec-
tory cytokines (IFN-γ, IL-1, IL-6, TNF-γ) in the blood. Monitoring cir- tious mononucleosis has been observed in 50 to 60 percent of cases, and
culating soluble CD25 (IL-2Rα) is also useful as a measure of increased EBV-related lymphoma in 30 percent of the cases. Most lymphomas are
cellular activation. of B-cell origin, and approximately half are of the Burkitt type. Persis-
Flow-cytometry enables analysis of perforin expression, which is tent dysgammaglobulinemia, with low IgG and low to increased levels
absent except for hypomorphic mutations, and may thus facilitate diag- of IgM, is common among survivors. Other clinical manifestations of
nosis of FHL2. The diagnosis of FHL forms that are characterized by XLP1 include vasculitis, marrow aplasia secondary to hemophagocytic
reduced NK cell degranulation (such as UNC13D and STX11 defects) lymphohistiocytosis, and lymphoid granulomatosis.
may be facilitated by the analysis of membrane expression of the lysoso- Although less frequently encountered, other viral infections (CMV,
mal marker CD107a. 240 other herpes viruses) may unmask the clinical phenotype of XLP1. 256

Kaushansky_chapter 80_p1211-1238.indd 1228 9/18/15 10:02 AM