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720 Part VI Non-Malignant Leukocytes

X-Linked Lymphoproliferative Disease X-Linked Agammaglobulinemia

In normal individuals, primary infection with EBV causes infectious X-linked agammaglobulinemia (XLA), also known as Bruton’s agam-
mononucleosis, a self-limiting disease. EBV establishes latency in B maglobulinemia, is the most common monogenic cause of failure of
lymphocytes, salivary glands, and some epithelial cells, and is main- B-cell development. Males with XLA lack circulating B cells, caused
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tained under control by CD8 CTLs, and NK lymphocytes. Males by mutations of the Bruton’s tyrosine kinase or BTK gene, which
with X-linked lymphoproliferative disease type 1 (XLP1) are uniquely encodes for a tyrosine kinase involved in signaling through various
susceptible to life-threatening complications of EBV infections. receptors, including the pre–B-cell receptor (pre-BCR) and the BCR.
XLP1 is caused by mutations of the SH2D1A gene, which encodes Impaired signaling through the pre-BCR causes a severe, but incom-
for a small adaptor molecule, SLAM-associated protein (SAP). In the plete, block at the pre–B-cell stage in the bone marrow (see Fig. 51.2).
absence of SAP, cytotoxic responses to EBV-infected cells are mark- Clinical manifestations of XLA include recurrent sinopulmonary
edly reduced. Persistence of EBV triggers continuous activation of infections (pneumonia, bronchitis, sinusitis, otitis), particularly with
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CD8 CTLs that release high amounts of IFN-γ, ultimately resulting encapsulated organisms such as pneumococcus and Haemophilus
in a macrophage activation syndrome. In addition to HLH, patients influenza, bacterial skin infections (cellulitis, impetigo, pyoderma
with XLP1 are also at high risk of B-cell lymphoma. SAP is also gangrenosum, perirectal abscess), and sepsis with Pseudomonas or
important for the function of follicular helper T cells (T FH ), which Staphylococcus. Symptoms typically begin after 3–6 months of age
promote maturation of antibody responses. Consistent with this, when maternally derived antibodies disappear. The proportion of
XLP1 males often develop hypogammaglobulinemia with a lack of circulating B cells is markedly reduced (typically 0.05% to 0.3% of
memory B lymphocytes. Finally, XLP1 is also associated with impaired lymphocytes) and there is profound deficiency of all immunoglobulin
development of NK T (NKT) lymphocytes. Flow cytometric analysis isotypes. Milder mutations that are permissive for BTK protein
of SAP expression and mutation analysis at the SH2D1A locus expression are associated in vivo with higher levels of serum IgM
confirms the diagnosis. and later age at diagnosis. Neutropenia, secondary to severe infec-
A minority of patients with XLP carry defects in another gene tions, is observed in approximately 10% to 25% of patients; typi-
(BIRC4) that encodes for the X-linked inhibitor of apoptosis (XIAP). cally, it resolves with antibiotics and immunoglobulin-replacement
Consistent with this, lymphocytes from patients with this disease therapy.
(XLP2) show increased susceptibility to activation-induced apoptosis. In addition to bacterial infections, patients with XLA are uniquely
Compared with XLP1, patients with XLP2 have a higher incidence susceptible to enteroviral infections (including chronic meningoen-
of HLH (with or without EBV infection), but do not show increased cephalitis) caused by poliovirus, coxsackie virus, and others. However,
risk of lymphoma. Severe inflammatory bowel disease has been such complications have become rare after the introduction of
reported in several patients. Hypogammaglobulinemia is often optimal doses of immunoglobulin-replacement therapy. Patients with
present. Flow cytometric analysis of XIAP expression and mutation XLA are also at higher risk of infections caused by Mycoplasma and
analysis at the BIRC4 locus are used to confirm the diagnosis. Ureaplasma species, which affect the joints, prostate, or lungs; and
Both XLP1 and XLP2 are life-threatening disorders. Administra- Giardia lamblia, causing protracted diarrhea and malabsorption. An
tion of immunoglobulins may be beneficial; however, the only increased incidence of lymphoma, colorectal cancer, and gastric
curative approach is HCT. adenocarcinoma has been reported in XLA.
Therapy is based on life-long regular administration of immuno-
globulins intravenously or subcutaneously, and on prompt and
DEFECTS OF B-CELL DEVELOPMENT AND FUNCTION aggressive treatment of infections. With this regimen, survival
approaches that of the general population. Antibiotic prophylaxis
The previous section covered defects that predominantly affect T may be beneficial, but its role has not been firmly established. Patients
lymphocyte development and/or function. This section covers on immunoglobulin-replacement therapy should be monitored for
primary immunodeficiencies in which abnormalities of B-cell devel- side effects and adverse reactions, and for liver and renal function.
opment and/or function predominate (see Figs. 51.2 and 51.3).
Autosomal Recessive Agammaglobulinemia

While the majority of agammaglobulinemia cases are caused by the
X-linked form, about 15% of cases are presumed to be autosomal
Diagnostic and Therapeutic Approach to Cytotoxicity Defects recessive (see Fig. 51.2). Mutations of the immunoglobulin µ heavy
• Primary immunodeficiency with defects of cell-mediated chain gene (IGHM) are the second most common cause of agam-
cytotoxicity include a heterogeneous group of disorders maglobulinemia. Other cases are caused by defects in other compo-
characterized by increased susceptibility to severe viral infections. nents of the pre-BCR/BCR complex including the signaling moieties
• Typical clinical features include high fever, liver and spleen Igα (CD79A) and Igβ (CD79B), and λ5 (IGLL1), the surrogate light
enlargement, lymphadenopathy, coagulation defects, chain that pairs with Vpre-B, and the scaffold protein BLNK, which
abnormalities of liver function, and cytopenias after viral brings BTK into the signaling complex. Finally, congenital agam-
infections. maglobulinemia may also be caused by mutations of the PIK3R1
• Two major groups of cell-mediated cytotoxicity defects include gene, causing complete loss of the p85α subunit of phosphatidylino-
familial forms of HLH (fHLH) and X-linked lymphophroliferative sitol 3-kinase (PI3K), and to heterozygous, dominant-negative
disease. In the former, diagnosis is based on demonstration
of abnormal cytotoxic function of T and NK lymphocytes. mutations of the TCF3 gene encoding for the transcription factor
Defective expression of CD107a on activated lymphocytes or E47.
reduced expression of perforin may help define the nature of the
underlying disorder causing fHLH.
• Prompt recognition and treatment of the underlying infection Common Variable Immunodeficiency
is essential. Immunosuppression is also required to block
exaggerated inflammatory responses. However, the only curative CVID is the most common primary immunodeficiency severe
approach to defects of cell-mediated cytotoxicity is represented enough to require treatment, with a prevalence estimated to be 1 in
by hematopoietic cell transplantation. Mixed chimerism is 25,000 to 1 in 30,000 Caucasians, and accounting for approximately
sufficient to allow immune reconstitution. This goal can be
achieved with reduced intensity conditioning, with a lower risk of 10% to 20% of humoral immunodeficiencies. While a growing
treatment-related toxicity. number of genetic defects have been found to be associated with a
CVID phenotype, these defects account for a minority of cases. The