Patients with antibody deficiency syndromes usually present with
a history of recurrent pyogenic infections of the respiratory tract
or other organs and chronic gastrointestinal disease, including
giardiasis. The bacterial infections are mainly due to encapsulated,
pyogenic organisms such as Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus
aureus, and Neisseria meningitidis. Otherwise
intact cell-mediated immunity allows viral infections to be cleared,
although they are prone to recur given absent protective antibody
responses. Tonsils are absent in patients with agammaglobulinemia. Radiological
studies may be helpful in evaluating the size of the adenoid tissue
and in assessing the sinuses and lung fields. Evidence for recurrent
infections, such as scars from previous abscesses or chronic otitis
media, are often noted.
Measurement of serum immunoglobulins and specific antibody responses
are critical screening tests in the diagnosis of antibody deficiencies.
The determination of serum antibody titers after tetanus or diphtheria
immunizations or immunization with Haemophilus influenzae and
pneumococcal vaccines provides valuable information about the individual’s
ability to mount specific antibody responses. When a patient is
found to have low immunoglobulin levels, additional in vitro tests
are used to characterize the nature of the B-cell defect, including
enumeration and surface phenotyping of circulating B lymphocytes
and in vitro immunoglobulin production assays.
to Defects in Early B-Cell Development
Rare genetic abnormalities affecting early B-cell development
result in deficiency of mature B cells, leading to agammaglobulinemia. Prevalence
is about 1 per 100,000. Most (85%) of the affected subjects
are males who suffer from X-linked agammaglobulinemia (XLA),
and the remainder are both males and females suffering from a heterogeneous
group of autosomal recessive disorders.35,36
XLA is characterized by profoundly low serum concentrations of
all immunoglobulin classes and the virtual absence of B cells in
peripheral blood and lymphoid tissues in the face of normal T-cell
number and function. XLA is caused by mutations in BTK,
encoding Bruton tyrosine kinase. Bruton tyrosine kinase deficiency
results in arrested B-cell development in the bone marrow due to
a severe block in their transition from CD19+ pro-B
cells to the cytoplasmic μ-positive pre–B-cell
stage. B cells of obligate heterozygote females are normal. However,
the active X chromosome in the B cells is exclusively that which
harbors the normal BTK allele, indicative of the
critical role of Bruton tyrosine kinase in B-cell maturation.
Male infants with X-linked agammaglobulinemia (XLA) frequently
become symptomatic late in the first year of life following the consumption
of placentally acquired maternal immunoglobulins. However, affected
males of the same family may vary in clinical disease onset and
severity. Recurrent infections, especially with encapsulated pyogenic
organisms, commonly involve the upper and lower respiratory tract,
causing pneumonia, otitis, purulent sinusitis, and bronchiectasis.
Additional infections include meningitis, sepsis, pyoderma, osteomyelitis,
and giardiasis. Although most infections respond to appropriate
antibiotics, the disease would eventually prove fatal unless immunoglobulin
therapy is instituted. In its absence, many children with XLA develop
progressive bronchiectasis and ultimately die of pulmonary or other
end organ complications.
Children with XLA have an increased susceptibility to infection
with enteroviral infections, including echo, coxsackie, and both
wild-type and vaccine-associated polio virus. These agents can cause
a dermatomyositis-like syndrome or fatal chronic encephalitis. The
use of immunoglobulin replacement therapy has markedly decreased
chronic enteroviral infection in patients with X-linked agammaglobulinemia,
and high-dose therapy can be effective in therapy of acute infections.
Chronic inflammation and swelling of the large joints, which resembles
rheumatoid arthritis, develop in one third to one half of these
children before the diagnosis is established, but resolves with
the institution of immunoglobulin replacement.
Serum IgG levels are usually less than 1 g/L, and serum
IgA and IgM levels are less than 1% of adult values. In
most patients, the B cells are less than 0.2% of peripheral
blood lymphocytes. The lymph nodes and tonsils are small and lack
germinal centers and plasma cells. A positive family history of
affected brothers or maternal uncles is supportive of the diagnosis.
Carrier females can be identified by assessing X chromosome skewing
in their B-cell population or by direct mutation analysis.
Immunoglobulin replacement therapy is a life-saving and effective
treatment in X-linked agammaglobulinemia. Antibiotics should be used
as appropriate for acute infections. Patients with X-linked agammaglobulinemia
do not produce antibodies upon immunization, and they should not
be given vaccines.
Patients with autosomal recessive agammaglobulinemia suffer
from a heterogeneous set of defects affecting B-cell development.
About one third have mutations in the μ-heavy chain
gene. Others have defects in components of the pre–B-cell
receptor, including the surrogate light chain (IGLL1 or λ5),
the B-cell receptor–associated signal transducers CD79A
(Iga) and CD79B (Igb), or the B-cell linker protein BLNK (see Fig. 188-2). In a few patients, the disease cause(s)
remains unknown. Clinically, autosomal recessive agammaglobulinemia
is very similar to X-linked agammaglobulinemia, although there is
a tendency for patients with autosomal recessive agammaglobulinemia
to present at a younger age and with more severe complications.
The spectrum of infections is identical to that of X-linked agammaglobulinemia.
Therapy mirrors that for X-linked agammaglobulinemia, including
immunoglobulin replacement and antibiotics.
B-cell intrinsic immunoglobulin class switch recombination (Ig-CSR)
deficiencies, previously termed hyper-IgM syndromes, are genetically
determined conditions characterized by normal or elevated serum
IgM levels and an absence or very low levels of IgG, IgA, and IgE.37 The
secondary antibody response is characterized by the production of
immunoglobulins of various isotypes with high affinity for antigens
by means of two distinct processes: class-switch recombination and
somatic hypermutation. Class-switch recombination allows the replacement
of the IgM heavy chain (Cμ) with heavy chains of
different isotypes (Cg1-4 for IgG1-4, Ca for IgA, or Ce for IgE).
This results in the production of immunoglobulins of different isotypes
with distinct functional properties while leaving the immunoglobulin
variable sequences (VDJ), and hence the antibody specificity and
affinity, intact. Somatic hypermutation is the process through which
mutations are introduced into the variable regions of immunoglobulins,
resulting in a higher affinity and specificity for antigen. The
hyper-IgM syndromes are typically associated with impaired class-switch
recombination and, to a variable extent, defective somatic hypermutation.
X-linked hyper-IgM syndrome results from loss
of function mutations in CD40L, encoding CD40 ligand.38 This
is an inducible T-cell surface protein expressed on activated T
helper cells that serves as a counter-receptor for the tumor necrosis
factor family member CD40, which is expressed on B cells. Failure
to engage CD40 by activated T cells blocks class-switch recombination
and impairs somatic hypermutation (see Fig. 188-2).
Consequently, patients with X-linked hyper-IgM syndrome have profoundly
decreased serum concentrations of IgG and IgA levels in the face
of normal or elevated IgM levels. They are particularly susceptible
to infections with bacterial pathogens commonly associated with
hypogammaglobulinemia. Because CD40 is also expressed on macrophages and
dendritic cells where it mediates interactions with T helper cells,
its deficiency is also associated with infections that are reflective
of failure of those interactions. These infections include Pneumocystis
jiroveci pneumonia, to which patients with X-linked hyper-IgM
syndrome are particularly susceptible, and cryptosporidium-induced
diarrhea and ascending cholangitis. Some patients with hypomorphic
mutations also present with persistent anemia associated with parvovirus
infection. Other manifestations include neutropenia and autoimmunity.
An identical disease picture arises in both boys and girls due to
rare autosomal recessive mutations in the CD40 gene.
Engagement of CD40 results in activation of the transcription
factor nuclear factor-kappa B (NF-κB), which plays
a critical role in class-switch recombination and somatic hypermutation.
CD40 activates a kinase complex known as the inhibitors of NF-κB
kinase, which mediates the phosphorylation of the inhibitors of
NF-κB, leading to inhibitor of NF-κB
degradation and NF-κB activation. Boys with X-linked
hypohidrotic ectodermal dysplasia with immunodeficiency frequently
present with a picture of hyper-IgM syndrome, with low levels of
serum IgG and IgA, normal to increased IgM levels, and impaired
antibody responses, particularly to polysaccharide antigens. In
most cases, X-linked ectodermal dysplasia with immunodeficiency
is caused by hypomorphic mutations in the zinc-finger domain of
NF-κB essential modulator (also known as inhibitor
of NF-κB kinase γ), a scaffolding
protein that binds to the inhibitors of NF-κB kinase
complex (NEMO).39 Hypomorphic mutations outside
the zinc-finger domain of NF-κB essential modulator
result in osteopetrosis, lymphedema, and atypical mycobacterial
infections, but spare immunoglobulin production.
B-cell–restricted defects also result in hyper-IgM syndrome.
Activation-induced cytidine deaminase, a DNA editing enzyme that
is induced by T helper cell–B cell interaction, plays an
essential role in both class-switch recombination and somatic hypermutation. Activation-induced
cytidine deaminase deficiency results in an autosomal recessive
form of hyper-IgM syndrome that presents with recurrent bacterial and
viral infections of the respiratory, gastrointestinal, and central
nervous systems. Lymphoid hyperplasia is a prominent feature of
the disease. Though lacking the opportunistic infections associated
with CD40L deficiency, they do suffer autoimmune manifestations,
including arthritis and cytopenias. A phenotypically related though
less common autosomal recessive hyper-IgM syndrome disorder results
from deficiency in uracil N-glycosylase, which
mediates deglycosylation and removal of deoxyuridine residues, a
necessary step in the process of class-switch recombination.
Common Variable Immunodeficiency
Common variable immunodeficiency syndrome represents a heterogeneous
group of disorders characterized by the presence of hypogammaglobulinemia
in the face of normal or low numbers of B cells in circulation.40-42 The
hypogammaglobulinemia involves two or more immunoglobulin isotypes
(IgG, IgA, and/or IgM), and impaired functional antibody
responses include absent isohemagglutinins, poor responses to protein
(diphtheria, tetanus) or polysaccharide vaccines (Streptococcus pneumoniae),
or both. Additional clinical findings may include autoimmunity,
granulomatous disease, and lymphoproliferative disease/neoplasia.
Common variable immunodeficiency affects both sexes, and family
members have a higher incidence of hypogammaglobulinemia, selective
IgA deficiency, and autoimmune disease.
Most cases present during the second decade of life onward, although
earlier onset is well established. Recurrent and chronic respiratory
tract infections, particularly paranasal sinusitis, bronchitis,
and pneumonia are prominent features. Gastrointestinal symptoms,
including diarrhea, malabsorption, steatorrhea, and protein-losing enteropathy
are common, resulting from complications of bacterial overgrowth,
jejunal villous atrophy. Intestinal nodular lymphoid hyperplasia is
often prominent. Giardia lamblia infection is common
and appears to be responsible for many of the gastrointestinal complications
seen in these patients.
Patients with common variable immunodeficiency frequently have
associated hematologic disorders, including pernicious anemia, hemolytic
anemia (including Coombs test–positive hemolytic anemia),
anemia from folate or vitamin B12 malabsorption, leukopenia, and/or thrombocytopenia.
Autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus,
and idiopathic thrombocytopenic purpura are seen in patients with
common variable immunodeficiency and their relatives at a much higher
incidence than in the general population.43 Another
distinguishing feature is the frequent occurrence of noncaseating
granulomas of the lungs, spleen, liver, and skin. An infectious
etiology for these lesions has not been identified, but steroids
and anti-tumor necrosis factor therapy have been reported to be
helpful in their treatment.
Three distinct genetic lesions have been identified in small
subsets of common variable immunodeficiency patients. The most prevalent
of these are heterozygous mutations in transmembrane activator and
CAML interactor (TACI), a component of a network of tumor necrosis
factor ligand and receptor superfamily members that play essential
roles in B-cell differentiation and antibodies.44,45 These
include the ligands B-cell activation factor of the tumor necrosis
factor family, a proliferation-inducing ligand, and their three
receptors: B-cell activation factor of the tumor necrosis factor
family receptor, B-cell maturation antigen, and TACI. Failure of
this system is associated with autoimmune disease, lymphoproliferation,
and antibody deficiency. TACI mutations act in a dominant negative manner
to impair isotype switching and antibody production. TACI mutations
account for about 5% of all common variable immunodeficiency
Rare mutations give rise to two other subtypes of common variable
immunodeficiency. The inducible T-cell costimulator, expressed on
activated T cells in B-cell follicles (so called follicular T helper
cells), interacts with the inducible T-cell costimulator ligand,
which is expressed on the surface of B cells to enable germinal
center formation and class-switch recombination. Inducible T-cell
costimulator deficiency results in deficiency of follicular T helper
cells and decreased peripheral B cell numbers. It impairs terminal
B-cell differentiation and leads to hypogammaglobulinemia. A second
set of mutations lead to the deficiency of CD19, a B-cell–specific
surface protein that plays an important role in B-cell activation
and differentiation. The number of B cells in the periphery is normal,
whereas the number of memory B cells is decreased.
X-Linked Lymphoproliferative Disease
In the majority of patients with X-linked lymphoproliferative
disease (known as XLP1), the underlying defect involves mutations
in SH2D1A, encoding the protein SAP, signaling lymphocyte
activation molecule (SLAM)–associated protein. SAP is a
128-amino acid peptide composed of an SH2 domain that associates
with SLAM family proteins. SAP controls signal transduction via
SLAMs, and failure to regulate SLAM signaling results in an exaggerated
yet ineffective T-cell response to EBV infections (see Fig.
188-2).46 SAP deficiency results in the absence
of a small subset of T cells known as natural killer T cells that
is involved in immune regulation and antitumor responses. Natural
killer T-cell deficiency contributes to the immune dysregulation
in this syndrome. SAP deficiency also impairs the development of
the differentiation of follicular T cells, leading to inability
to support B-cell differentiation and profound humoral immunodeficiency.
Affected males suffer from severe, often fatal infections with
Epstein-Bar virus (EBV) associated with fulminant hepatitis, B-cell
lymphomas, agranulocytosis, aplastic anemia, or acquired hypogammaglobulinemia.
These complications result from uncontrolled polyclonal T- and B-cell expansion
triggered by the EBV infection. Approximately half of the affected
individuals die of fatal infectious mononucleosis. Survivors suffer
from hypogammaglobulinemia or agammaglobulinemia and malignant lymphomas.
Most of the lymphomas are extranodal, Burkitt type, many involving
A second subset of patients with X-linked lymphoproliferative
disease (known as XLP2) suffer from mutations in BIRC4 gene,
encoding the X-linked inhibitor of apoptosis protein (XIAP).47 XLP2
is phenotypically similar to XLP1, except for an early onset splenomegaly, which
is the first clinical manifestation of the condition. XLP2 is also
associated with natural killer T-cell deficiency. Management of
both XLP1 and XLP2 involves immunoglobulin replacement therapy and
vigilance for lymphoid malignancies. Bone marrow transplantation
provides definitive therapy if attempted early in life, ideally
before Epstein-Barr virus infection sets in.
The normal full-term newborn has a serum IgG level that is the
same or sometimes slightly higher than the mother’s, reflecting
the active transport of maternal IgG across the placenta during
the last trimester of pregnancy. Infants do not begin significant
synthesis of IgG until 2 to 3 months of age. Catabolism of the maternal
IgG (half-life of 25–30 days) precipitates a physiologic
hypogammaglobulinemia between 4 and 6 months of age. In transient
hypogammaglobulinemia of infancy, there is an abnormal prolongation
and accentuation of the physiologic hypogammaglobulinemia resulting
from a delay in the onset of immunoglobulin synthesis.48 Transient
hypogammaglobulinemia of infancy affects both male and female infants,
and in some cases shows a familial occurrence. It usually presents
at around 6 months of age, with recurrent infections, most commonly otitis
media and bronchitis. The numbers of T and B lymphocytes are normal,
and patients are capable of mounting high-titer antibody responses
to diphtheria and tetanus toxoid vaccination, even though the immunoglobulin concentrations
are low. A transient defect in T helper-cell function has been implicated
in transient hypogammaglobulinemia of infancy pathogenesis.
Patients with transient hypogammaglobulinemia of infancy usually
recover spontaneously by the age of 2 to 4 years.49,50 The
majority do not require immunoglobulin replacement therapy and can
be followed conservatively with periodic determinations of serum
immunoglobulin level. For those patients with severe recurrent infections
or dangerously low immunoglobulin levels, replacement therapy is
indicated; it is discontinued when there is evidence of normalized in
vivo IgG production.
and IgG Subclass Deficiencies
IgA deficiency is the most prevalent primary immunodeficiency,
with an estimated frequency those of European ancestry of 1 in 600.51 Primary
IgA deficiency is caused by a defect of terminal lymphocyte differentiation,
which leads to underproduction of serum and mucosal IgA; affected
individuals have normal IgA genes. A number of non-immunoglobulin genes
have been implicated in IgA deficiency. IgA in the serum is predominantly
IgA1, and equal amounts of IgA1 and IgA2 are present in secretions.
The overwhelming majority of IgA-deficient individuals are deficient
in both subclasses.
Most IgA-deficient individuals are asymptomatic, but some suffer
from recurrent respiratory and gastrointestinal tract infections.
There is also an increased incidence of allergic and autoimmune
diseases. Many develop anti-IgA antibodies and are at high risk
for anaphylactoid reactions after receiving blood products, including
immunoglobulin preparations, that contain IgA. A subset of those
with IgA deficiency and recurrent infections also have deficiencies
of IgG2 and IgG4 subclasses, indicating a more general abnormality
in antibody production. The genetic cause of IgA deficiency remains
unknown, although a strong association to genes within the MHC (HLA),
in particular the class II and the class III regions, has been found.
There have been many diseases reported in association with IgA
deficiency, particularly autoimmune diseases. The most common association
is with coeliac disease (CD), which has special significance since
CD is usually diagnosed by detection of specific IgA antibodies
that are obviously lacking in IgA deficiency. There is no specific
treatment for patients with symptomatic IgA deficiency.
Selective IgG subclass deficiency affects one
or more of the IgG subclasses, including IgG1 (approximately 65% of
serum IgG), IgG2 (20–25%), IgG3 (5–10%),
and IgG4 (less than 5%).52 Each IgG subclass
corresponds to a specific constant chain gene and is endowed with distinct
effector functions. In most individuals with IgG subclass deficiency,
the deficient subclass(es) are produced at low levels despite normal
constant chain gene(s). Most individuals with IgG subclass deficiency
are asymptomatic, but a few suffer from recurrent sinopulmonary
infections and diarrheal illnesses with bacterial and viral pathogens.
Symptomatic patients frequently have more than one affected IgG
subclass, commonly IgG2 and IgG4, in isolation or together with
IgA deficiency. A clue to the diagnosis is the presence of borderline
or low-normal levels of IgG in the face of recurrent infections.
Measurement of IgG subclass serum concentrations is diagnostic.
Immunoglobulin replacement therapy is beneficial in symptomatic
patients.53 Subclass deficiencies may normalize
in some children with maturation.54