B-cell deficiencies include (a)
X-linked hypogammaglobu-linemia, (b)
selective immunoglobulin deficiencies, (c)
hyper-IgM syndrome, and (d)
interleukin-12 receptor deficiency.
X-linked hypogammaglobulinemia, or infantile agammaglob-ulinemia or
agammaglobulinemia (XLA), is the pro-totype of “pure” B-cell
deficiency. In the majority of cases, the disease is transmitted as a
sex-linked trait. The defective gene is located on Xq21.2–22, the locus coding
for the B-cell pro-genitor kinase or Bruton’s tyrosine kinase (Btk). Btk plays
an important role in B-cell differentiation and maturation, and is also part of
the group of tyrosine kinases involved in B-cell signaling in adult life. Most
cases of infantile agammaglobu-linemia are associated with mutations affecting
Btk. X-linked hypogammaglobulinemia shows the follow ing features:
It is characterized by extremely low IgG levels and by the absence
of other immunoglobulin classes.
Individuals with XLA have no peripheral B cells and suf-fer from
recurrent bacterial infections, beginning at about 9 months of age. Patients
suffer from repeated infections caused by common pyogenic organisms (Streptococcuspneumoniae, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus, etc.) causing pyoderma, purulent
con-junctivitis, pharyngitis, otitis media, sinusitis, bronchitis, pneumonia,
empyema, purulent arthritis, meningitis, and septicemia. Chronic obstructive
lung disease and bronchiec-tasis develop as a consequence of repeated
bronchopulmo-nary infections. Infections with Giardia lamblia are diagnosed with increased frequency in these
patients and may lead to chronic diarrhea and malabsorption.
Agammaglobulinemic patients are at risk of developing para-lytic
polio after vaccination with the attenuated virus; they also are at risk of
developing chronic viral meningoencephali-tis, usually caused by an echovirus.
Arthritis of the large joints develops in about 30–35% of the cases and is believed
to be infectious, caused by Ureaplasma
urealyticum. This condition is best treated with replacement therapy using
gamma globulin (a plasma fraction containing predominantly IgG, obtained from
normal healthy donors) administered intravenously.
In this condition, only one or more of the immunoglobulins are
deficient in serum, while the others remain normal or ele-vated. IgA deficiency
is the most common example of selective immunoglobulin deficiencies. IgA deficiency
is characterized by nearly absent serum and secretory IgA. The IgA level is
less than 5 ng/dL, but the remaining immunoglobulin class levels are normal or
elevated. The disorder is either familial or it may be acquired in association
with measles or other types of viral infection, or toxoplasmosis.
The etiology of IgA deficiency is unknown, but is believed to be
due to arrested B-cell development. The principal defect appears to be in IgA
B-cell differentiation. The adult patients with selective IgA deficiency
usually express the immature phe-notype, only a few of which can transform into
IgA-synthesizing plasma cells. Although IgA cells are produced, these cells
fail to secrete IgA.
IgA is the principal immunoglobulin in secretions and is an important
part of the defense of mucosal surfaces. Thus, IgA-deficient individuals have
an increased incidence of respi-ratory, gastrointestinal, and urogenital
infections. They also have an increased incidence of autoimmune diseases, such
as systemic lupus erythematosus and rheumatoid arthri-tis. There is an
increased incidence of the disorder in certain atopic individuals. Some
selective IgA-deficiency patients form significant titers of antibody against
IgA. They may develop anaphylactic reactions upon receiving IgA-containing
Selective IgA deficiency is diagnosed by the demonstration of less
than 5 mg/dL of IgA in serum. They, however, have normal levels of IgG and IgM
antibodies. Some individuals develop antibodies against IgG, IgM, and IgA.
This condition is characterized by high concentration of serum IgM
but very low concentration of serum IgG, IgA, and IgE. They have normal numbers
of T cells and B cells. Some of these immunodeficiencies are X-linked and some
are inherited as autosomal recessives. Patients with this condition are
suscep-tible to recurrent microbial infections and many autoimmune disorders,
such as thrombocytopenia, neutropenia, and hemo-lytic anemia.
Patients with interleukin-12 receptor deficiency are highly
susceptible to disseminated mycobacterial infections. Lack of interleukin-12
receptor prevents IL-12 initiating a Th-1 response, which is essential to
prevent mycobacterial infections.