Page 505 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 34 Primary Antibody Deficiencies 485

Before making the diagnosis of IgG3 deficiency, serum levels of Analysis of a group of well-characterized patients, mostly
IgG3 should be rechecked when the individual is asymptomatic. female, with a history of RESPIs and normal serum Ig levels
Compared with the serum, IgG4 is overrepresented in secre- revealed a high prevalence of the same MHC haplotypes observed
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tions, and IgG4-committed B cells are present at mucosal sites, in IgAD, selective IgG subclass deficits, and CVID. These patients
suggesting a role in mucosal immunity. Since IgG4 is normally tend to respond to aggressive antibiotic therapy, including
present in the serum in very low concentrations, the significance prophylaxis.
of a low serum level in a patient with recurrent infection remains
unclear. SELECTIVE LIGHT-CHAIN DEFICIENCY
Origin and Pathogenesis Selective deficiencies of either κ or λ light chains have been
The origin of IgG subclass deficiency is unknown. Homozygous reported. 44-46 In one such case, the patient was the offspring of
deletions of portions of the Ig heavy chain constant locus associ- a consanguineous (uncle–niece) union; and in the second, a
ated with total absence of IgG2, IgG3, and IgG4 or combinations molecular analysis demonstrated different loss of function
of these isotypes have been described in healthy individuals. mutations in the patient’s Cκ alleles. The parents of these children
IgG2 deficiency is often found in association with selective had no health difficulties, but each of the patients required medical
IgA deficiency with or without IgG4 deficiency, and patients attention for recurrent sinopulmonary infections and diarrhea.
with selective IgG subclass deficiencies have been shown to have Two of the patients with κ deficiency exhibited IgA deficiency,
inherited the same MHC haplotypes as those who suffer from and the remaining patients with κκ deficiency and λ deficiency
IgAD and CVID. These observations suggest that patients with had panhypogammaglobulinemia.
recurrent infections have a more complex defect than the mere
elimination of one or more IgG isotype. In some instances, TRANSIENT HYPOGAMMAGLOBULINEMIA
subclass deficiency is associated with a T-cell defect, as in OF INFANCY
chronic mucocutaneous candidiasis and ataxia–telangiectasia.
IgG subclass deficiency can be acquired. Acute infections, Diagnosis
medications, chemotherapy, irradiation, surgery, and human As infants make the transition from dependence on maternal
immunodeficiency virus (HIV) infection have all been temporally Ig to reliance on endogenously produced antibodies, they suffer
linked to the development of a deficiency in one or more IgG a physiological nadir of serum Ig at 4–6 months of age, a period
subclass. 41 associated with susceptibility to mild upper respiratory infections
and otitis media (see Fig. 34.2). Children who (i) exhibit serum
Treatment and Prognosis concentrations of one or more of the three major Ig classes that
The natural history of IgG subclass deficiency plus or minus fall below the 95% confidence interval (CI) for age on ≥2 occasions
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IgA deficiency, especially in children, is not constant. Associated during infancy, (ii) demonstrate a rise in these values to or toward
allergic rhinosinusitis and asthma must be aggressively treated normal over time, and (iii) lack features consistent with other
with conventional therapy for these disorders, as these conditions forms of primary immunodeficiency fall within the catch-all
increase the risk of purulent sinusitis and pneumonia. Causes diagnosis of transient hypogammaglobulinemia of infancy
of anatomical obstruction should be sought when persistent (THI). 47,48 By definition, the diagnosis of THI can be made with
infection of a sinus or pulmonary segment is the presenting certainty only in retrospect.
complaint; the role of surgical therapy for anatomical obstruction
should not be overlooked. Clinical Manifestations
Many patients with IgG subclass deficiency do well on pro- Ig concentrations are rarely measured in infants unless there
phylactic antibiotics and will never need Ig supplementation. is some reason to suspect an immunodeficiency. Most patients
However, Ig replacement therapy can be beneficial in patients with this diagnosis come to medical attention because of either
with severe, recurrent infections. Patients who begin therapy recurrent infections or as a result of routine screening studies of
should improve within the first 2 months, but to avoid the placebo relatives of other patients with immunodeficiency. Yet bearing
effect, a full 6-month trial is recommended. in mind that 2.5% of normal infants will fall below the 95% CI
range at any one time, the diagnosis of THI is remarkably rare.
ANTIBODY DEFICIENCY WITH NORMAL SERUM Among two major centers, one in the United States and one in
IMMUNOGLOBULIN LEVELS Germany, the diagnosis was given to only 16 of 18 000 children
in whom the index of suspicion warranted Ig determinations. 49,50
Occasional patients may present with normal serum Ig concentra- Patients with THI typically are able to synthesize specific
tions and a selective inability to respond to infections with antibodies in response to immunization with T-dependent
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pyogenic organisms. Diagnosis requires documentation of an antigens (e.g., tetanus and diphtheria toxoids). They may have
inability to respond to antigenic challenge. These patients may difficulty, however, responding to polysaccharide antigens (e.g.,
respond to replacement Ig therapy. The antibody response to isohemagglutinins and vaccination with Pneumovax23). Some
specific polysaccharide antigens can be very selective. In human, will fail to sustain protective antibody responses to antigens.
most protective anti-H. influenzae type b (anti-Hib) antibodies Most patients with THI, especially those ascertained as a result
utilize the rare VκA2 gene. The Navajo population in the of family studies or mild upper respiratory infections alone,
Southwestern United States suffers a 5- to 10-fold increased exhibit fewer infections over time. The great majority of infants
incidence of Hib disease. This population also exhibits a high with THI will normalize their serum Ig levels within 24 months
prevalence of an A2 allele with a defective recombination signal of age. However, a minority fails to normalize IgG, continues to
sequence, preventing use of germline-encoded antibodies that suffer with recurrent infections, and may develop evidence of
can generate protective antigen-binding sites. 43 autoimmune disease. These patients often become part of the