Page 495 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 34 Primary Antibody Deficiencies 475

CLINICAL PEARLS should be assayed simultaneously to avoid confusion that may
Interpreting Quantitative Immunoglobulins (Igs) result from single-tube dilution differences at the time the assay
is performed. As a general rule, a high baseline titer or ≥4-fold
• Normal ranges of serum immunoglobulin levels vary with age (Appendix rise in a specific titer in individuals with a low baseline titer
2); hence evaluation should take the age of the patient into account. confirms that a specific humoral response is intact. The develop-
• As the mother’s transplacental contribution of IgG is catabolized, ment of conjugated polysaccharide vaccines complicates analysis
total serum IgG concentrations reach a nadir at 4–6 months of age for those who have received such a vaccine, although information
• IgG2 and IgG4 subclass levels rise more slowly than IgG1 and can still be gleaned from study of responses to polysaccharide
IgG3; hence reference to adult controls can lead to the false diagnosis antigens present only in multivalent unconjugated vaccines.
of IgG subclass deficiency in young children.
• Serum IgA concentrations typically do not achieve adult values until Because of its relatively low molecular weight and slow
puberty. They are often the first to decline in many primary turnover compared with other isotypes, protein loss through
immunodeficiencies the kidneys or GI tract can result in the selective loss of IgG.
Should symptoms warrant, 24-hour urine for protein or a stool
sample for alpha-1-antitrypsin level can document protein loss.
An elevated IgE level may support a suspicion of allergy as
4
may continue to rise. The physiological significance of this an underlying explanation of sinopulmonary symptoms. Serum
increase in older adults is unclear, although in some cases it IgE concentrations are often elevated in patients with IgA
reflects an accumulation of expanded B-cell clones or monoclonal deficiency. Extreme elevations of IgE suggest the hyper-IgE
gammopathies (Chapter 80). syndrome.
Enumeration of B cells and of T cells should be performed
KEY CoNCEPtS for any individual who has severe panhypogammaglobulinemia.
The most widely used method of demonstrating B cells relies
Functional Tests of Specific Antibody Production on immunofluorescent labeling of surface CD19, which is
restricted in expression to mature B cells. Because an infant may
• Immunoglobulin M (IgM) T-independent responses can be assessed
by measurement of serum isohemagglutinins (anti-A and anti-B titers) have serum IgG of maternal origin for the first several months
in patients who are not blood type AB. of life, the determination of the number of circulating B cells is
• IgG T-independent responses can be assessed by measurement of the single most useful test in making the presumptive diagnosis
antibodies produced in response to immunization with unconjugated of XLA, a disorder in which pre-B cells in bone marrow fail to
purified pneumococcal polysaccharide vaccine. develop to cells of mature phenotype. Absence of circulating B
• IgG T-dependent recall responses can be assessed by measurement cells also characterizes the immunodeficiency associated with
of ≥4-fold rise in titer of antibodies to diphtheria or tetanus toxoid
alter booster immunization. thymoma in adults, whereas adults with chronic lymphocytic
leukemia may have hypogammaglobulinemia with an overabun-
dance of circulating B cells that typically express CD5.
The common laboratory practice of defining the lower range HIGM1 represents the product of a loss-of-function mutation
of normal for serum Ig levels as two standard deviations below of the CD154 (CD40L) gene. CD154, a surface antigen found
the age-adjusted mean carries with it the risk of falsely labeling on activated T cells, binds CD40 on B cells to facilitate class
otherwise normal patients as having immunodeficiency. Ig levels switching, survival, and proliferation (Chapter 8). A fluorescent-
vary widely with environmental exposure, and normal biological labeled CD40 fusion protein can be used to evaluate the expression
variation is much broader than that defined by the mean of the of functional CD154 on T cells by flow cytometry. Confirmation
population. Patients with a combined deficiency of IgA and an of the diagnosis, carrier detection, and prenatal diagnosis often
IgG subclass may benefit from more aggressive therapy; thus depend on molecular or sequence analysis of the gene.
quantitative measurements of all four IgG subclasses—IgG1,
IgG2, IgG3, and IgG4—can be useful in fully defining the extent Replacement Therapy With Human Immunoglobulin
of humoral immune deficiency. There are a number of commercial preparations of human Ig
Among patients with borderline serum IgG levels, tests to that are approved by the US Food and Drug Administration
evaluate the host’s ability to produce functional specific antibody (FDA) and available in the United States (Chapter 84). No com-
should be performed before making a decision to institute a mercial preparations in this country are available to supplement
more aggressive therapy, especially among patients receiving IgM or IgA exclusively, but some of the preparations contain
corticosteroids, which can lower total serum IgG while preserving minute amounts. All commercial human Ig preparations are
function. The most commonly employed tests include measure- effective in treating patients with immunodeficiency disorders.
ment of isohemagglutinins (naturally occurring IgM antibodies to Clinically relevant differences relate to the route of administration,
the polysaccharide antigens that define the ABO blood type system which can be by intravenous or subcutaneous means, to the
on red blood cells [RBCs]) and postimmunization responses to method of stabilization and storage, and to quantities of con-
polysaccharide antigens (e.g., Pneumovax23 or unconjugated taminating serum IgA in the preparations. Low IgA content is
H. influenzae B vaccine) and protein antigens (e.g., tetanus or a concern for those rare individuals with immunodeficiency and
diphtheria toxoids). IgM is made by the newborn, and most absent IgA, who manufacture IgG or IgE antibodies directed
infants can generate isohemagglutinins, making determination of against IgA and have a history of anaphylactic reactions upon
anti-A and anti-B titers a useful measurement of B-cell function infusion of IgA-containing blood products. 7
even in infants. In older children and adults, isohemagglutinin Ig replacement therapy is not indicated for patients whose
titers <1 : 8 are considered significantly decreased. 6 immune deficiency is limited to the selective absence of IgA
Serum for specific antibody titers should be obtained before because of the risk of anaphylaxis upon receipt of IgA-containing
7
and 4–6 weeks after immunization. Optimally, the paired sera products, even though such reactions are extremely rare. However,