Excerpt from IgA and IgG Subclass Deficiencies

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Background

B cells are lymphocytes responsible for the production of antibody. The most common type of primary immunodeficiency (>50% of cases) involves deficient in antibody production. Primary humoral deficiencies vary from complete absence of B cells and/or serum immunoglobulin (Ig) to lacunar deficits involving specific antibody responses to polysaccharides. The spectrum of antibody deficiency is broad, ranging from decreased total IgG levels to normal IgG levels and from primary B-cell defects to combined immunodeficiencies with antibody abnormalities associated with other immune and often nonimmune abnormalities.

Although this article discusses agammaglobulinemia and hypogammaglobulinemia, the emphasis is on selective Ig deficiencies, including the decreased production of IgA and/or the various IgG subclasses and impaired antibody responses to polysaccharide antigens.

Pathophysiology

When IgA-bearing B lymphocytes fail to mature into IgA-secreting plasma cells, serum IgA levels are reduced, and specific IgA deficiency results. (If B-cell development arrest leads to clinically significant decreases in or an absence of all Ig production, the result is agammaglobulinemia or hypogammaglobulinemia; see Agammaglobulinemia.) Some, though reduced, numbers of IgA-bearing B cells are in the circulation, or IgA-bearing plasma cells are in the GI lamina propria in most cases with IgA deficiency. Failure of terminal B-cell differentiation is attributed to (1) an intrinsic B-cell defect, (2) inadequate or defective T-helper cells, (3) presence of or excessive IgA-specific T-cell suppressor cells, and (4) passage of maternal anti-IgA antibodies that suppress fetal IgA development.

In intrinsic B-cell defect, the alpha1 gene may be deleted along with other heavy-chain genes. Ig heavy-chain genes are located on chromosome 14q32 in the following order: 3'-XV-D-J-mu-delta-gamma1-psi/epsilon1-alpha1-psi/gamma1-gamma2-gamma4-epsilon-alpha2-5'. Therefore, homozygous deletions of large portions of the Ig heavy-chain locus result in individuals with complete absence of 3 or more Ig classes (IgG2, IgG4, IgA1, occasionally IgE). Investigators have described gene deletions of the heavy chain for Cƒ×1, Cƒ×2, Cƒ×4 and CƒÑ1 genes (in a patient with IgG1, IgG2, IgG4 and IgA1 deficiency) and Cƒ×2, Cƒ×4, CƒÕ, and CƒÑ1 genes (in patients with IgG2, IgG4, IgE, and IgA1deficiencies). However, in general, the molecular mechanisms of IgG subclass deficiencies have not been clearly delineated.

Selective IgA deficiency is probably the most common of the primary immunodeficiency disorders, but it may also be asymptomatic. In 1993, Plebani et al described 2 siblings who appeared to be healthy and who did not have increased infections, but they did have normal responses to immunization with protein and polysaccharide antigens. However, the authors did not measure secretory IgA.

Deficient secretory IgA with normal serum IgA levels is reported in few patients. Lack of severe infections in patients with IgA and secretory IgA deficiency may be attributed to compensatory increases in secretory IgM. Other concomitant immune defects may be required to increase the risk for respiratory and GI infections and various autoimmune diseases frequently described in patients with IgA deficiency. These concomitant immune defects may include deficiencies of certain IgG subclasses or of mannose-binding lectin (MBL) (Santaella, 2005). The most common IgG-subclass deficiency associated with IgA deficiency is that of IgG2. IgA-IgG2 deficiency can also be seen with other IgG-subclass deficiencies, especially that involving IgG4.

The importance of IgG-subclass deficiency is reflected in the isotypes of IgG antibodies produced against microbial antigens. Antibodies against pneumococcal polysaccharide antigens are predominantly IgG2 and, to a lesser degree, IgG4. In contrast, antibodies against protein antigens, such as tetanus, are predominantly IgG1 and, to a lesser degree, IgG3. Finally, antibodies against large extracellular parasites, such as Schistosoma and Filaria organisms, exclusively belong to IgG4 subclass (Anantaphruti, 2005).

This difference in isotypes of IgG antibodies may also extend to IgG antibodies against common dietary proteins, such as wheat (gliadin). Constantin et al (2005) found a difference in isotypes of antigliadin IgG antibodies in patients with celiac disease and those with IgE-mediated food allergy to wheat.

Selective IgA deficiency is associated with an increased incidence of autoimmune and allergic diseases. This association may be due to increased exposure and subsequent sensitization with allergens due to the absence of secretory IgAs, which serve as blocking antibodies and which appear to have a role in tolerance induction.

Frequency

United States

Selective IgA deficiency is the most common primary immunodeficiency, with a prevalence ranging from 1 in 223-1000 in community studies to 1 in 400-3000 in healthy blood donors. These various results may reflect differences in population-selection or diagnostic criteria. To establish the diagnosis, some investigators use a serum IgA level of <5-10 mg/dL, whereas others used <2 standard deviations from age-appropriate control levels.

International

Large population studies in Czech Republic of >15,000 subjects revealed a IgA deficiency rate of 1 per 408, or 0.24% (Litzman, 2000).

The frequency of IgA deficiency in 7923 healthy Caucasians in Austria revealed prevalence of IgA deficiency to be 0.21%, similar to the rate in the Czech study (Weber-Mzell, 2004). However, in this study, IgA deficiency was found predominantly in male subjects; it occurred in 1 woman and 14 men.

The prevalence of IgA deficiency in these studies appears to be similar to those reported in the United States.

Mortality/Morbidity

The risk for frequent and recurrent infections seems to be lower in patients with selective B-cell deficiency than in patients with agammaglobulinemia (patients who do not make any Ig). However, they have an increased risk of developing atopic or autoimmune diseases. Many patients have selective IgA or IgG subclass deficiency but remain asymptomatic. However, the clinician must be aware of any potential risk or atopic or autoimmune diseases to conduct careful monitoring. In patients with IgA and/or IgG subclass deficiency, treatment decisions depend on their clinical features, eg, the degree of their morbidity with infections and concomitant diseases.

Individuals with selective IgA or IgG subclass deficiency are usually asymptomatic. However, patients with IgA-IgG2 deficiency frequently have recurrent and chronic sinopulmonary infections.

Data from many clinical studies suggest that patients with IgG subclass deficiency are particularly susceptible to various infections, but no direct cause-and-effect relationship has been established. This lack of data may be due to the difficulty of accurately measuring IgG subclass levels and to intravariability and intervariability of IgG subclass levels in individuals.

Patients with IgG subclass deficiency appear to have an increased incidence of asthma or sinusitis.

Although patients with deficiencies in IgA subclasses are usually asymptomatic, their incidence of allergic and autoimmune disorders appears to be high. Therefore, treatment of the associated medical conditions must be considered.

Race

Individuals of Finnish descent may have the highest frequency of IgA deficiency. IgA deficiency also appears to be more prevalent in African-American than Caucasians, whereas Asians have the lowest incidence. IgA deficiency is associated with defects of other Igs, especially those of the IgG subclass, with a high frequency. IgG2 deficiency is reported in 19% and 8% of Swedish and American patients with IgA deficiency, respectively.

Sex

Most studies of healthy individuals without medical concerns reveal no sex predilection. However, 1 study showed an elevated prevalence of IgA deficiency in hospitalized male patients. In studies of healthy Caucasians in Austria, the prevalence of IgA deficiency was also increased in male subjects.

Age

Most selective IgA or IgG subclass deficiencies manifesting with clinical symptoms are detected during early childhood. The frequency and severity of infections decrease as patients age, and their quantitative Ig levels may increase. Indeed, patients with IgA deficiency may compensate over time with increased IgG1 and IgG3 antibody levels. On the contrary, some patients initially identified as having IgG2 and IgA deficiency may progress to have typical common variable immunodeficiency (CVID) with panhypogammaglobulinemia. Slyper and Pietryga (1997) described a patient with chromosomal deletion (18q-) who initially had IgA deficiency but subsequently developed CVID.

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