eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

IgA and IgG Subclass Deficiencies

Author: Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Contributor Information and Disclosures

Updated: Feb 19, 2009

Introduction

Background

B cells are lymphocytes responsible for the production of antibody. The most common type of primary immunodeficiency (>50% of cases) involves deficient antibody production. Primary humoral deficiencies vary from complete absence of B cells, serum immunoglobulin (Ig), or both to lacunar deficits that involve 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 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, although 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 IgA1 deficiencies). 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 despite extensive deletion of immunoglobulin heavy chain locus.1 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).2 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.3

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.4

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 less than 5-10 mg/dL, whereas others used less than 2 standard deviations from age-appropriate control levels.

International

Large population studies in Czech Republic of more than 15,000 subjects revealed a IgA deficiency rate of 1 per 408, or 0.24%.5

The frequency of IgA deficiency in 7923 healthy whites in Austria revealed prevalence of IgA deficiency to be 0.21%, similar to the rate in the Czech study.6 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 of 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). In general, IgA deficiency with concomitant immune defects such as defects in specific antibody production have higher rates of recurrent infections and bronchiectasis.7,8

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 blacks than whites, 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, one study showed an elevated prevalence of IgA deficiency in hospitalized male patients. In studies of healthy whites 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.9

Clinical

History

  • As many as 80% of patients with immunoglobulin (Ig)A deficiency are asymptomatic. A compensatory increase in IgM production and subsequent increase in secretary IgM in the mucosal lumen may account for lack of clinical symptoms, but the data are conflicting. Another explanation for lack of clinical symptoms is normal levels of secretary IgA despite decreased serum IgA levels. However, patients with IgA deficiency can present with broad spectrum of medical conditions, including recurrent sinopulmonary infections, atopic disorders (atopic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergy), GI disease (especially celiac disease), neurologic diseases, autoimmunity, and malignancy.
    • Gastric carcinomas or lymphomas are malignancies frequently associated with IgA deficiency.
    • Various autoimmune diseases are associated with IgA deficiency. These include rheumatoid arthritis, systemic lupus erythematosus, pernicious anemia, and immune thrombocytopenic purpura (ITP). Even in absence of overt clinical symptoms, the sera of patients of IgA deficiency often reveal a wide spectrum of autoantibodies. In 1981, Cunningham-Rundles et al reported that patients with IgA deficiency are most likely to have high titers of IgG antibodies to cow's milk and that these patients were most likely to develop various autoantibodies.10
    • Various GI diseases also are associated with IgA deficiency. These diseases often cause chronic diarrhea with or without malabsorption. Persistent and recurrent infection with Giardia lamblia, and autoimmune GI diseases (eg, celiac, ulcerative colitis, regional enteritis) must be considered and ruled out in patients with IgA deficiency and GI symptoms. Biopsy specimens may show nodular lymphoid hyperplasia with flattened villi.
    • Recurrent sinopulmonary infection is the illness most frequently encountered in patients with selective IgA deficiency. These infections often alert the clinician to order a test of serum Ig levels. Reduced IgA levels establish the diagnosis. Most upper and lower respiratory tract infections are caused by relatively less virulent microbes, or patients present without overt causative pathogens. Patients with a concomitant IgM or IgG subclass deficiency present with recurrent infection more frequently than patients with isolated IgA deficiency.
    • IgA deficiency is also frequently detected in patients with various neurologic disorders. Genetic defects that affect DNA repair enzymes cause ataxia telangiectasia and Nijmegan breakage syndrome. These lead to progressive neurodegenerative disorders. They are also associated with declining IgA levels with age. Anti-convulsants can cause hypogammaglobulinemia or selective IgA deficiency.
    • Food allergy and other atopic disorders (eg, allergic conjunctivitis, rhinitis, allergic urticaria, atopic dermatitis, asthma) are more common in patients with IgA deficiency than in the general population.
  • Controversy surrounds the clinical relevance of IgG subclass deficiency because many patients with IgG2 subclass deficiency (level of 0) can be asymptomatic. Therefore, the patient's ability to produce specific antibodies against polysaccharide antigens is important in determining the need for therapeutic intervention. One report indicated that as many as 20% of children with recurrent or chronic infections due to encapsulated bacteria have IgG subclass deficiency.
  • Although the IgG2 isotype is generally thought to dominate the antibody responses to polysaccharide antigens, a direct causal relationship between decreased serum IgG2 and infection with encapsulated organisms has not been definitively shown. The concept that antibodies against polysaccharide antigens are mainly IgG2 (with some IgG4) and that most antibodies against protein antigens are predominantly IgG1 and IgG3 does not appear to be universally valid. Notable crossover among IgG isotypes appears to occur with both protein and polysaccharide antigens.
  • In contrast, antibody deficiency against microbial polysaccharide antigens is a well-established clinical entity and has been referred to as either antigen specific antibody deficiency (ASAD) or specific antibody deficiency (SAD). These patients generally present with recurrent upper and/or lower respiratory infections due to an encapsulated organism (Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, or Staphylococcus aureus). Examining patients with increased susceptibility to airway infections show 8-15% with SPAD.11,12,13 The latter authors suggest a particular high association with a history of otitis media and chronic otorrhea. 
  • Patients may also present with concomitant atopic disorders (eg, asthma, atopic dermatitis). Authors have indicated a need to assess antibody responses to polysaccharide vaccines (eg, Pneumovax) in patients with bronchiectasis of unknown etiology.14 This is strongly indicated for IgA deficiency patients with a history of recurrent or chronic otitis media and/or sinusitis, IgG2 subclass deficiency, and low levels of baseline specific antibodies.15,7,8   
    • Frequent, recurrent episodes of otitis media are most commonly observed in patients with selective IgA deficiency and decreased IgA or IgG subclass levels (especially IgG2).16 These patients also frequently have specific antibody deficiency due to bacterial polysaccharide antigens. Frequent infections were reported in 92% of patients with SAD (sinusitis, 77%; pneumonia, 42%; otitis media, 25%; bronchitis, 28%).17
    • As many as 50% of patients with idiopathic bronchiectasis have an absence of antipolysaccharide IgA or IgG2 antibodies.14 Although others find such a defect only in 11%.15 However, laboratory measures of IgA-IgG subclass antibodies against pneumococcal antigens are not readily available. Costa Carvalho et al (2005) also reported the absence of a positive association between unresponsiveness to unconjugated pneumococcal vaccines (for polysaccharide antigens [Pneumovax]) and IgA and/or IgG subclass deficiencies in children with recurrent sinusitis.18
  • Deficiency of antibodies of certain IgG subclasses may have clinical relevance in identifying patients with relatively severe atopic dermatitis.19 It may also be associated with nonresponsiveness to interferon alfa in patients with hepatitis B viral infection.20

Physical

  • Patients appear to be healthy between infections.
  • Any abnormal physical findings may indicate various diseases to which patients with selective IgA deficiency have an increased susceptibility.
  • Patients with IgA deficiency and abnormalities of chromosome 18 may present with the following:
    • Facial abnormalities
    • Ear abnormalities
    • Hand abnormalities
    • Growth retardation
    • Muscular hypotonia
    • Mental retardation

Causes

In most cases, IgA-deficiency appears to occur in a sporadic fashion, but familial inheritance is described in a mode of autosomal-recessive or autosomal-dominant pattern with variable or incomplete expression. IgA deficiency is also most commonly found in family members with common variable immunodeficiency (CVID).

  • Transplacental passage of anti-IgA antibodies also can cause IgA deficiency in an offspring by inducing IgA-specific T-cell suppressor activity. This was suggested in a report of 2 mothers with IgA deficiency whose infants had excessive T-cell suppressor function specific for IgA and IgA deficiency.21
  • IgA deficiency is also reported in individuals with various chromosomal abnormalities, particularly those with chromosome 18 abnormalities. Decreased or absent IgA is described in 2 of 6 patients with ring 18, in 5 of 15 patients with deletion of the long arm of 18 (18p-), and in 2 of 5 patients with deletion of the short arm (18q-). Patients with 18p- also have an increased incidence of autoimmune diseases. The actual mechanism is not known because no specific area in chromosome 18 has been consistently associated with IgA deficiency. Partial deletions of chromosome 4 (Wolf-Hirschhorn syndrome) have also resulted in immune defects, including CVID, IgA and IgG2 subclass deficiency, IgA deficiency, and impaired antibody responses to polysaccharide antigens.
  • Other data indicate an association with certain major histocompatibility complex (MHC) haplotypes, suggesting a role with another gene located in chromosome 6 that may explain the high prevalence of autoimmune diseases with IgA deficiency. Certain MHC haplotypes, such as human leukocyte antigen (HLA)-A1, HLA-B8, HLA-DR3; HLA-B57, HLA-SC61, HLA-DR7; and HLA-B44, HLA-FC31, HLA-DR7, have been associated with primary IgA deficiency. Linkage with other haplotypes, eg, HLA-A1, HLA-B8, HLS-DR3, HLA-DQB1*0201, C4B-Sf, C4A-null, G11-15, Bf-0.4, C2a, HSP70-7.5, and tumor necrosis factor (TNF)-a5 is described in a family with IgA deficiency or CVID.
  • Certain drugs can induce transient IgA deficiency which resolve after the causative drugs are removed. This is implicated with induction of suppressor T-cell activity specific for IgA. Agents that can cause IgA deficiency with such mechanisms include sulfasalazine, hydantoin, cyclosporine, gold, fenclofenac, sodium valproate, and captopril. Indeed, 20-40% of patients treated with phenytoin may develop IgA deficiency.22
  • Certain viral infections, such as congenital rubella infection or Epstein-Barr virus (EBV) infection, may result in persistent IgA deficiency.
    • Ig heavy-chain genes are located on chromosome 14 in the following order: 3'-V-D-J–mu-delta-gamma1-psi/epsilon1-alpha1-psi/gamma1-gamma2-gamma4-epsilon1-alpha2. Therefore, deletions of the 1 result in absent IgA1 and also may involve IgE, IgG4, and IgG2, or deletions of the 2 may result in absent IgE, IgG2, and IgG4. No individuals have been described with both IgA1 and IgA2 gene deletions. Individuals with a selective IgA subclass deficiency are usually asymptomatic.
    • Patients in whom homozygous deletions have resulted in absent IgG2, IgG4, IgA1, and IgE Igs appear to be healthy and have normal responses to protein and polysaccharide antigens. Therefore, the most valid indication of immunodeficiency may be the child's ability to make specific antibody.
    • During normal development, synthesis of IgG2 and IgG4 lags that of IgG1 and IgG3. Measurement of IgG subclass levels in children younger than 4 years may simply reflect maturational delay. In 1999, Lawton did not consider a diagnosis of IgG subclass deficiency in young patients before excluding a long list of conditions that might contribute to recurrent respiratory diseases.
  • IgG subclass levels can be affected by placental passage, maturational age, presence of infection, protein loss, or the use of drugs, such as corticosteroids. An example of the differential response can be found in measles. In children younger than 3 years, measles IgG antibodies are predominantly IgG3 in isotype whereas those older than 4 years of age, IgG2 antibodies are predominant.23

More on IgA and IgG Subclass Deficiencies

Overview: IgA and IgG Subclass Deficiencies
Differential Diagnoses & Workup: IgA and IgG Subclass Deficiencies
Treatment & Medication: IgA and IgG Subclass Deficiencies
Follow-up: IgA and IgG Subclass Deficiencies
References
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Further Reading

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Keywords

IgG subclass deficiency, B-cell disorders, immunoglobulin A deficiency, IgA deficiency, immunoglobulin M deficiency, IgM deficiency, immunoglobulin G subclass deficiency, IgG subclass deficiency, antigen-specific antibody deficiency, ASAD, specific antibody deficiency, SAD, bronchiectasis, asthma, sinusitis, combined variable immunodeficiency, CVID, panhypogammaglobulinemia, atopic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergy, gastric carcinomas, lymphomas, rheumatoid arthritis, systemic lupus erythematosus, pernicious anemia, immune thrombocytopenic purpura, ITP, celiac, ulcerative colitis, regional enteritis, Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, Staphylococcus aureus, otitis media, otorrhea, facial abnormalities, ear abnormalities, hand abnormalities, growth retardation, muscular hypotonia, mental retardation, Wolf-Hirschhorn syndrome

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Contributor Information and Disclosures

Author

Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Terry Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Ann O'Neill Shigeoka, MD †, Former Clinical Associate Professor, Department of Pediatrics, Division of Immunology-Rheumatology, University of Utah School of Medicine
Ann O'Neill Shigeoka, MD † is a member of the following medical societies: American Federation for Medical Research, Clinical Immunology Society, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

John Wilson Georgitis, MD, Consulting Staff, Lafayette Allergy Services
John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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