IgA and IgG Subclass Deficiencies

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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 specific antigens such as polysaccharide proteins present on certain bacteria.

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. Therefore, in surveys of patients followed for immunodeficiency, common variable immunodeficiency is the most common, followed by IgA deficiency. [1] 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. [2] 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. The importance of IgA can be demonstrated in animal models that lack IgA and have problems clearing rotavirus infection. [3] 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). [4] 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. [5]

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. [6]

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.

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 various Caucasian countries show a frequency of 1 in 400-500 or 0.2-0.25%. [7, 8]

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

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. [9, 10]

Individuals with selective IgA or IgG subclass deficiency are usually asymptomatic. However, certain infections such as by influenza virus may be more persistent. [11] Patients with IgA-IgG2 deficiency do 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. In one Turkish study, [12] the most common clinical conditions associated with IgA deficiency were various infections (84%), allergies (43%), and autoimmune disorders (17%). Another study examining selective IgA deficiency in Israel found 40% with infections (mainly pneumonia and ear infections), 32% with allergies, 21% with autoimmune diseases, and 5% with malignancies. [13] Therefore, treatment of the associated medical conditions must be considered. There have been other recent surveys questioning the association of IgA deficiency and atopy, [14, 15] although the latter may have been underpowered since they looked at the Asian population. Other studies indicated an increased risk for upper airway obstruction and food hypersensitivity. [16]

Recently, attention has been focused on psychiatric conditions that have been associated with IgA deficiency. [17]

Large population studies in various Caucasian countries show a frequency of 1 in 400-500 or 0.2-0.25% [7, 8] IgA deficiency also appears to be more prevalent in blacks than in whites, whereas Asians have the lowest incidence, with only 7 cases found in 22,609 blood donors in one survey. [18] A study of over 20,000 Turkish school children shows an incidence of 1:188 (0.52%). [19]

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.

Most studies of healthy individuals without medical concerns reveal no sex predilection.

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.

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Plebani A, Ugazio AG, Meini A, et al. Extensive deletion of immunoglobulin heavy chain constant region genes in the absence of recurrent infections: when is IgG subclass deficiency clinically relevant?. Clin Immunol Immunopathol. 1993 Jul. 68(1):46-50. [Medline].

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Constantin C, Huber WD, Granditsch G, et al. Different profiles of wheat antigens are recognised by patients suffering from coeliac disease and IgE-mediated food allergy. Int Arch Allergy Immunol. 2005 Nov. 138(3):257-66. [Medline].

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Aytekin C, Tuygun N, Gokce S, Dogu F, Ikinciogullari A. Selective IgA Deficiency: Clinical and Laboratory Features of 118 Children in Turkey. J Clin Immunol. 2012 May 1. [Medline].

Shkalim V, Monselize Y, Segal N, Zan-Bar I, Hoffer V, Garty BZ. Selective IgA deficiency in children in Israel. J Clin Immunol. 2010 Sep. 30(5):761-5. [Medline].

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Ramanujam R, Piehl F, Pirskanen R, Gregersen PK, Hammarstrom L. Concomitant autoimmunity in myasthenia gravis–lack of association with IgA deficiency. J Neuroimmunol. 2011 Jul. 236(1-2):118-22. [Medline]. [Full Text].

Jorgensen GH, Ornolfsson AE, Johannesson A, et al. Association of immunoglobulin A deficiency and elevated thyrotropin-receptor autoantibodies in two Nordic countries. Hum Immunol. 2011 Feb. 72(2):166-72. [Medline].

Chow MA, Lebwohl B, Reilly NR, Green PH. Immunoglobulin A Deficiency in Celiac Disease. J Clin Gastroenterol. 2012 Apr 2. [Medline].

Carr TF, Koterba AP, Chandra R, et al. Characterization of specific antibody deficiency in adults with medically refractory chronic rhinosinusitis. Am J Rhinol Allergy. 2011 Jul-Aug. 25(4):241-4. [Medline]. [Full Text].

Tuerlinckx D, Vermeulen F, Pekus V, et al. Optimal assessment of the ability of children with recurrent respiratory tract infections to produce anti-polysaccharide antibodies. Clin Exp Immunol. 2007 Aug. 149(2):295-302. [Medline]. [Full Text].

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van Kessel DA, van Velzen-Blad H, van den Bosch JM, Rijkers GT. Impaired pneumococcal antibody response in bronchiectasis of unknown aetiology. Eur Respir J. 2005 Mar. 25(3):482-9. [Medline].

Vendrell M, de Gracia J, Rodrigo MJ, et al. Antibody production deficiency with normal IgG levels in bronchiectasis of unknown etiology. Chest. 2005 Jan. 127(1):197-204. [Medline].

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Cheng YK, Decker PA, O’Byrne MM, Weiler CR. Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome. Ann Allergy Asthma Immunol. 2006 Sep. 97(3):306-11. [Medline].

Costa Carvalho BT, Nagao AT, Arslanian C, et al. Immunological evaluation of allergic respiratory children with recurrent sinusitis. Pediatr Allergy Immunol. 2005 Sep. 16(6):534-8. [Medline].

Mrabet-Dahbi S, Breuer K, Klotz M, et al. Deficiency in immunoglobulin G2 antibodies against staphylococcal enterotoxin C1 defines a subgroup of patients with atopic dermatitis. Clin Exp Allergy. 2005 Mar. 35(3):274-81. [Medline].

Gregorek H, Dzierzanowska-Fangrat K, Woynarowski M, Jozwiak P, Witkowska-Vogtt E, Socha J, et al. Persistence of HBV-DNA in children with chronic hepatitis B who seroconverted to anti-HBs antibodies after interferon-alpha therapy: correlation with specific IgG subclass responses to HBsAg. J Hepatol. 2005 Apr. 42(4):486-90. [Medline].

de Laat PC, Weemaes CM, Bakkeren JA, et al. Familial selective IgA deficiency with circulating anti-IgA antibodies: a distinct group of patients?. Clin Immunol Immunopathol. 1991 Jan. 58(1):92-101. [Medline].

Swedo SE, Leckman JF, Rose NR. (2012) From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome. Pediatr Therapeut. 2012. 2:2.

Murphy TK, Storch EA, Lewin AB et al. (2012). Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Pediatr. 2012. 160:314-9.

Schaffer FM. Clinical assessment and management of abnormal IgA levels. Ann Allergy Asthma Immunol. 2008 Mar. 100(3):280-2. [Medline].

Browning MJ. Specific polysaccharide antibody deficiency in chromosome 18p deletion syndrome and immunoglobulin A deficiency. J Investig Allergol Clin Immunol. 2010. 20(3):263-6. [Medline].

Toptygina AP, Pukhalsky AL, Alioshkin VA. Immunoglobulin G subclass profile of antimeasles response in vaccinated children and in adults with measles history. Clin Diagn Lab Immunol. 2005 Jul. 12(7):845-7. [Medline]. [Full Text].

Tanaka M, Seki G, Ishizawa K, wet al. Resolution of Henoch-Schönlein purpura nephritis after acquired IgA deficiency. Pediatr Nephrol. 2010 Nov. 25(11):2355-8. [Medline].

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Freeman JA, Crassini KR, Best OG, et al. Immunoglobulin G (IgG) subclass deficiency and infection risk in 150 patients with chronic lymphocytic leukaemia. Leuk Lymphoma. 2012 Jun 27. [Medline].

Shakkottai A, Bupathi K, Patel AP, et al. Children with partial IgA deficiency: clinical characteristics observed in the pediatric rheumatology clinic. Clin Pediatr (Phila). 2012 Jan. 51(1):46-50. [Medline].

Fusaro AE, Fahl K, Cardoso EC, et al. Profile of autoantibodies against phosphorylcholine and cross-reactivity to oxidation-specific neoantigens in selective IgA deficiency with or without autoimmune diseases. J Clin Immunol. 2010 Nov. 30(6):872-80. [Medline].

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Brand(Manufacturer)

Manufacturing Process

pH

Additives (IVIg products containing sucrose are most often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs])

Parenteral Form and Final Concentrations

IgA Content mcg/mL

Carimune NF

(CSL Behring)

Kistler-Nitschmann fractionation; pH 4, nanofiltration

6.4-6.8

6% solution: 10% sucrose, < 20 mg NaCl/g protein

Lyophilized powder 3%, 6%, 9%, 12%

Trace

Flebogamma

(Grifols USA)

Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization

5.1-6

Sucrose free, contains 5% D-sorbitol

Liquid 5%

< 50

Gammagard Liquid 10%

(Baxter Bioscience)

Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation

4.6-5.1

0.25M glycine

Ready-for-use Liquid 10%

37

Gamunex

(Talecris Biotherapeutics)

Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation

4-4.5

Does not contain carbohydrate stabilizers (eg, sucrose, maltose), contains glycine

Liquid 10%

46

Gammaplex

(Bio Products)

Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation

4.8-5.1

Contains sorbitol (40 mg/mL); do not administer if fructose intolerant

Ready-for-use solution 5%

< 10

Iveegam EN

(Baxter Bioscience)

Cohn-Oncley fraction II/III; ultrafiltration; pasteurization

6.4-7.2

5% solution: 5% glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

Polygam S/D

Gammagard S/D

(Baxter Bioscience for the American Red Cross)

Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated

6.4-7.2

5% solution: 0.3% albumin, 2.25% glycine, 2% glucose

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

Octagam

(Octapharma USA)

9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events

Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization

5.1-6

10% maltose

Liquid 5%

200

Panglobulin

(Swiss Red Cross for the American Red Cross)

Kistler-Nitschmann fractionation; pH 4 incubation, trace pepsin, nanofiltration

6.6

Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl

Lyophilized powder 3%, 6%, 9%, 12%

720

Privigen Liquid 10%

(CSL Behring)

Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration

4.6-5

L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)

Ready-for use liquid 10%

< 25

Terry W Chin, MD, PhD Associate Clinical Professor, Department of Pediatrics, University of California, Irvine, School of Medicine; Associate Director, Cystic Fibrosis Center, Attending Staff Physician, Department of Pediatric Pulmonology, Allergy, and Immunology, Memorial Miller Children’s Hospital

Terry W 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 Federation for Clinical Research, American Thoracic Society, California Society of Allergy, Asthma and Immunology, California Thoracic Society, Clinical Immunology Society, Los Angeles Pediatric Society, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter’s University Hospital

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 Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

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.

IgA and IgG Subclass Deficiencies

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