Anti-IgA antibodies can cause severe anaphylactoid reactions in the case of blood transfusion or substitution immunoglobulin therapy in patients with hypogammaglobulinemia. We found a significant amount of anti-IgA antibodies in 10 % of patients with the most common primary hypogammaglobulinemia (selective IgA deficiency and common variable immunodeficiencies) where the serum IgA level was lower than 0.05 g/L. Knowledge of the presence of antibodies against IgA is important in clinical practice in order to prevent an anaphylactic reaction during blood transfusion or during immunoglobulin substitution therapy.
by Dr V. Thon

The occurence of antibodies against IgA in sera of patients with selective IgA deficiency (IgAD) was first described by Fudenberg et al in 1968 [1]. The presence of these antibodies is connected with a higher risk of severe anaphylactoid reaction after treatment with blood transfusion or substitution therapy with gammaglobulins containing IgA. The first description of anaphylactoid reaction associated with anti-IgA was published by the same group in 1968 [2]. During the following decades the results were confirmed, e.g. in the Nordic population by the studies from Finland and Sweden [3, 4]. The incidence of anti-IgA antibodies in persons with IgA deficiency has been reported to vary from 9.6% to 44% [5, 6]. Recently, in a blinded study we analysed severe adverse reactions and investigated anti-IgA antibodies in a population of German patients after intravenous immunoglobulin infusions (IVIG) and found anaphylactoid reactions specifically in subjects with a high level of IgG anti-IgA antibodies [7]. Anaphylactoid reactions are mediated by activation of complement with generation of vasoactive anaphylatoxines such as C3a, C4a and C5a. The clinical picture is characterised by urticaria, hypotension, and respiratory distress with bronchospasm or stridor [7].

Primary immunodeficiencies
Primary immunodeficiencies are hereditary disorders characterised by the mutation(s) of genes coding for certain molecules or receptors important for normal function of the immune system. According to the first National Database of Primary Immunodeficiencies established in Europe in the Czech Republic in 1993, the prevalence of primary immunodeficiencies (PID) studied in the Czech Republic is 5.8/100 000 inhabitants. Figure 1 clearly shows that among cases of PID, antibody deficiencies are predominant. Similar results were reported from a more recent European ESID database of primary immunodeficiencies [8].

Selective IgA deficiency
Selective IgA deficiency (IgAD) is the most common primary immunodeficiency and  is characterised by low serum levels of IgA, with both genetic and environmental factors contributing to the pathogenesis of the disorder. Some individuals with IgAD may be clinically healthy, while others are susceptible to respiratory and gastrointestinal infections, allergy, autoimmune diseases and malignancy.

The occurrence of IgAD is fairly high. For example, the prevalence of IgAD in a clinically healthy Czech population of blood donors is 1:408 [9]. This is in accordance with other published data from European and North American countries as well as a recent report of screened Canadian Blood Services donors [10]. Genetically, IgAD seems to be connected with autoimmunity disorders (Hammarstrom, personal communication).

Common variable immunodeficiency
Common variable immunodeficiency (CVID) is another primary immunodeficiency and is  heterogeneous group of diseases characterized by impaired antibody production of all major Ig classes, predisposing patients to frequent infections of the respiratory tract with encapsulated bacteria. However, the number of B-lymphocytes in peripheral blood is usually normal and in most patients the T cell help for B cells is impaired [11]. As is the case with IgAD,  both males and females are affected equally. IgAD can develop into CVID. For treatment, substitution immunoglobulin therapy is needed [12].

As mentioned above we systematically studied the prevalence of anti-IgA antibodies and related anaphylactoid reactions following immunoglobulin infusions (IVIG) in CVID patients. Serum immunoglobulins were measured by nephelometry and low concentrations of IgA were confirmed by sensitive ELISA. Cell analysis was performed by flow cytometry [7, 13]. New modifications of the ELISA method were used for sensitive and specific investigation of anti-IgA antibodies. In the first screening step the occurrence of anti-IgA antibodies of IgG class was examined. In the second step the specificity of detection of anti-IgA antibodies was confirmed by an inhibition test and the amount of anti-IgA antibodies was quantified.
 
In one study we investigated 279 patients from the Czech Republic and Germany with common variable immunodeficiency (CVID, n = 131) and IgA deficiency (n = 148). Patients were characterised using diagnostic criteria recommended by the  European Society of ImmunoDeficiencies (ESID) and Pan American Group for ImmunoDeficiency (PAGID) and the European Primary Antibody Deficiencies group (EURO-PADnet). We found that 10% of hypogammaglobulinemic patients in central Europe were positive for anti-IgA antibodies [13]. Specific anti-IgA antibodies occur only in patients with undetectable IgA serum level (IgA lower than 0.05 g/L).

From the German cohort of CVID patients (n = 88) we identified eight patients with anti-IgA antibodies (titre 1:100 - 1:6400). All patients lacked IgA+ B cells in peripheral blood. Five of them had a history of severe anaphylactoid reaction to IVIG (anti-IgA antibody titre 1:400 - 1:6400). However, four of these five patients tolerated subcutaneous immunoglobulin substitution (SCIG) [7].

A positive finding of anti-IgA antibodies enables better recognition and management of true cases of anti-IgA anaphylactoid reactions and enables assessment of the risk for the blood transfusion services. Anti-IgA mediated anaphylactoid reaction can be prevented by auto transfusion (if this procedure is possible) or by using blood from donors completely lacking IgA, or by thoroughly washing the blood cells to remove donor’s IgA. Therefore both positive and negative results in screening for anti-IgA antibodies in IgAD and CVID subjects with serum IgA levels below 0.05 g/L provide valuable information and guidance for blood transfusion service [7, 14, 15, 16].

Conclusion
The occurrence of anti-IgA antibodies at high titre is a risk factor associated with anaphylactoid reaction in hypogammaglobulinemic patients. The presence or absence of anti-IgA antibodies is also considered important basic information in the European ESID database of primary immunodeficiencies. Screening for anti-IgA antibodies in patients lacking IgA may be helpful for determing the best therapeutic strategy, including the route of administration of substitution immunoglobulin therapy or the transfusion of IgA-free blood products. From a hematological point of view tested IgA-deficient blood components without anti-IgA antibodies are a precious resource that should be allocated with care and reserved for IgAD patients at risk of anaphylactoid reaction [14]. The combined use of quantitative ELISA for detection of anti-IgA antibodies and the measurement of serum IgA concentration by nephelometry provides an effective and safe strategy for the diagnosis and prevention of IgA anaphylactic transfusion reactions.

References
1. Fudenberg HH et al. Human Antibodies to Human IgA Globulins. Immunochemistry. 1968;5:203-6.
2. Vyas GN, Perkins HA, Fudenberg HH. Anaphylactoid Transfusion Reactions Associated with Anti-IgA. Lancet 1968;2:312-5.
3. Koskinen S, Tolo H, Hirvonen M, Koistinen J. Long-term Follow-Up of Anti-IgA Antibodies in Healthy IgA-Deficient Adults. J Clin Immunol 1995;15:194-8.
4. Sundin U, Nava S, Hammarstrom L. Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy. Clin Exp Immunol. 1998;112:341-6.
5. Koistinen J, Sarna S. Immunological abnormalities in the sera of IgA-deficient blood donors. Vox Sang 1975;29(3):203-13.
6. Nadorp JH et al. The significance of the presence of anti-IgA antibodies in individuals with an IgA deficiency. Eur J Clin Invest 1973;3(4):317-23.
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8. Gathmann B et al. The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008. Clin Exp Immunol. 2009 Sep;157 Suppl 1:3-11.
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10. Palmer DS et al. Screening of Canadian Blood Services donors for severe immunoglobulin A deficiency. Transfusion. 2010 Feb 11. [Epub ahead of print]
11. Thon V et al. Defective integration of activating signals derived from the T cell receptor (TCR) and costimulatory molecules in both CD4+ and CD8+ T lymphocytes of common variable immunodeficiency (CVID) patients. Clin Exp Immunol 1997;110
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12. Chapel H et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood 2008;112(2):277-86.
13. Thon V et al. The prevalence of anti-IgA antibodies in central Europe and relation to anaphylactoid reactions in patients with hypogammaglobulinemia. Annual meeting of the Austrian Society for Allergology and Immunology. Abstract book 2007:MI7.
14. Yuan S, Goldfinger D. A readily available assay for anti-immunoglobulin A: is this what we have been waiting for? Transfusion 2008;48(10):2048-50.
15. Bjorkander J et al. Immunoglobulin prophylaxis in patients with antibody deficiency syndromes and anti-IgA antibodies. J Clin Immunol1987;7:8-15.
16. Sandler SG et al. IgA anaphylactic Transfusion Reactions. Transfus Med Rev 1995;9:1-8.

The author
Vojtech Thon, M.D., Ph.D.
University Centre for Primary Immunodeficiencies
Department of Clinical Immunology and Allergology
St. Anne University Hospital,
Masaryk University
Pekarska 53,
CZ-656 91 Brno
The Czech Republic
Tel. +420-54318 3128
Fax: +420-54318 3143
e-mail: vojtech.thon@fnusa.cz