Anti-IgA antibody associated reactions to intravenous gammaglobulin in a patient who tolerated intramuscular gammaglobulin

A patient with common variable immunodeficiency syndrome tolerated intramuscular IgG (which contains IgA) and an initial infusion with intravenous (IV) IgG, but developed reactions to subsequent IV IgG. High-titre, class-specific anti-IgA antibodies were detected suggesting immunization by the IgA-contaminated IV immunoglobulin. Subsequent IgG replacement was achieved with IgA-deficient plasma infusions. Patients who tolerate intramuscular IgG may not tolerate the IV preparations.     

Immunoglobulin prophylaxis in patients with antibody deficiency syndromes and anti-IgA antibodies

Sera from three hundred five patients with immunoglobulin deficiencies were analyzed for the presence of anti-IgA antibodies by using indirect agglutination and enzyme-linked immunosorbent assay (ELISA). Anti-IgA antibodies were observed in 15 of 68 (22%) patients with hypogammaglobulinemia and 53 of 185 (29%) patients with selective IgA deficiency, both groups having serum IgA<0.05 g/liter. The highest frequency, 6 of 10 or 60%, was noted for patients with a combined IgA-IgG2 deficiency. No anti-IgA antibodies were detected in 25 patients with serum IgA between 0.05 and 0.27 g/liter and normal amounts of serum IgM and IgG or in 17 patients with hypogammaglobulinemia who had serum IgA of 0.05–0.7 g/liter. The anti-IgA antibodies were primarily of the IgG class, but IgD and IgM anti-IgA were occasionally found. IgE anti-IgA antibodies could not be detected with the presently used technique. The IgG anti-IgA antibodies were mainly of the IgG1 subclass but occasionally also of the subclasses IgG2, IgG3, and IgG4. Of eight patients with anti-IgA antibodies, seven tolerated Ig prophylaxis with a commercial immunoglobulin preparation low in IgA when given either intramuscularly or intravenously. The titers of anti-IgA in the sera of these patients did not rise in relation to the prophylaxis. Only one of the eight patients had a history of previous anaphylactic reactions to IgA-containing blood products. He tolerated six Ig infusions during 5 months with the IgA-depleted preparation without any adverse effects but showed increasing levels of anti-IgA antibodies and ultimately experienced a near-fatal reaction at the seventh infusion.     

Anti-IgA antibodies in selective IgA deficiency and in primary immunodeficient patients treated with gamma-globulin

Sera from 106 blood donors, 40 patients with primary immunodeficiencies (ID) treated with gamma-globulin, and 46 patients with selective IgA deficiency were analyzed by an enzyme-linked immunosorbent assay for anti-IgA antibodies. Increased levels of antibodies to IgA were found in 5.6% of the blood donors, 17.5% of the ID patients, and 36.8% of the isolated IgA deficiencies. The percentage was higher in patients with IgA and IgG2 deficiencies (50%). The percentage of patients having increased levels of anti-IgA antibodies was similar to the total prevalence of the 10 other autoantibodies studied. These anti-IgA antibodies were mainly of the IgG class, except from one blood donor with IgM antibodies, and two patients, one with isolated IgA deficiency and the other with common variable immunodeficiency who had anti-IgA antibodies of the IgE class. The latter patient developed a near fatal anaphylactic reaction when intravenous gamma-globulin was administered. Most of the patients with severe adverse reactions to gamma-globulin did not present anti-IgA antibodies. Our data suggest that at least in some immunodeficient patients the elevated amounts of anti-IgA antibodies are not related to the administration of exogenous IgA. The importance of measuring anti-IgA antibodies of the IgG and IgE isotypes in IgA-deficient patients as well as in patients in treatment with gamma-globulin is emphasized.     

IgG Anti-IgA Subclasses in Common Variable Immunodeficiency and Association with Severe Adverse Reactions to Intravenous Immunoglobulin Therapy

The current therapy for common variable immunodeficiency is based on the administration of intravenous immunoglobulin preparations which may cause severe adverse reactions. Some reports have associated these reactions with IgG anti-IgA antibodies, although this is not yet clear. We analyzed 20 sera from common variable immunodeficiency patients by an enzyme immunoassay to detect IgG anti-IgA and determine its subclass profile. Five patients presented high levels of these antibodies, all of them had IgG1, two had IgG2 and IgG4 and one had IgG3. Three of these five patients were receiving non IgA depleted intravenous immunoglobulin and had no severe adverse reactions. One patient had persisted with similar high levels of IgG anti-IgA during three years. Therefore, the IgG anti-IgA antibodies, regardless to their subclass profile in the common variable immunodeficiency patients sera do not seem to be associated with severe adverse reactions to intravenous immunoglobulins.     

Anti-IgA antibodies in IgA-deficient children

IgG and IgM isotype antibodies to polyclonal human IgA, myeloma IgA₁, and myeloma IgA₂ were estimated in 38 IgA-deficient children aged between 0.9 and 15 years. All children had IgM anti-IgA antibodies. IgG antibodies against either polyclonal IgA, IgA₁, or IgA₂ were present in 63% of the IgA-deficient children. IgG anti-IgA antibodies were detected against all three antigens in 8 of 11 severely IgA-deficient children and in 7 of 27 partially IgA-deficient children, but in only 1 of 23 healthy adult controls. The proportion of children with IgG anti-IgA antibodies was significantly greater in the severely IgA-deficient group in comparison with the partially IgA-deficient group and the adult controls (chi-square test,P<0.01 andP<0.005, respectively). There was a strong correlation within each IgG subclass between antibody responses toward each of the three IgA antigens. Twenty-four children were followed over a period ranging from 0.9 to 11 years (mean, 2.3 years). Three children who were initially IgG anti-IgA antibody negative became antibody positive and three who were antibody positive became antibody negative. Five children with severe IgA deficiency remained severely IgA deficient and IgG antibodies to IgA persisted in all five at follow-up. The presence of IgG anti-IgA antibodies did not influence the normalization of serum IgA at follow-up in 14 of 19 children who were initially partially IgA deficient.     

Anti-IgA in Selective IgA Deficiency

Anti-IgA antibodies were found in 14 of 33 (42%) IgA-deficient donors. In healthy IgA-deficient blood donors anti-IgA appeared associated with the presence of HLA DR3. The antibodies were mainly of the IgG1 and, in high-titred sera, IgG4 subclasses. Sera containing high-titred anti-IgA selectively impaired IgA synthesis in vitro as induced by direct and indirect polyclonal B-cell activators. These antibodies may play a role in the pathogenesis and/or the maintenance of IgA deficiency.     

Cross-reactive antibodies induced by xenogeneic IgA can cause selective IgA deficiency

Selective immunoglobulin A deficiency (sIgAD) is the most common immunodeficiency in humans. Auto-reactive antibodies to human immunoglobulin A (IgA) are found in the serum of 20–40% of individuals with sIgAD. It is unknown whether these antibodies play a role in the pathogenesis of this immunodeficiency and although the prevailing thought is that they are secondary to the onset of sIgAD, there is very little, if any, support for this notion. Here, we propose that anti-IgA antibodies are in fact responsible for the removal of IgA from serum, and that the inducing antigen is most probably a xenogeneic IgA. This hypothesis is based on data obtained from an sIgAD patient in whom changes in dietary consumption of beef and/or bovine dairy products resulted in changes in anti-IgA levels in the serum. To test the hypothesis, the presence of anti-bovine IgA antibodies was tested by a highly specific enzyme-linked immunosorbent assay in serum samples from IgA-deficient and control individuals. All 13 sIgAD individuals with anti-IgA antibodies had a higher titer against bovine IgA than against human IgA. Of 23 control individuals, a surprisingly high proportion (65%) was also found to have IgG anti-bovine IgA antibodies. These results support the hypothesis that the anti-human IgA antibodies found in IgA-deficient individuals are originally produced against bovine IgA. These antibodies are found in many normal individuals, but only in cases where they cross react with endogenous human IgA, sIgAD may develop.     

Anti-IgA antibodies in common variable immunodeficiency (CVID): diagnostic workup and therapeutic strategy

Common Variable Immunodeficiency (CVID) patients who are seropositive for anti-IgA antibodies have a predisposition for anaphylactoid reactions to intravenous immunoglobulin replacement therapy (IVIG). Among 88 CVID patients, we identified eight with IgG anti-IgA antibodies (9%). All eight completely lacked IgA (<0.0009 g/l). Five of them had a history of anaphylactoid reactions to IVIG. However, four of these five patients tolerated subcutaneous immunoglobulin replacement therapy (SCIG). To identify predisposing factors for anti-IgA antibodies and related anaphylactoid reactions, we analyzed the clinical and immunological phenotype of affected patients. All eight IgG anti-IgA-positive patients lacked IgA(+) B cells in peripheral blood. Moreover, CVID patients with retained class-switched CD27(pos) IgM(neg) IgD(neg) memory B cells (Freiburg classification group II) and total IgA deficiency seem to have an increased risk for developing anti-IgA antibodies. In seven of the eight patients, lymphoproliferation was observed (most prominently nodular lymphatic hyperplasia), two had granulomatous disease, and two showed autoimmune phenomena.     

IgG anti-IgA1 and anti-IgA2 antibodies: their measurement by an enzyme-linked immunosorbent assay and their relationship to disease

IgG anti-IgA antibodies were measured by an enzyme-linked immunosorbent assay using one IgA1 and one IgA2 (m1) myeloma and a pooled IgA protein preparation as antigens. Class-specific anti-IgA antibodies occurred in 0.8% of non-IgA-deficient sera and 24.3% of IgA-deficient sera. Antibodies reacting with IgA1 only occurred in 2.6% of non-IgA-deficient sera and 6.7% of IgA-deficient sera. Antibodies reacting with IgA2 only occurred in 0.6% of non-IgA-deficient sera and 2.7% of IgA-deficient sera. The prevalence of anti-IgA in IgA deficients with inflammatory disease was higher (81.8%) than in IgA deficients without disease (24.1%) and was accounted for by class-specific antibodies.     

Gm allotypes in IgA deficiency

Gm phenotypes were examined in 90 Swedish IgA-deficient (less than 0.05 g/litre of serum IgA) donors and 40 normal first and second degree relatives of six of these donors. The G1m1,2, G3m5 and Km1 frequency in the group of IgA-deficient donors did not differ from that found in the normal population. Among the relatives, HLA and/or Gm identical normal sibs were observed. Anti-IgA antibodies were present in 29 of the IgA-deficient donors and anti-IgG in seven. No association between the two was found. A statistically significant association between the G1m-2 phenotype and the presence of anti-IgA antibodies was observed. When subdivided according to HLA type, a non-random distribution of Gm phenotypes was seen in HLA-B8/DR3 positive individuals with anti-IgA antibodies (HLA-B8/DR3 being the haplotype associated with IgA deficiency). These data suggest an association between IgA deficiency, anti-IgA and the studied Gm allotypes.     

Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products

Despite yielding a definitive diagnosis in fewer than 20 percent of anaphylactic transfusion reactions, investigation for IgA deficiency and the presence of presumably pathogenic IgG anti-IgA is useful in patient management. Individuals with demonstrated anti-IgA are thereafter committed to receiving IgA-depleted cellular products or IgA-deficient plasma and derivatives to prevent recurrent severe reactions. Unfortunately, in populations of IgA-deficient individuals screened for anti-IgA, the predictive value of the test in the absence of a prior reaction is quite low. Anti-IgA testing is complex and limited to a few reference laboratories, many of which still employ a labor-intensive hemagglutination assay developed in the late 1960s. Timely decisions regarding further transfusion management of patients experiencing anaphylaxis often rely upon more rapidly obtained assays of the IgA concentration as an indicator of the likelihood of subsequent demonstration of anti-IgA. The scarcity of IgA-deficient banked plasma products and dedicated plateletpheresis donors has led to the development of American Rare Donor Program policies designed to appropriately allocate these precious resources. The test methods used to establish the diagnosis of IgA deficiency and identify the approximately one third of these individuals with anti-IgA are discussed, along with the incidence of abnormal tests in various populations. Also presented are testing recommendations for the identification of an IgA-mediated mechanism for transfusion-associated anaphylaxis and qualification of patients to receive rare IgA-deficient plasma-containing products.     

Long-term use of IgA-depleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies

The use of intravenous immunoglobulin is standard practice for antibody replacement in the humoral immunodeficiency diseases. Most infusions proceed uneventfully, but a proportion of infusions (5–8%) produces some degree of an infusion reaction. While the cause of most of these infusion reactions is unknown, an established, but rare cause of reactions is IgA antibodies in the serum of the patient, which apparently forms an immune complex with the traces of IgA in the infused immunoglobulin. This article describes our studies of five immunodeficient patients who had high-titered anti-IgA antibodies and a history of severe infusion reactions to intravenous immunoglobulin products not depleted of IgA (IgA content, 270–720 µg/ml). Over a 6-year period we gave these patients IgA-depleted intravenous immunoglobulin for a total of 170 infusions. These infusions were generally well tolerated; however, mild to moderate infusion reactions did occur in 9 of the 170 infusions (5.3%). These reactions were not related to the IgA content of the immunoglobulin solutions used—ascertained to vary between 0.4 and 2.9 µg/ml of IgA. Levels of plasma C3a and C4a increased after immunoglobulin infusions but the appearance of these components was not accompanied by any infusion reaction. We conclude that the long-term infusions of IgA-depleted intravenous immunoglobulin, within the range of IgA concentrations investigated, into patients with even very high-titered antibodies to IgA, is a safe practice.     

An enzyme immunoassay for the determination of low levels of IgA in human serum

An enzyme immunoassay (EIA) has been developed which facilitates the detection of low levels of immunoglobulin A in human serum. IgA is captured by an anti-IgA antibody linked to micron-sized polyacrylamide beads and subsequently detected by an anti-IgA horseradish peroxidase conjugate. The standard curve is linear in the region between 25-1000 ng/ml IgA. The assay is particularly suited to measure IgA antibodies in sera from IgA-deficient individuals and IgA contaminants in blood products.     

Anti-IgA antibodies in pregnancy

A survey of 28,000 pregnant women revealed an incidence of IgA deficiency (serum IgA less than 1 mg per deciliter) of 1 in 450, which is identical to that in a normal blood-donor population of both sexes. Using an enzyme-linked immunosorbent assay (ELISA) in a study of 61 serum samples from IgA-deficient pregnant women, we observed antibodies to IgA2 alone in 20 per cent, as compared with 7.5 per cent of pregnant women not deficient in IgA and no IgA-deficient blood donors. Antibodies reacting with IgA1 alone were present in occasional serum samples (2 to 7 per cent) from all groups studied, and class-specific anti-IgA antibodies were present in 17 per cent of IgA-deficient blood donors and in 16 per cent of IgA-deficient pregnant women. Blocking experiments showed that some serum samples contained an antibody that reacted with both IgA1 and IgA2, whereas others contained two antibodies, one reacting with IgA1 and the other with IgA2. The anti-IgA2 antibodies tended to diminish in titer after delivery. The ELISA was, as expected, more sensitive than the hemagglutination assay. The offspring of IgA-deficient mothers (but not of IgA-deficient fathers) had levels of serum IgA below the normal mean (21 of 27); 12 had levels more than 1 S.D., and seven had levels more than 2 S.D., below the normal mean. Of the seven infants with serum IgA levels more than 2 S.D. below the normal age-related mean, five had mothers with anti-IgA antibodies during gestation. It is possible that maternal anti-IgA exerts a transplacental effect on the fetal immune system, causing IgA deficiency in some instances.     

Specific antibodies in infants with gastrointestinal intolerance to cow's milk protein

Antibodies of various immunoglobulin classes against cow's milk proteins were studied in infants and children with cow's milk protein intolerance, gluten-sensitive enteropathy and acute gastroenteritis. Their IgE, IgG, IgM and IgA antibody levels determined with the enzyme-linked immunosorbent assay (ELISA) and the IgE antibodies also determined with RAST, were compared with reference groups of children and adults. IgE, IgT or IgA antibodies against unseparated cow's milk proteins, alpha-lactalbumin, beta-lactoglobulin, alpha-casein and beta-casein were present in many of the studied samples, but did not discriminate between the individuals with and without intolerance symptoms. As a group, the infants with late reactions to cow's milk showed increased levels of IgE and IgG antibodies detected with the ELISA, while patients with gluten-sensitive enteropathy had significantly increased levels of IgG and IgA antibodies of cow's milk proteins compared to the reference group. By combining the findings of antibody increases in various immunoglobulin classes, an individual discrimination could be reached. Thus, 8 of 9 of the patients with late reactions to cow's milk had increased levels of IgE or IgG + IgA antibodies as compared to 3 of 22 in the reference group. Serodiagnosis with the ELISA may, therefore, be of some use in patients with a suspicion of cow's milk protein intolerance.     

Effect of immunotherapy on appearance of antibodies to ragweed in external secretions

Studies on 50 nasal washings, 16 parotid salivas from ragweed-allergic patients, and 10 secretions from normal subjects showed considerable variation in protein and immunoglobulin concentrations. Only 2 immunoglobulins, A and G, were found in nasal washings. Of 26 parotid salivas studied (allergic and controls), IgA was found in 26, IgG in 4, and IgM in 3 specimens. Anti-ragweed antibodies in the serum and exocrine secretions of allergic patients were examined by means of Prausnitz-Küstner (PK) test, radioimmunoelectrophoresis, radioimmunodiffusion, and tanned cell hemagglutination (TH) tests. The incidence of IgE, IgA, and IgG antibodies to ragweed in the sera and nasal washings in a group of 22 patients with previous immunotherapy was compared to that of 28 patients without immunotherapy. The immunotherapy seemed to affect the incidence of serum IgE and IgG antibodies but has no influence on the incidence of anti-ragweed antibodies in the nasal washings. PK activity of nasal washings could be removed by absorption with anti-IgE but not anti-IgA or anti-IgG immunosorbents. Anti-ragweed antibodies could be detected in parotid salivas only by the TH test.     

Immune tolerance induction in patients with IgA anaphylactoid reactions following long-term intravenous IgG treatment

To date, there is very little information regarding the pathomechanism of IgA anaphylactoid reactions and the management of affected patients. Five adult patients with common variable immunodeficiency (CVID) and a history of anaphylactic reactions due to the administration of immunoglobulin preparations were studied. The activity of anti-IgA was determined by the gel agglutination technique using IgA-coated beads. Antibodies to IgA were detected in the serum of all five patients. Initially, IgA 'depleted' intravenous (i.v.) IgG preparations were infused carefully into the patients until the activity of anti-IgA was decreased significantly or became undetectable. Subsequently, unselected i.v. IgG preparations were infused, and the activity of anti-IgA was abolished in all cases. Intravenous IgG long-term administration results in tolerance induction in patients with IgA anaphylactoid reactions. This tolerance appears to be related to antibody blockage in the circulation and an inhibition of antibody production. Most importantly, IgA appears to play an important role in the treatment of CVID. Patients with IgA anaphylactoid reactions can be treated safely with IgA containing i.v. IgG preparations following tolerance induction.     

Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy

Patients with IgA deficiency often demonstrate circulating antibodies against IgA, which have been suggested to be associated with transfusion reactions. Sera from three patients with common variable immunodeficiency (CVID) and one with a selective IgA deficiency with anti-IgA antibodies receiving subcutaneous gammaglobulin replacement therapy were analysed for serum levels of IgG, IgA and anti-IgA before and during a treatment period of 4–7 years. Treatment with gammaglobulin preparations containing significant amounts of IgA (< 5 mg/ml) resulted in a decrease or disappearance of the anti-IgA antibodies. Analysis of serum fractions, however, revealed anti-IgA activity in the complex-containing fractions. In vitro experiments gave similar results with a shift of anti-IgA activity from the monomeric to the complex-containing fractions (that could not be detected in whole serum). When the patients were subsequently switched to treatment with a preparation containing less IgA (< 80 μg/ml) or made an interruption in the treatment schedule, the anti-IgA antibodies reappeared. Importantly, however, one of the patients lost his anti-IgA activity during a 3-month period on the preparation containing the higher IgA levels, and these antibodies did not reappear after switching to the low IgA-containing preparation. After 5 years on this preparation, anti-IgA can still not be detected, suggesting induction of unresponsiveness.     

Celiac Disease and Immunoglobulin A Deficiency: How Effective Are the Serological Methods of Diagnosis?

Immunoglobulin A (IgA) deficiency is 10 to 15 times more common in patients with celiac disease (CD) than in healthy subjects. Serological tests have become the preferred methods of diagnosing CD in both symptomatic and asymptomatic patients. However, commercially available serological methods are limited in that they detect only the IgA isotype of antibodies (with the exception of IgG gliadin assays); hence, IgA-deficient patients with CD may yield false-negative serology. Fifteen pediatric patients with CD and 10 IgA-deficient pediatric patients without CD were examined for IgA and IgG antibodies to endomysium, gliadin, and tissue transglutaminase. Twenty-five specimens from patients with IgA deficiency were examined. Fifteen were from patients with CD, and 10 were patients without CD. All 15 IgA-deficient patients with CD were positive for endomysium antibodies of the IgG isotype and for IgG gliadin antibodies. All but one of the IgA-deficient patients with CD were also positive for IgG tissue transglutaminase antibodies. None of the IgA-deficient patients without CD were positive for any of the antibody markers. All the specimens examined were also negative for IgA-specific antibodies to endomysium, gliadin, and tissue transglutaminase. IgG-specific antibody tests for endomysium, gliadin, and tissue transglutaminase are useful for the identification of IgA-deficient patients with CD. IgG antibody tests along with tests routinely being used in clinical laboratories can reliably detect all active patients with CD. In addition, the levels of these CD-specific IgG antibodies could be used to monitor patient dietary compliance.     

Immunoglobulin G (IgG) Anti-Tissue Transglutaminase Antibodies Used as Markers for IgA-Deficient Celiac Disease Patients

The role of immunoglobulin A (IgA) anti-tissue transglutaminase antibodies (IgA-tTG) as predictors of untreated celiac disease (CoD) is well documented, and the presence and levels of these antibodies are most accurately monitored with native or recombinant human antigens. However, IgA-deficient CoD patients are not identified by IgA serology, and conflicting results concerning the diagnostic validity of IgG antibodies against gliadin (IgG-AGA), endomysium (IgG-EmA), and tTG (IgG-tTG) have been reported. The aim of the present study was to evaluate the utility of IgG-tTG for the detection of CoD in IgA-deficient patients. Samples from 115 IgA-deficient and 200 IgA-sufficient subjects were collected and tested for the presence of IgA and IgG antibodies against tTG, EmA, and AGA. Antibodies against tTG were measured by an enzyme-linked immunosorbent assay based on recombinant human tTG, and antibodies against EmA were determined by immunofluorescence. The values for IgG-tTG showed a higher correlation (correlation coefficient [r] = 0.91) with those for IgG-EmA for the IgA-deficient subjects than for the IgA-sufficient subjects (r = 0.88). The overall concordance of the positive and negative results between IgG-tTG and IgG-EmA was 97%, and the IgG-tTG assay discriminated between IgG-EmA-positive and -negative subjects with IgA deficiency at a rate of 100%. Elevated levels of IgG-tTG and IgG-EmA were measured in 70% of the IgA-sufficient subjects. IgG-tTG detection with recombinant human tTG is a good alternative to IgG-EmA detection, and the addition of IgG-tTG assessment to present screening methods may improve the ability to identify IgA-deficient subjects with CoD.