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.     

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.     

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.     

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.     

Serum IgA deficiency and anti-IgA antibodies in pernicious anemia

Three pernicious anemia (PA) patients with selective IgA deficiency and anti-IgA antibodies in their sera were followed for over 3 years. After instituting therapy with cyanocobalamin there was a slight increase in the anti-IgA antibodies. After 1 year the titers of anti-IgA antibodies in the sera of these patients declined significantly as compared to the values before treatment (P less than 0.02), and after 2 years one patient had no measurable anti-IgA antibodies, yet no IgA appeared in the serum of any of the three. Further, in a medium with no anti-IgA the lymphocytes of these patients were not capable of producing IgA in vitro. Thus, the reason for the IgA deficiency in PA appears to be linked to the function of B cells rather than to anti-IgA antibodies.     

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.     

Systemic immunization against IgA in immunoglobulin deficiency.

The presence of serum IgM and IgG antibodies against IgA is common among individuals with IgA deficiency. The route of immunization is still unknown, but it is possible that immunization occurs through the gut. We analysed anti-IgA antibody production in gastrointestinal lavage, saliva and breast milk from patients with IgA deficiency. In no case was there any evidence of local production of anti-IgA antibodies. Immunization may thus be due to exposure to endogenous IgA and therefore represent a 'true' autoimmune phenomenon which may possibly be involved in the pathogenesis of the disease.     

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.     

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.     

Lmmunobiology of human anti-lgA: a serologic and immunogenetic study of immunization to IgA in transfusion and pregnancy*

Human antibodies to human IgA are detected by a sensitive passive hemagglutination assay using IgA paraproteins. The antibodies have a dichotomy of specificities: (1) class-specific with titers frequently higher than 1:1000 produced by persons lacking IgA, and (2) antibodies with limited specificity (titers less than 1:256) produced by persons with normal IgA when repeatedly transfused. Either type of anti-IgA belonging to the IgG class was present in 86 per cent of the patients with anaphylactoid and urticarial transfusion reactions, which was consistent with binding of the complement by such antibodies. Anti-IgA antibodies were detected in 16 per cent of the cases with multiple transfusions received during openheart surgery procedure; they also have a significantly high incidence in the sera of recently delivered women. One fetus had IgM anti-IgA, probably as a result of immunization to maternal IgA. Serum obtained from a Caucasian woman before and after an anaphylactoid reaction to a blood transfusion contained anti-IgA antibodies of limited specificity of the IgG class, possibly as a result of isoimmunization in pregnancy. The patient's serum was used as an agglutinator in passive hemagglultination assays on normal serum, which resulted in the definition of Am(l), the first genetically determined allotype of human IgA. On the basis of serologic and immunochemical evidence, Am(1) was localized in the a chains. Based on its gene frequencies and on family studies, Am(l) was established as a mendelian dominant trait. The isoantigen is associated with γA₂ subclass but not with the serum γA₂ levels. Am(1) is different from the other allotypes of human immunoglobulins, the Gm and Inv types. Am(1) is detectable in salivary IgA; it was not detectable in cord sera. Its polymorphism makes it suitable for studies of population genetics and the molecular biology of IgA.     

Long-term follow-up of anti-IgA antibodies in healthy iga-deficient adults

A follow-up study of anti-IgA antibodies in 159 healthy blood donors with severe deficiency of serum IgA (<0.05 mg/L) and in 45 donors with decreased serum IgA levels (0.05–799 mg/L), identified in 1971–1980, was carried out. Initially anti-IgA antibodies were determined by a hemagglutination (HA) method and two reexaminations were done in 1990–1992 by an enzyme immunoassay. The median follow-up period was 19 years, during which anti-IgA level was changed considerably in only four persons, increased in two, and high level antibodies (>1/1000 by HA) appeared in two. In reexaminations anti-IgA antibodies were found in 30 (19%) subjects with severe IgA deficiency and the antibody levels remained relatively constant in those who had high and medium antibody levels. Anti-IgA antibodies were not found in subjects with decreased, but detectable serum IgA. Thus it seems that only those healthy adults who have severe IgA deficiency develop anti-IgA antibodies and their anti-IgA levels remain fairly constant Of the 159 subjects with severe IgA deficiency, 66 had a history of IgA exposure, but no correlation to anti-IgA development was noted.Portions of the work have been presented in a poster form at the XXIIIrd Congress of the International Society of Blood Transfusion in Amsterdam, the Netherlands, July 2–9, 1994.     

Antibodies to polyclonal IgA,IgA1, and IgA2 and isotype-specific immune complexes in IgA nephropathy

The concentrations of serum IgG and IgM antibodies to polyclonal IgA (IgA_p), IgA₁, and IgA₂ were determined by enzyme immunoassay in 31 patients with IgA nephropathy and 30 healthy controls. Patients with IgA nephropathy had significantly raised concentrations of serum IgA compared to controls (Mann-WhitneyU test,P=0.001) and increased concentrations of conglutinin-binding IgA immune complexes (P=0.024). No differences in the median concentrations of IgG and IgM anti-IgA antibodies were found between the patients and the controls. In serum samples from healthy controls there was a significant positive correlation between IgM anti-IgA_p and IgA immune complex concentrations (P=0.05), which contrasted with the finding of an inverse correlation between IgM anti-IgA_p and IgA immune complex concentrations in patients with IgA nephropathy (P<0.05). In addition, the concentrations of conglutinin binding IgM immune complexes in serum were found to correlate with the concentration of IgM anti-IgA_p (0.010<P<0.025), IgM anti-IgA₁, and IgM anti-IgA₂ (P«0.005 for both) in patients with IgA nephropathy but not in controls. IgM anti-IgA antibodies may be important in augmenting the clearance of IgA immune complexes from the serum of patients with IgA nephropathy.     

Alpha-fetoprotein concentrations in sera from epileptic patients with immunodeficiency

The alpha-fetoprotein serum concentration was determined by radioimmunoassay in 22 epileptic patients treated with phenytoin. The concentration was normal in all of the patients. The IgA concentration in serum was below 0.20 g/l in 15 of the patients and normal in 7 (0.60-3.30 g/l). IgG and IgM concentrations were normal. The total number of lymphocytes was significantly reduced in the epileptic patients compared to healthy controls, while the relative percentage of various mononuclear blood cell sub-populations did not differ between the patients and the controls. The response to PHA stimulation was lower in the patients than in the controls for all PHA concentrations tested, the differences, however, were not significant at a 5% level. The results indicate that alpha-fetoprotein does not participate in the pathogenesis of the immune disturbances observed in patients with epilepsy.     

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 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.     

The significance of immunofluorescent immunoglobulin inclusions in polymorphonuclear leucocytes for the detection of circulating immune complexes

Cytoplasmic inclusions of immunoglobulins and complement, detected by fluorescent antibodies in polymorphonuclear leucocytes (PMNs) that have been incubated with sera of certain patients, are considered to represent immune complexes (IC). The usefulness of this test--the indirect PMN phagocytosis test (IPPT)--for the detection of circulating IC was investigated using preparations of free and heat-aggregated immunoglobulins. Free IgG and IgM were phagocytozed by PMNs at high concentrations only, while free IgA was not phagocytozed at all. Normal human serum slightly enhanced the uptake of free IgG and IgM, but not of free IgA. Aggregates of IgG and IgA underwent phagocytosis at low concentrations, but IgM aggregates were not taken up more readily than free IgM. The uptake of IgG aggregates decreased in the presence of serum, while there was no influence upon the phagocytosis of IgA aggregates. Phagocytosis of C3 occurred only with IgG aggregates. In the presence of aggregates of IgG or IgA the phagocytosis of free immunoglobulins of other classes, in particular IgM, increased. The results of the IPPT for patients' sera showed that inclusions of C3 were found more frequently in combination with IgA or IgM than with IgG. Comparison with the 125I-Clq binding assay and the anti-IgA inhibition binding assay disclosed significant correlation between the phagocytosis of IgG and the precipitation of 125I-Clq and between the phagocytosis of IgA and the results of the anti-IgA inhibition binding assay. The PMN phagocytosis test may be useful for the detection of IgG and IgA containing IC but inclusion of IgM and C3 should be interpreted with some reserve.     

Serum IgE levels in patients with selective IgA deficiency.

In this study serum IgE levels were measured by a double-antibody radioimmunoassay in 31 patients with serum IgA concentration less than 0.01 mg/ml who were followed in the arthritis and allergy clinics. On a group basis there was no significant difference in mean serum IgE levels between the IgA deficient patients and normal subjects of the same age. However, in the absence of atopic disease, IgA deficient patients had significantly lower serum IgE levels. When atopy was associated with IgA deficiency IgE levels were the same as in the normal subjects but significantly lower than those of atopic non-IgA deficient patients. IgE levels in those with recurrent respiratory tract infection were not different. Adults with anti-IgA antibodies had significantly lower IgE values. IgE levels in patients with RA, JRA or SLE were not significantly different. Selective IgA deficient patients may have a relative deficiency of serum IgE depending on the comparison group.     

Autoantibodies in patients with IgA and IgG2 deficiencies

Patients with primary immunodeficiencies have a high incidence of autoantibodies, mainly of no clinical significance. It has recently been suggested that patients with a combined IgA-IgG2 deficiency have more autoantibodies than those patients with isolated deficiencies. We have studied 42 patients with selective IgA deficiency, nine with isolated IgG2 deficiency and 13 with combined IgA-IgG2 deficiency, and have found that the combined IgA-IgG2 deficiency has no influence on autoantibody prevalence, except for anti-IgA antibodies. The presence of chronic respiratory infections (a clinical feature commonly associated with both selective IgA and IgG2 deficiencies) is unrelated to the prevalence of autoantibodies. The most frequent autoantibodies found are anti-IgA and anti-cardiolipin. Most of the autoantibodies have been found to be devoid of actual clinical significance. Only three patients had overt autoimmune disease.     

The role of anti-IgA antibodies in causing adverse reactions to gamma globulin infusion in immunodeficient patients: a comprehensive review of the literature

Anaphylactic reactions to immunoglobulin infusions in immunodeficient patients with undetectable IgA have been attributed in several reports to IgG or IgE anti-IgA antibodies. However, other reports have not supported an association between such antibodies and the development of severe reactions. We have reviewed the articles reporting reactions to immunoglobulin products in IgA-deficient patients, as well as those describing the presence of such antibodies in the absence of reactions to infusions. A?variety of factors might influence the association of adverse reactions with anti-IgA antibodies, including the serum concentration and isotype (IgG or IgE) of the anti-IgA antibody, its specificity (class or subclass specific), the method of measurement, and the IgA content of the gamma globulin infusion and its route of administration. The role of anti-IgA antibodies in causing anaphylaxis in IgA-deficient patients receiving gamma globulin therapy is still controversial. Larger (multicenter) studies are needed to further evaluate this association.     

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.