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.     

IgG subclass distribution of antibodies against S. aureus teichoic acid and alpha-toxin in normal and immunodeficient donors

IgM, IgG, IgA and IgE class and IgG and IgA subclass levels were determined in 18 IgG2 deficient and six IgG3 deficient donors. IgG2 deficiency was associated with concomitant IgG4, IgA (in particular IgA2) and IgE deficiency. This pattern is compatible with a regulation defect of the downstream switch in the heavy chain locus on chromosome 14. IgG3 subclass deficiency was not associated with further deficiencies. Specific anti-teichoic acid antibodies were lacking in most IgG2 deficient donors supporting the notion that anti-teichoic acid antibodies are normally of this subclass. This was also confirmed in a subclass-specific ELISA using sera from normal donors although substantial amounts of specific IgG1 antibodies were also noted. Two IgG2 deficient donors had normal IgG titres (IgG1 in the subclass specific ELISA) and the lack of IgG1 anti-teichoic acid antibodies in most IgG2 deficient donors may suggest a lack of maturation of the appropriate idiotype. IgG antibodies to alpha-toxin, a pure protein, were within the lower normal range in a large proportion of IgG2 deficient donors but largely normal in the IgG3 deficient donors.     

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.     

Serum IgG subclass levels in patients with primary immunodeficiency syndromes or abnormal susceptibility to infections

Serum IgG subclass levels were measured using an indirect competitive immunoenzymatic assay with monoclonal antibodies in 221 patients affected with definite immunodeficiency (ID) syndromes and 229 patients presenting with infection patterns suggestive of ID, but with normal immunoglobulin class levels and no clear evidence of ID. In common variable ID and IgG-IgA deficiency with normal or high IgM, subclass imbalance (mostly IgG1-IgG3 or IgG2-IgG4 deficiency) was the rule, with a higher incidence of severe infections in IgG2-IgG4 defects. One-fifth of patients with IgA deficiency, especially those with autoimmune cytopenia, had subclass deficiencies with no significant correlation with the occurrence of infections. Subclass (mostly IgG2-IgG4) deficiencies were also observed in severe combined ID, defective expression of HLA class II antigens, chronic mucocutaneous candidiasis, and IgM deficiency. Subclass levels were normal in all but one (who was IgG3 deficient) patient with the Wiskott-Aldrich syndrome and in the Buckley's syndrome, except for an unusual patient who presented with low IgG and IgA levels. Subclass (mainly IgG2) deficiency occurred in 24% of infected patients without known ID.     

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.     

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.     

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.     

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.     

A comprehensive IgA service provided by a blood transfusion center

IgA is best known in transfusion practice for its deficiency when anti- IgA antibodies cause severe anaphylactic reactions. Following the realization that IgA deficient products were needed on demand, blood donors were routinely screened, initially by latex agglutination inhibition and subsequently by hemagglutination inhibition using an Olympus PK-7200 blood grouping machine. IgA deficiency (<.0016 g/L) was found in 357 (with anti-IgA in 28%) of 301,310 donors, an incidence of 1 in 844. By screening new donors and directed call-up, group O, D- red blood cell (RBC) units are always in stock. During 1 year, the center supplied 79 units of RBCs and 64 units of fresh frozen plasma to a variety of patients with IgA deficiency, including three undergoing liver transplantation. The center also provides a reference service for IgA/anti-IgA status. The technique used (hemagglutination inhibition) has a sensitivity well below the threshold of standard quantitation methods. Samples were most commonly referred from departments investigating possible immunodeficiency and suspected transfusion reactions. Of 247 patients investigated, 122 had IgA deficiency, 43 with anti-IgA (of whom 5 had suffered a transfusion reaction). Donors and patients with anti- IgA were issued blood group cards warning that they should only receive IgA deficient products.     

Anti-IgA antibodies in epileptic patients with a low serum IgA concentration

Sera from 22 phenytoin-treated epileptic patients with a serum IgA less than 0.30 g/l were examined for anti-IgA antibodies using an ELISA. Only one patient had a complete IgA deficiency. Anti-IgA antibodies of restricted specificity were detected in serum from two of the patients. Their serum IgA concentrations were 0.03 and 0.27 g/l. The serum concentrations of IgM, IgG and the IgG subclasses were normal in both these patients. The frequency of this type of anti-IgA antibody is not higher in epileptic patients with a low serum IgA than in healthy controls, and class-specific anti-IgA antibodies are not a pathogenetic factor in the IgA deficiency occurring in epilepsy.     

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.     

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.     

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.     

Subclass restriction pattern of antigen-specific antibodies in donors with defective expression of IgG or IgA subclass heavy chain constant region genes

We have developed a method for the measurement of the IgG and IgA subclass distribution of antigen-specific human antibodies. The controls for the specificity of the assay include the use of a number of monoclonal human antibodies and sera from individuals with deletions of particular immunoglobulin heavy chain constant region genes. The system was used to determine the shift in immunoglobulin subclass patterns of specific antibodies against a variety of protein and polysaccharide antigens in individuals with a regulatory deficiency of a given IgG or IgA subclass. Normally, the pattern is quite distinct and antibodies against protein antigens are mainly of the IgG1 subclass, whereas antibodies against polysaccharide antigens are mainly of the IgG2 subclass. The results on serum from an IgG1 deficient donor suggested that IgG3 and IgG4 appear to compensate for a lack of IgG1, whereas isolated deficiencies of IgG3, IgG4, or IgA2 do not markedly influence the expected distribution of specific antibodies. In IgG2-deficient individuals a more complex pattern was observed where antibodies against protein antigens were retained, whereas levels of antibodies against polysaccharide antigens could vary markedly between donors, which appeared to be dependent on whether the IgG2 deficiency was an isolated defect or combined with IgG4/IgA deficiency. However, all the IgG2-deficient donors had a skewed pattern of anti-polysaccharide antibodies with a shift to IgG1 to IgG3.     

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.     

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.     

Human antibodies to bovine alpha-globulin.

Antibodies to bovine gamma-globulin (anti-BGG antibodies) were detectable by a radio-immunoassay in 70% of healthy blood donors but, generally, the titres were low. Significantly increased concentrations of anti-BGG antibodies were found in patients lacking IgA but not in patients with allergic disorders. The anti-BGG antibodies were shown to give rise to falsely high IgE values in the radio-immunosorbent test for IgE determination (RIST) when a sheep anti-IgE antiserum was used. Furthermore, falsely positive results can sometimes be caused by such antibodies in the determination of cow-dander- or cow's-milk-specific IgE by the radio-allergosorbent test (RAST). When a rabbit anti-IgE antiserum was used instead of the sheep anti-IgE, normal IgE levels and negative RAST results were obtained. The difference is explained by the higher degree of cross-reactivity between the anti-BGG antibodies and sheep alpha-globulin than between anti-BGG antibodies and rabbit alpha-globulin.     

Heterogeneity of Serum IgG Subclass Deficiencies in B Chronic Lymphocytic Leukemia

The occurrence of abnormally low serum immunoglobulin (Ig) levels is well-known in B chronic lymphocytic leukemia (CLL), but published data on IgG subclass levels are virtually absent. We measured serum IgG subclass levels in 52 B CLL outpatients, most in stage A and untreated, using an indirect immunoenzymatic assay with monoclonal antibodies. Mean levels of all Ig isotypes were lower than in normal controls in the whole group of patients, except for IgG2 in those studied at diagnosis. Levels of IgG1, IgG2, IgA, and IgM were lower in patients with a long disease duration than in those studied earlier. IgG subclass deficiencies occurred in 54% of cases and the most frequently affected isotype was IgG1. Every possible combination of IgG subclass and Ig class deficiencies from the selective deficiency of a single subclass to a combined deficiency of all isotypes was observed. This marked heterogeneity argues against the occurrence of isolated defects of one of the cytokines involved in Ig switching as a cause of hypoimmunoglobulinemia in CLL.     

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.     

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.