IgG anti-IgA Antibodies Research Articles

IgG anti-IgA antibodies in paediatric antibody-deficient patients receiving intravenous immunoglobulin

BackgroundImmunoglobulin replacement therapy is an effective route of management for both infections and non-infectious complications in predominantly antibody deficiency (PAD). Trace levels of IgA (ranged from 0.4 to 2500mg/ml), which exist in all immunoglobulin products, could lead to an increased susceptibility for adverse reactions in PAD patients. Furthermore, the exact mechanism which stimulates the anti-IgA antibody production in PAD is still unknown. The aim of this study was to evaluate IgG anti-IgA antibodies in PAD patients receiving intravenous immunoglobulin (IVIg) and its predisposing factors. MethodsAvailable patients with confirmed diagnosis of PAD, who underwent regular IVIg replacement therapy in our centre, were enrolled in the study. Control group included 24 healthy individuals as the negative control and eight symptomatic patients with IgA deficiency as the positive control groups. IgG anti-IgA antibodies level was measured by the ELISA method. ResultsA significant difference was observed between Anti-IgA level of common variable immunodeficiency (CVID) and other PAD groups (p=0.02). Moreover, six CVID patients were seropositive for the IgG anti-IgA antibody, with higher susceptibility to the adverse reactions (p<0.001). IgG anti-IgA level has a negative relationship with serum IgA level (r=−0.06) and IVIg treatment duration (r=−0.006). ConclusionOur data suggested that there was a significant association between anti-IgA antibody presence and the adverse reactions, especially in CVID patients with higher susceptibility to produce this constitutional antibody.

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. Avariety 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.

Association of anti-IgA antibodies with adverse reactions to γ-globulin infusion

Association of anti-IgA antibodies with adverse reactions to γ-globulin infusion

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.

Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology

Human immunoglobulin prepared for intravenous administration (IGIV) has a number of important uses in the treatment of disease. Some of these are in diseases for which acceptable treatment alternatives do not exist. In this review we have evaluated the evidence underlying a wide variety of IGIV uses and make specific recommendations on the basis of these data. Given the potential risks and inherent scarcity of IGIV, careful consideration of the indications for and administration of IGIV is warranted.

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-immunoglobulin antibodies in children with Schönlein-Henoch syndrome. Absence of serum anti-IgA antibodies

Circulating immune complexes (CIC) that simultaneously contain IgG and IgA are frequently found in IgA nephropathy (IgA-N) and the Schönlein-Henoch syndrome (SHS). The presence of anti-immunoglobulin antibodies (IgA anti-IgG and IgG anti-IgA) was studied by ELISA in the serum of 39 children with SHS and compared to 30 normal children. The mean level of IgG anti-IgA antibodies (240 +/- 104 u/ml) in SHS patients was similar to control values (251 +/- 85 u/ml); the IgA anti-IgG antibodies were increased, although only the antibodies against Fc fraction of IgG were elevated (185 +/- 71 u/ml in patients vs 127 +/- 24 mu/ml in controls, P < 0.0001) without a significant increase of IgA anti-IgGFab antibodies (141 +/- 54 mu/ml vs. 137 +/- 25 u/ml); 16/39 (41%) of the patients had increased levels of IgA anti-IgGFc and 6 of these had also high IgA anti-IgGFab. None of these patients had high IgA anti-IgGFab antibodies without simultaneous augmentation of IgA anti-IgGFc. Only 3/39 (7.7%) of SHS patients showed high levels of IgG anti-IgA antibodies. The correlation of IgA anti-IgGFc antibodies with IgA anti-IgGFab was very strong (P < 0.0001) but lower with IgG anti-IgA antibodies (P < 0.002). In addition, 8/39 children had renal involvement, nevertheless in these patients the findings were quite similar, with a non-significant elevation of IgA anti-IgGF ab antibodies. These results show that the IgA anti-IgG antibodies are more frequently increased than IgG anti-IgA antibodies in the SHS; moreover they are mainly directed against Fc fraction and are IgA-FR isotype. Our findings suggest that the CIC in SHS are likely formed by the reaction of IgA anti-bodies against IgG and not vice versa.

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 (IgAp), 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-Whitney U 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-IgAp and IgA immune complex concentrations (P = 0.05), which contrasted with the finding of an inverse correlation between IgM anti-IgAp and IgA immune complex concentrations in patients with IgA nephropathy (P less than 0.05). In addition, the concentrations of conglutinin binding IgM immune complexes in serum were found to correlate with the concentration of IgM anti-IgAp (0.010 less than P less than 0.025), IgM anti-IgA1, and IgM anti-IgA2 (P much less than 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.

Immunoglobulin-Antiimmunoglobulin Interactions and Immune Complexes in IgA Nephropathy

IgA nephropathy (IgAN) is characterized by mesangial co-deposition of IgA and C3. Elevated levels of circulating immune complexes containing these components in significant numbers of patients have been found in several studies; IgAN is therefore assumed by many investigators to be an immune complex-mediated disease. Our studies have shown that IgG is often co-complexed with IgA within circulating immune complexes, and we have begun to examine the potential mechanisms for these observations. In this regard, elevated levels of IgA rheumatoid factor and of IgG anti-IgA antibodies were found in some patients. Nevertheless, we were unable to correlate levels of circulating immune complexes with any clinical index of disease. Furthermore, many individuals with the acquired immune deficiency syndrome (AIDS) also have elevated levels of circulating immune complexes containing IgG and IgA, IgA rheumatoid factor, and IgG anti-IgA antibodies, although these patients apparently do not have mesangial IgA deposits. Therefore, the role of circulating IgA-containing immune complexes in the pathogenesis of IgAN requires further evaluation.

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 less than 0.01 and P less than 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.

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 less than 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 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.

Anaphylactic reactions to plasma infusions in patients with hypogammaglobulinemia and anti-IgA antibodies

Two patients with common variable hypogammaglobulinemia developed anaphylactic reactions when given very small infusions of normal human plasma containing IgA. Their sera were examined for antibodies to human IgA by passive hemagglutination against human erythrocytes coated by the chromic chloride method with a panel of purified IgA myeloma and normal proteins, and specificity was determined by inhibition of agglutination. Both patients were found to have IgG anti-IgA antibodies of multiple specificity. Differential absorption studies in the second case showed antibodies to IgA 1 and IgA 2 and to A2m(1) and A2m(2). To our knowledge, this is the first report of anti-IgA antibodies with multiple specificities in a single patient. These two cases illustrate the possibility of sensitization to human IgA in patients with severe humoral antibody deficiency syndromes, who might not be expected to form antibodies to new antigens. Presumably and kind of anti-IgA, regardless of specificity, can cause severe anaphylactic reaction.