Detection of IgG Subclasses with Anti-lgE Activity in Patients with Atopic Diseases

Nelson

Int Arch Allergy Immunol

1996

The levels of naturally occurring IgG and IgG subclass anti-IgE autoantibodies (a-E Ab) were studied in 71 randomly collected cord sera with ELISA using solid-phase IgE-DES myeloma protein. IgG a-E Ab were present in all cord sera, and the range was 300-fold (1.8–540 arbitrary units/ml; median =11.8). However, this acticity is the sum of two major types of a-E Ab that we refer to as isotype-specific (IS) and non-isotype-specific (NIS) because they react with E-chain-specific and myeloma-restricted epitopes, respectively. These two types of a-E Ab were distinguished in IgG subclass a-E Ab inhibition ELISA for all samples using unheated IgE-PS and heated IgE-DES as inhibitors. IS and NIS a-E Ab were found among all four IgG subclasses though with different prevalences. No significant influence of gender was observed. Comparisons within each subclass indicate that NIS a-E Ab were more common than IS a-E Ab for the IgG1 (p < 0.00005), IgG2 (p = 0.07) and IgG3 (p < 0.005) subclasses while the reverse was true for IgG4 (p < 0.00005). In fact, only a minor part of the IgG1 (7%), IgG2 (13%) and IgG3 (9%) a-E Ab activity towards IgE-DES was IS while for IgG4 it was a major part (82%). Attempts to quantify IS and NIS IgG subclass a-E Ab using chimeric IgG subclass antihapten Ab suggested that the pool of IgG a-E Ab against IgE-DES was dominated by NIS a-E Ab particularly of the IgG1 subclass. The 75 percentiles for NIS IgG1, IgG2, IgG3 and IgG4 a-E Ab were 24, < 2, 2.1 and 0.27 ng/ml, respectively, whereas the corresponding figures for IS a-E Ab were 7, < 2, < 2 and 0.90 ng/ml. The findings raise questions on the definition of a-E Ab and suggest that caution should be exercised in the interpretation of any a-E Ab results that are detected with IgE myeloma proteins. The potentially more interesting IS a-E Ah may be overshadowed by the bulk of ubiquitous NIS a-E Ab and background. Consequently, discriminatory assays are necessary if the physiological implication of naturally occurring IS IgG subclass a-E Ab is to be elucidated and these considerations are not limited to studies of cord serum.

Section: Calibrationsupporting

confidence: 88%

Disproportional Distribution of Isotype and Non-lsotype-Specific IgG Subclass Anti-lgE Autoantibodies in Human Cord Serum

Nelson

Int Arch Allergy Immunol

1996

“…In general, the measurement of IgG4 to food allergens has no diagnostic value, because such antibodies are so commonly found in the general population. However, when a strong IgG4 immune response to such an antigen is associated with a strong Th2‐biased autoantibody response (such as IgG4 autoantibodies to IgE 49,50 ) immunopathology might potentially ensue. An example where this might occur is the IgG4‐associated skin disease pemphigus foliaceus 51 or perhaps even in systemic lupus erythematosus 52 …”

Section: Biological Implicationsmentioning

confidence: 99%

IgG4 breaking the rules

2002

SUMMARYImmunoglobulin G4 (IgG4) antibodies have been known for some time to be functionally monovalent. Recently, the structural basis for this monovalency has been elucidated: the in vivo exchange of IgG half-molecules (one H-plus one L-chain) among IgG4. This process results in bispeci®c antibodies that in most situations will behave as functionally monovalent antibodies. The structural basis for the abnormal behaviour of IgG4 seems to be largely the result of a single amino acid change relative to human IgG1: the change of a proline in core hinge of IgG1 to serine. This results in a marked shift in the equilibrium between interchain disulphide bridges and intrachain disulphide bridges, which for IgG4 results in 25±75% absence of a covalent interaction between the H-chains. Because of strong non-covalent interactions between the CH3 domains (and possibly also between the CH1 domain and the trans-CH2 domain) IgG4 is a stable four-chain molecule and does not easily exchange halfmolecules under standard physiological conditions in vitro. We postulate that the exchange is catalysed in vivo by protein disulphide isomerase (PDI) and/or FcRn (the major histocompatibility complex (MHC)-related Fc receptor) during transit of IgG4 in the endosomal pathway in endothelial cells. Because IgG4 is predominantly expressed under conditions of chronic antigen exposure, the biological relevance of this exchange of half-molecules is that it generates antibodies that are unable to form large immune complexes and therefore have a low potential for inducing immune in¯ammation. In contrast to monovalent immunoglobulin fragments, these scrambled immunoglobulins have a normal half-life. The signi®cance of the ensuing bispeci®city needs further evaluation, because this will be relevant only in situations where high IgG4 responses are found to two unrelated antigens that happen to be present in the body at the same time and place. In this context the signi®cance of IgG4 autoreactivity might have to be re-evaluated. The main function of IgG4, however, is presumably to interfere with immune in¯ammation induced by complement-®xing antibodies, or, in the case of helminth infection or allergy, by IgE antibodies.

Int Arch Allergy Immunol

“…Most groups have used immunological assays based on xenogeneic anti-IgE antibodies [7][8][9][10][11][12], However, it is difficult to decide whether an antibody has pan-specificity for multiple immunoglobulin classes or whether the anti-IgE antibody recognizes variable do mains and thus represents an anti-idiotypic antibody [10]. Rheumatoid factors, e.g., may also interfere with the im munological assays used for the detection of anti-IgE au toantibodies because sera can usually not be highly diluted for detection.…”

Section: Difficulties In Determination Of Anti-lge Autoantibodiesmentioning

confidence: 99%

Biological Activities of Anti-IgE Antibodies

Stadler

Stämpfli

Miescher

et al. 1993

Naturally occurring anti-IgE autoantibodies represent a heterogeneous mixture of antibodies with diverse specificities and biological functions. By using murine monoclonal anti-IgE autoantibodies directed against different epitopes on the IgE molecule as a model for autoantibodies, we could show that only a minority of antibodies combine all beneficial biological activities, such as the activity of inhibiting in vitro IgE synthesis, removing IgE from the surface of CD23+ cells and not being anaphylactogenic. While it is difficult to isolate and measure anti-IgE antibodies in human serum, it is now possible to generate such human anti-IgE antibodies by the method of repertoire cloning. Thus, human recombinant antibodies against IgE may become available for the treatment of atopic disease.