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Allergen-specific IgG4 has often been regarded as a two-headed phenomenon: potentially harmful as well as potentially protective However, when more is found out about IgG4 antibodies, the harmful effects are hard to substantiate. The protective effects are still debated, but particularly from the field of parasitology the evidence is accumulating that IgG4 does, under certain conditions, effectively interfere with allergen-induced, IgE-medical effector cell triggering, i.e. IgG4 acts as a blocking antibody. Recent data indicate a striking similarity with respect to the type of antigen that triggers the IgG4 and IgE immune responses. Since a marked difference in epitope specificity exists between the IgG4 and IgE antibodies, only a fraction of the allergen-specific IgG4 can interfere effectively with IgE binding. The use of IgG4 antibody assays to monitor immunotherapy is justifiable, but its value should not be overrated. However, if no IgG4 antibody is induced by conventional immunotherapy, the therapy is likely to have been ineffective. An immunotherapy may be considered to be immunologically effective if a substantial increase (10 to 100 fold) in allergen-specific IgG4 is induced (89).
4.4 IgG subclasses in other diseases
Decreased or increased levels of IgG subclasses in serum are associated with several other diseases, examples of which will be given here (90).
4.4.1 Infectious diseases (6)
In most infections the first antibodies to appear will be of the IgM class, while those of the IgG class will be produced later. In general, microbial protein antigens will mainly evoke antibody responses of the IgG1 and IgG3 subclasses, with a minor contribution of IgG2 and IgG4. On the other hand, polysaccharide antigens will predominantly induce IgG2 antibodies.
Some disease-specific observations:
- Pneumococcal otitis media in children is associated with a decreased level of IgG2.
- Patients with recurrent infections by encapsulated bacteria often show decreased levels of IgG2 and IgG4.
- Recurrent respiratory infections with bronchiectasis are often associated with decreased levels of IgG2, IgG3 and IgG4.
- Cystic fibrosis with chronic Pseudomonas aeruginosa infection is associated with an increased level of IgG2 and IgG3, the latter of which seems to be of prognostic significance.
In autoimmune diseases the levels of IgG subclasses do mostly not differ from those in healthy individuals, but specific autoantibodies show variable subclass restrictions: frequently, autoantibodies are of the IgG1 and IgG3 subclasses (91,92,118).
- Human rheumatoid factors (RF) are defined as IgG, IgA or IgM antibodies against the Fc fragment of immunoglobulin. In most cases, RF have been found to bind to the Fc fragments of IgG. As for their subclass specificity, most RF have been shown to react with IgG1, followed by IgG2 and IgG4. Binding of RF to IgG3 is rare.
- Abnormal IgG1: IgG2 ratios have been reported in patients suffering from connective tissue diseases. In case of a selective polyclonal increase of IgG1, one should be alert for the possibility of Sjögren's syndrome. It has been suggested that this immunoglobulin abnormality is the product of a restricted oligoclonal B cell response and may thus be the consequence of a benign B cell lymphoma (93,94,95,96).
- Autoantibodies to neutrophil cytoplasmic antigens (ANCA) are predominantly of the IgG1 and IgG4 subclass (97,98). Autoantibodies of the IgG3 subclass almost exclusively occur in patients with renal involvement(98).