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4 IgG subclasses in disease

Deficiencies of IgG subclasses are an indication of a disturbed immune response, although symptomatically decreased IgG subclass levels may occur as well. Several disease states are associated with decreased or increased levels of IgG Subclasses.

4.1 IgG subclass immunodeficiencies, clinical relevance (61)

An antibody response may result in changes in the distribution of IgG subclasses in plasma, dependent upon the nature of the antigen (e.g. protein or polysaccharide) and the frequency and duration of the antigenic stimulation. This may result in increased or diminished levels of one or more IgG subclasses. The most conspicuous consequence of a deficiency in one of the IgG subclasses is a defect of humoral immunity, although this does not necessarily lead to clinical manifestations. Over the last decades a large number of reports have appeared on deficiencies of IgG and its subclasses. A deficiency of total IgG will generally result in serious infectious problems. A decreased level of individual subclasses will have less dramatic consequences, although important infections may occur. Deficiencies can occur in single or multiple IgG subclasses. Deficiencies of IgG subclasses can be subdivided in different groups. When the serum level of a subclass is below detection levels of the most sensitive techniques (ELISA/RIA), it is considered as a complete deficiency /absence or a total lack. A complete deficiency of one or more subclasses, caused by deletions in chromosome 14 loci, is rare. Such a total lack of one or more IgG subclasses due to deletions of the immunoglobulin heavy chain constant region genes is occasionally found in healthy individuals. The fact that these individuals still produce protective antibody titers in the residual immunoglobulin classes or subclasses suggests that the deletion of the isotype (s) occurs by chance and can be compensated adequately.

In (relative) deficiencies one or more of the IgG subclass levels are below the normal (reference) range of healthy individuals. The association of decreased IgG subclasses with recurrent infections becomes more likely when the deficiency is an expression of immune dysregulation (e.g. at the level of cytokine production). Among the combined IgG subclass deficiencies, an IgG2/IgG4 deficiency predominates.

Since a decreased level of one IgG subclass may be accompanied by increased levels of one or more of the other subclasses, the total IgG level may well be normal. Consequently, the determination of IgG subclass levels is important, even when the total IgG level is within or only slightly below the reference range of healthy individuals. An IgG subclass deficiency may result in a disturbed production of certain categories of antibodies. The most frequently identified selective antibody deficiency is an impaired response to polysaccharide antigens, such as those present in the capsule of pneumococci, meningococci and Haemophilus influenza type B (HiB). Since IgG2 is the predominant antibody isotype produced in response to some polysaccharide antigens, it is not surprising that patients with decreased IgG2 levels may have an impaired response to infections with encapsulated bacteria.

The major clinical indication for measuring IgG subclasses is the occurrence of abnormally frequent and/or prolonged or severe infections that cannot be explained by the usual clinical and laboratory data. Especially in patients in whom the possibility of IgG treatment is considered, it is advisable to determine IgG subclass levels(62). In a proportion of these cases decreased IgG subclass levels are found. The actual percentage will depend upon the methodology of patient recruitment (e.g. children or adults), method of IgG subclass measurement and the normal reference values used.

The finding of a decreased level of one of the IgG subclasses can never provide a definite diagnosis, but should rather be considered as an indication of a disturbance of the immune system, requiring further diagnostic investigation.

It appears that patients with IgG1 and/or IgG3 deficiency are more likely to have difficulty with chronic and recurrent infections of the lower airways, while those with IgG2 and/or IgG4 deficiency are more likely to have sinusitis and otitis (63).

Deficiencies and complete deficiency/absence of individual IgG subclasses may have several consequences:

IgG1: IgG1 deficiencies often result in a decreased level of total IgG (hypogammaglobulinemia). A deficiency of this quantitatively most important subclass is often associated with recurrent infections and might occur in combination with (individual) deficiencies of other subclasses, e.g.IgG3 (36,64). In a recent evaluation of IgG1 concentrations in adults (n=1175) with suspected IgG subclass abnormalities, decreased IgG1 level were observed in 28% of the individuals (table IV).

Read et al. reported IgG1 subclass deficiencies in patients with chronic fatigue syndrome, whereas all other immunoglobulin isotypes were normal (65).

IgG2: In about half of all IgG subclass deficiencies the IgG2 concentrations are decreased. An isolated IgG2 deficiency is associated with decreased responses to infections with encapsulated bacteria and after immunisation with polysaccharide antigens(38,66). These patients show recurrent respiratory tract infections with pneumococci and/or Haemophilus influenza type B(67,68,69). Low concentrations of IgG2 often occur in association with a deficiency in IgG4 and IgA.

IgG3: Along with IgG1, the IgG3 subclass is most frequently present in the antibody response to protein antigens. IgG3 deficiency has been associated with a history of recurrent infectious, leading to chronic lung disease. Decreased IgG3 levels are frequently associated with IgG1 deficiency (63).

IgG4: An IgG4 deficiency is difficult to assess. In healthy children, IgG4 may have very low concentrations. Methods that are used to measure IgG4 levels have not always been sensitive enough to distinguish complete absence of IgG4 from low-normal IgG4 levels. Thus, in most studies the assessment of IgG4 deficiency is hampered by the high frequency of undetectable IgG4 levels, which is especially common in young children. Although several studies have shown that a large population of patients with recurrent respiratory tract infection have low IgG4 concentrations, the significance of this finding is not clear since a low concentration of IgG4 also occurs in a substantial percentage of healthy children (63,70).

TABLE IV Frequency (%) of decreased IgG subclass concentrations in adults

IgG subclass deficiency is a common feature in a number of primary as well as secondary immunodeficiency syndromes. The primary immunodeficiency diseases are the naturally occurring defects of the immune system. These primary defects may read to recurrent protozoal, bacterial, fungal and viral infections of varying severity. The immune system can also be adversely affected secondarily by a variety of pathological conditions (including malignancy, metabolic diseases and malnutrition) and drugs; these result in secondary immunodeficiencies. Primary as well as secondary immunodeficiencies may result in recurrent or persistent infections. A selective deficiency of one or more IgG subclasses may in itself present a primary immunodeficiency syndrome.

In table V and VI, a few examples are given of primary and secondary immunodeficiency diseases in which IgG subclass deficiencies may occur.

Table V: IgG Subclass in primary immunodeficiency syndromes

4.3 IgG subclasses and allergy (85,86,87)

Among allergen-specific IgG antibodies in allergic individuals, there is a preponderance of IgG1 and IgG4, while IgG2 and IgG3 responses are small. Other findings in allergic patients include the following:

-Elevated IgG4 concentrations often occur in sera of patients with atopic eczema and dermatitis, probably as the result of prolonged antigenic stimulation (88).

-In allergy to many different allergens, allergen-specific IgG antibodies are predominantly of the IgG4 subclass and their levels increase during desensitisation therapy. In the antibody response to desensitization/immunotherapy, initially mainly IgG1 is formed, whereas IgG4 becomes more prominent after 1-2 years.

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).

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.

4.4.2 Autoimmunity

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).
- 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).

4.4.3 Hemolytic disease of the newborn

Hemolytic disease of the new-born (HDN) is a disease in which new-born babies show an anemia caused by breakdown of the erythrocytes. This is triggered by maternal (IgG) antibodies, which have passes the placental barrier and bind to the foetal erythrocytes. During pregnancy, but most pronounced during childbirth, erythrocytes exchange between foetus and mother. If the foetal erythrocytes express antigens which are not present on the maternal erythrocytes (e.g. Rhesus D antigen), antibodies directed against these blood groups can be produced by the mother.

Antibodies to blood group antigens show a more or less IgG subclass-distinct profile. The influence of of the IgG subclass of anti-Rhesus D antibodies on the severity of hemolytic disease of the newborn has been examined by many groups (99,100,101,102). In the majority of samples tested, both IgG1 and IgG3 antibodies were detected and the hemolytic disease was more severe than when only IgG1 was present. The significance of IgG3 antibodies is controversial. Some authors have suggested that IgG3 is always associated with overt hemolysis, but others could not confirm this. Blood group antibodies of the IgG4 subclass, in contrast to those of IgG1, IgG2 and IgG3 subclasses, are known not to cause clinical problems (hemolysis), which finding is mainly explained by the inability of such antibodies to activate complement(22,103,104,105).The determination of IgG subclasses is indicated especially when there is a clear discrepancy between serological findings and signs of increased red cell destruction in vivo (106).

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