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 occaaionally 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 indentified 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 immunization 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 l;ow-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