rev:January 30, 1997
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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 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
| Sample Origin | Number of samples | IgG1 | IgG2 | IgG3 | IgG4 |
| Patients * | 1175 | 28% | 17% | 13% | 9% |
| Healthy individuals | 162 | 8% | 3% | 1% | 1% |
*Samples were sent to CLB for diagnosis of suspected IgG subclass deficiency
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