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The IgG subclass deficiencies
are a subgroup of primary antibody deficiency. Dr Alison Jones,
of Great Ormond Street Hospital for Children NHS Trust, provides
an overview of this rather poorly defined group of disorders.
IgG
Subclass DeficiencY:
the Medical Background
Three major classes
of immunoglobulin (or antibody) are normally present in the
blood: IgG, IgA and IgM. IgG is found in the highest concentration
and can be subdivided biochemically into four distinct subclasses,
which have differing biological functions. Low levels of total
IgG are usually associated with frequent infections.
The four IgG subclasses
are:
- IgG1. This is the most
abundant subclass. It is thought to recognise protein antigens
in particular, and therefore to be important in fighting
viral infections.
- IgG2. This is the second
highest subclass in concentration. It plays an important
part in neutralising infections caused by bacteria with
polysaccharide capsules, such as pneumococcus and haemophilus.
- IgG3. This is present
in smaller quantities, and has a similar function to IgG1.
- IgG4. Normal concentrations
of this subclass can be very low, and its functional role
is not established, although it may have a role in allergic
reactions.
People with IgG
subclass deficiency have low levels of one or more of the
subclasses. The two IgG subclasses most usually linked with
frequent infections are IgG1 and IgG2.
It is difficult
to predict the significance of low levels of IgG subclasses.
Some people may have low levels of one or more IgG subclasses,
yet are perfectly healthy. Conversely, other people may have
very minor abnormalities of immunoglobulin production (or
abnormalities so minor that they cannot even be demonstrated),
but are severely compromised by infections.
In general, the
significance of a low IgG subclass level needs to be assessed
in the context of the clinical picture. If a low level is
found, it should be checked more than once. If low levels
are found in a person who is having more than an acceptable
number of infections, then the subclass deficiency may be
interpreted as significant.
Where infections
are frequent or severe enough to justify long-term treatment,
low levels of one or more IgG subclasses are commonly associated
with abnormalities of IgA and/or IgM production.
Unfortunately,
as with many other immunodeficiencies, the answer is usually
"we don't know".
In rare cases there
is a "deletion" of the part of the immunoglobulin
gene complex on chromosome 14 which is responsible for generating
one or more immunoglobulin "heavy chains". These
are the parts of the antibody that confer subclass specificity
on the molecule. In these cases the IgG subclass(es) in question
are completely absent.
It is more usual
simply to find lower levels than normal, implying that the
gene is present but does not function normally. In most cases
there is likely to be an abnormality of the mechanisms that
regulate the immune system and determine the relative quantities
in which the immunoglobulins of different classes are manufactured.
In some cases IgG
subclass deficiency may be the first indication of the future
evolution of common variable immunodeficiency (CVI).
In very unusual
cases, deficiency of IgG subclasses is the only quantitative
abnormality of antibody production in boys with X-linked agammaglobulinaemia
(XLA), usually a more severe condition. However, these boys
have only a very mild form of XLA.
People with clinically
significant IgG subclass deficiency most often present with
recurrent upper respiratory infections (e.g. throat, ears
and sinuses) and chest infections. Occasionally, they develop
more severe, sometimes life-threatening, infections.
If a person is
suffering from an unacceptable number of infections, one of
the first investigations is usually to measure his or her
immunoglobulin levels. However, in people with IgG subclass
deficiency, the total IgG concentration is often normal. This
is because the levels of the other subclasses may compensate
by being higher. Therefore, it is important to measure IgG
subclass levels even when no deficiency of total immunoglobulins
is found.
As already mentioned,
it is not uncommon to find low levels of either IgA or IgM
in association with low IgG subclasses. This probably reflects
the disordered regulation of immunoglobulin production.
Treatment depends
largely on the severity of the symptoms. If infections are
mild and infrequent, and the person's quality of life is not
significantly affected, treatment can be limited to the early
use of antibiotics when an infection occurs. In such cases
it is reasonable to keep a supply of antibiotics at home,
which can be started when symptoms develop.
More aggressive
treatment may be necessary if a person is suffering from predictably
frequent infections and is losing time at work or at school,
or if a child's growth and/or development is being affected.
Prophylactic antibiotics should be tried first, and in many
patients this is very successful. This means taking a single
daily dose of a broad spectrum antibiotic, which prevents
the development of infections. There are theoretical concerns
about the development of antibiotic resistance by bacteria,
but in practice this is not often a problem. In a few cases
it may be necessary to "rotate" different antibiotics
if symptoms break through.
A very small subgroup
of patients with IgG subclass deficiency have severe symptoms
which are resistant to antibiotic prophylaxis. In these cases,
a trial of immunoglobulin replacement is justified. Most of
this subgroup also have associated abnormalities of IgA and/or
IgM production, or defects
of production of specific antibodies to selected organisms.
They therefore fall into a more severe category.
This depends to
an extent on the underlying defect. If a gene has a structural
abnormality, then the condition will be life-long. However,
even in such a situation there may well be compensatory mechanisms
that diminish the clinical significance of the genetic defect.
If severe infections occur in infancy it is likely that life-long
treatment will be required.
The majority of
people with IgG subclass deficiency have abnormalities of
immune regulation. In children who present with recurrent
infections in infancy, IgG subclass abnormalities are relatively
common. The symptoms may be severe enough to justify antibiotic
prophylaxis and, occasionally, immunoglobulin therapy. However,
in these cases the subclass deficiency may reflect the immaturity
of the immune system, which will improve with time. Sometimes
the quantitative abnormality is not resolved, but the functional
significance decreases, so that treatment can be discontinued
without a recurrence of the symptoms.
Symptoms associated
with IgG subclass deficiency which start later in childhood
or in adulthood are less likely to be resolved. As already
indicated, they may be the first evidence of the development
of CVI. In these cases it is likely that treatment (if necessary)
will be life-long, and it is important that the function of
the immune system is reassessed from time to time.
Medical information published
by the PiA is approved by our Medical Advisory Panel. However,
it is intended for general guidance only, and should not be
used in place of the personal consultation needed with your
physician.
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