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IgG Subclass Deficiency?
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Primary Immune Deficiency
IDF PATIENT/FAMILY HANDBOOK | CHAPTER X
IgG Subclass Deficiency
There are five classes of immunoglobulins: IgG, IgA, IgM, IgD, and
IgE. The IgG class of immunoglobulins is itself composed of four
different subtypes of IgG molecules called the IgG subclasses.
Patients who lack, or have very low levels of, one or two IgG
subclasses, but whose other immunoglobulin levels are normal, are
said to have a selective IgG subclass deficiency.
 Definition of Subclass Deficiency:
Antibodies are made of proteins called
immunoglobulins. There are five types or classes
of immunoglobulin: IgG, IgA, IgM, IgD and IgE
(see chapter titled The Immune System and
Primary Immunodeficiency Diseases). Most of
the antibodies in the blood and the fluid that
bathes the tissues and cells of the body are of
the IgG class. The IgG class of antibodies is
itself composed of four different subtypes of IgG
molecules called the IgG subclasses. These are
designated IgG1, IgG2, IgG3 and IgG4. Patients
who suffer recurrent infections because they
lack, or have very low levels of, one or two IgG
subclasses, but whose other immunoglobulin
levels, including total IgG, are normal, are said to
have a selective IgG subclass deficiency.
While all the IgG subclasses contain antibodies,
each subclass serves somewhat different
functions in protecting the body against infection.
For example, the IgG1 and IgG3 subclasses
are rich in antibodies against proteins such
as the toxins produced by the diphtheria and
tetanus bacteria, as well as antibodies against
viral proteins. In contrast, antibodies against the
polysaccharide (complex sugar) coating (capsule)
of certain disease-producing bacteria (e.g. the
pneumococcus and Haemophilus influenzae) are
predominantly of the IgG2 type. Some of the IgG
subclasses can easily cross the placenta and enter
the unborn infant's bloodstream, while others do
not. Antibodies of certain IgG subclasses interact
readily with the complement system, while others
interact poorly, if at all, with the complement proteins.
Thus, an inability to produce antibodies of a specific
subclass may render the individual susceptible to
certain kinds of infections but not others.
The IgG circulating in the bloodstream is 60-70%
IgG1, 20-30% IgG2, 5-8% IgG3 and 1-3% IgG4.
The amount of the different IgG subclasses
present in the bloodstream varies with age. For
example, IgG1 and IgG3 reach normal adult levels
by 5-7 years of age while IgG2 and IgG4 levels
rise more slowly, reaching adult levels at about
10 years of age. In young children, the ability to
make antibodies to the polysaccharide coatings
of bacteria, antibodies that are most commonly
of the IgG2 subclass, develops more slowly than
the ability to make antibodies to proteins. These
factors must be taken into account before an
individual is considered to be abnormal, either
by virtue of having a low IgG subclass level or an
inability to make a specific type of antibody.
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Clinical Presentation of Subclass Deficiency:
Recurrent ear infections, sinusitis, bronchitis and
pneumonia are the most frequently observed
illnesses in patients with IgG subclass deficiencies.
Both males and females may be affected. Some
patients will show an increased frequency of
infection beginning in their second year of life. In
other patients the onset of infections may occur
later. Often a child with IgG subclass deficiency
will first come to the physician's attention because
of recurrent ear infections. Somewhat later in
life, recurrent or chronic sinusitis, bronchitis
and/or pneumonia may make their appearance.
In general, the infections suffered by patients
with selective IgG subclass deficiencies are not
as severe as those suffered by patients who
have combined deficiencies of IgG, IgA and IgM
(for example X-linked agammaglobulinemia or
common variable immunodeficiency). Very rarely,
IgG subclass deficient patients have suffered
recurrent episodes of meningitis or bacterial
infections of the bloodstream (e.g. sepsis).
Selective IgG1 subclass deficiency is very
rare. IgG2 subclass deficiency is the most
frequent subclass deficiency in children, while
IgG3 subclass deficiency is the most common
deficiency seen in adults. IgG4 deficiency most
often occurs in association with IgG2 deficiency.
The significance of isolated, or selective, IgG4
deficiency is unclear at this time. Since many
normal children under 10 years of age have
undetectable IgG4, IgG4 deficiency is generally
not accepted as a diagnosis in this age group.
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Diagnosis of Subclass Deficiency:
IgG subclass deficiency may be suspected in
children and adults who have a history of recurrent
infections of the ears, sinuses, bronchi and/or
lungs. An individual is considered to have a
selective IgG subclass deficiency if one or more
of the IgG subclass levels in their blood is below
the normal range for age and the levels of other
immunoglobulins (i.e. total IgG, IgA and IgM) are
normal or near normal.
An individual may have very low levels or absence
of one or more IgG subclasses and yet the total
amount of IgG in their blood may be normal or
near normal. Therefore, in order to make the
diagnosis of selective IgG subclass deficiency,
measurement of IgG subclasses is required along
with measurement of serum IgG, IgA, and IgM.
It is important to consider that the concentrations
of IgG subclasses vary up or down over time and
the normal ranges used in different laboratories
also vary. Normal values are usually "defined" as
those values between two standard deviations
below and above the average for that person's
age. Unfortunately, that may give the impression
to some physicians and patients that individuals
below the second standard deviation are abnormal
when 2.5% of normal individuals fall below this
level. The finding of a mild IgG subclass deficiency
should prompt re-evaluation over a period of
months before calling that person abnormal.
Subclass deficiencies need to be interpreted by
taking into account the clinical status of the patient
as well as the ability to produce specific antibodies
in response to childhood vaccines.
IgG subclass deficiencies may accompany
IgA deficiency (see chapter titled Selective IgA
Deficiency). Combined deficiencies of IgA with
IgG2 and IgG4 deficiency are frequently observed.
IgG2 and IgG4 deficiency as well as IgA and
IgE deficiency also occur in association with
Ataxia Telangiectasia (see chapter titled Ataxia
Telangiectasia).
Many patients with selective IgG2 subclass
deficiency or IgA and IgG2 deficiency are unable
to produce protective levels of antibody when
immunized with unconjugated polysaccharide
vaccines against Streptococcus pneumoniae (the
pneumococcus) or Haemophilus influenzae bacteria.
Some patients may also be unable to produce
protective levels of antibody when immunized with
polysaccharides that are also conjugated to proteins.
Patients with IgG subclass deficiencies usually make
normal amounts of antibodies to protein vaccines
such as the diphtheria and tetanus toxoids in the
routine DPT immunizations.
Patients with IgG subclass deficiencies have
normal numbers of B and T-lymphocytes and their
T-lymphocytes function normally when tested.
An additional subset of patients have normal
immunoglobulin levels and normal IgG subclasses,
yet fail to produce protective antibody levels
in response to infections with Streptococcus
pneumoniae or to vaccines against this bacteria.
These patients are thought to have a Specific
Antibody Deficiency (SAD) and are usually grouped
along with patients with IgG subclass deficiency.
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Natural History of Subclass Deficiency:
The natural history of patients with selective IgG
subclass deficiency is not completely understood.
Selective IgG subclass deficiencies occur more
often in children than in adults and the type of
subclass deficiency in children (i.e. predominantly
IgG2) differs from that most commonly seen in
adults (i.e. IgG3). These findings suggested that at
least some children may "outgrow" their subclass
deficiencies. In fact, recent studies have shown
that many, but not all, children who were subclass
deficient during early childhood (i.e. under the age
of 5 years) develop normal subclass levels as well
as the ability to make antibodies to polysaccharide
vaccines as they get older. However, IgG subclass
deficiencies may persist in some children as well
as in adults and in some instances a selective
IgG subclass deficiency may evolve into common
variable immunodeficiency. At the present time,
it is not possible to determine which patients will
have the transient type of subclass deficiency
and in which patients the subclass deficiency
may be permanent or the forerunner of a more
wide-ranging immunodeficiency, such as common
variable immunodeficiency. For these reasons,
periodic reevaluation of immunoglobulin and IgG
subclass levels is necessary.
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Inheritance of Subclass Deficiency:
No clear-cut pattern of inheritance has been
observed in the IgG subclass deficiencies.
Occasionally, two individuals with IgG subclass
deficiency may be found in the same family. In
some families IgG subclass deficiencies have been
found in some family members while other family
members may have IgA deficiency or common
variable immunodeficiency.
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Treatment of Subclass Deficiency:
Patients with IgG subclass deficiency frequently
suffer recurrent or chronic infections of the ears,
sinuses, bronchi and lungs. Treatment of these
infections usually requires antibiotics. One goal of
treatment is to prevent permanent damage to the
ears and lungs that might result in hearing loss or
chronic lung disease. Another goal is to maintain
patients as symptom-free as possible so that they
may pursue the activities of daily living such as
school or work. Sometimes antibiotics may be
used for prevention (i.e. prophylaxis) of infections
in patients who are unusually susceptible to ear or
sinus infections.
For immunodeficiency diseases in which patients
are unable to produce adequate levels of the
major immunoglobulin classes (i.e. IgG, IgA and
IgM) and fail to make antibodies against proteins
as well as polysaccharide antigens (for example,
X-linked Agammaglobulinemia and Common
Variable Immunodeficiency), immunoglobulin
replacement therapy is clearly needed (see
chapter titled Specific Medical Therapy). The use
of immunoglobulin replacement therapy in patients
with IgG subclass deficiencies is not as clear cut
as it is for X-linked agammaglobulinemia and
Common Variable Immunodeficiency patients.
Patients with IgG subclass deficiency and/or
specific antibody deficiency have a more limited
antibody and immunoglobulin deficiency than
patients with X-linked Agammaglobulinemia
and Common Variable Immunodeficiency. For
patients in whom infections and symptoms can
be controlled with antibiotics, immunoglobulin
replacement therapy may not be necessary.
However, for patients whose infections cannot
be readily controlled with antibiotics, or have
abnormal antibody responses, immunoglobulin
replacement therapy may be considered.
Since many young children appear to outgrow their
IgG subclass deficiencies as they get older, it is
important to reevaluate the patient to determine if
the subclass deficiency is still present. Reevaluation
requires discontinuation of immunoglobulin
replacement and at least 4-6 months of
observation before IgG levels are re-tested. If the
subclass deficiency has resolved, immunoglobulin
replacement therapy may be discontinued and the
patient observed. If the deficiency has persisted,
immunoglobulin therapy may be re-instituted.
In teenagers and adults, disappearance of the
subclass deficiency is less likely.
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Expectations for the Subclass Deficiency Patient:
The outlook for patients with IgG
subclass deficiency is generally good. Many children appear to outgrow their
deficiency as they get older. For those patients in whom the deficiency persists,
the use of antibiotics and, in certain circumstances, the use of gamma globulin
replacement therapy may prevent serious infections and the development of impaired
lung function, hearing loss or injury to other organ systems.
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