What is IgG, and how does the normal IgG system function? Five major classes of immunoglobulin (Ig) exist: IgM, IgA, IgD, IgG and IgE. IgG is the primary "isotype in the blood and extracellular fluid" (Janeway, et al., 1999). The IgG class of antibodies consists of four different subtypes: IgG1, IgG2, IgG3 and IgG4. Due to differences in structure, the four IgG subclasses differ in their biological and physiochemical properties (table I).

Table I: Physiochemical and biological properties of human IgG subclasses (Meulenbroek et al., 2000).

	IgG1	IgG2	IgG3	IgG4
Heavy chain type	gamma 1	gamma 2	gamma 3	gamma 4
Molecular mass (kd)	146	146	170	146
Amino acids in hinge region	15	12	62	12
Inter-heavy chain disulfide bonds (in hinge region)	2	4	11	2
Susceptibility to proteolytic enzymes	++	+/-	+++	+
Number of allotypes	4	1	13	0
Adult serum level range (g/l) (mean, g/l)	4.9-11.4 (6.98)	1.5-6.4 (3.8)	0.20-1.10 (0.51)	0.08-1.40 (0.56)
Proportion of total IgG (%)	43-75	16-48	1.7-7.5	0.8-11.7
Half-life (days)	21	21	7	21
Placental transfer	+	+	+	+
Antibody response to:
proteins	++	+/-	++	+/-
polysaccharides	+	++	(-)	(-)
allergens	+	(-)	(-)	++
Complement activation
C1q binding	++	+	+++	-
C1q binding, high epitope density enhancement alternative pathway	-	+	-	+/-
Binding to Fcg receptors:
FcGRI (CD64: monocytes, macrophages,  neutrophils, dendritic cells)	++	-	+++	+
FcGRII(CD32: monocytes, macrophages,  neutrophils, eosinophils, platelets, B cells, dendritic cells, endothelial cells)	++	(a)	+++	-
FcGRIIa-H131	++	+++	+++	-
FcGRIIa-R131	++	-	++	-
FcGRIII(CD16: neutrophils, eosinophils,  macrophages, NK cells, subsets of T cells)	++	-	++	-
FcGRIIIb-NA1	+++	-	+++	-
FcGRIIIb-NA2	++	-	++	-
Binding to Staphylococcal protein A	++	++	(b)	+
Binding to Staphylococcal protein G	++	++	++	++
(a): FCgammaRII allotype dependent
(b): IgG3 allotype dependent

The IgG subclass distribution in specific antibody responses varies according to the structure of the antigen, the way in which the antigen invades the host, especially the nature of the carrier, the epitopes' nature and quantity, the antigen's physiochemical nature, the amount of antigen, and the genetic make up of the host (Meulenbroek et al., 2000). Usually anti-viral IgG antibodies are chiefly restricted to IgG1 and IgG3. IgG3 ordinarily appears first in viral infections; however, in bacterial infections the IgG subclass distribution is usually more heterogeneous. This results from the fact that bacteria contain many considerably varied antigenic epitopes, with significant differences in their protein and carbohydrate structures (Meulenbroek et al., 2000).

IgG antibodies efficiently "opsonize pathogens for engulfment by phagocytes and activate the complement system" (Janeway et al., 1999). Because of the structural diversity in the hinge region of IgG subclasses (table 1), they have different abilities to activate complement. In the initial step to activate the complement cascade, the ability of the IgG subclasses to bind C1q decreases from  IgG3>IgG1>IgG2>IgG4, because of the effectiveness of the long hinge region of IgG3 (Meulenbroek et al, 2000). While IgG2 is only a weak activator of the classical complement cascade, it seems to have a significant role in activating the alternative complement cascade. This alternative complement cascade results in the opsonisation where the antibodies with complement attach to the pathogen, making the antigen recognizable to phagocytic cells which engulf the bacteria. As Meulenbroek and Zeijlemaker suggest "phagocytosis is initiated by an interaction between the Fc (fragment crystallizable) fragment of the immunoglobulin (figure I) and Fc receptors (table I), which are predominately expressed on effector cells of the immune system " (2000).

In such activities as phagocytosis, endocytosis, release of several inflammatory mediators, antibody-mediated cytotoxicity within the cell, the presentation of antigens and the subsequent clearing of immune complexes, the Fc receptor for IgG (FcgR) plays a major role. Furthermore, phagocytosis induced by FcgR is also significant in "antigen presentation and amplification of the immune response" against infectious agents (Meulenbroek et al., 2000). Clinical manifestations of IgG subclass deficiencies are also dependent on these characteristics of FcgR, since IgG subclasses vary in  their affinity to FcgR (Meulenbroek et al., 2000).

Figure I. Immunoglobulin Fc (Igg1) complexed with protein G (C2 fragment). MMDB Id: 3685 PDB Id: 1FCC

According to the Immune Deficiency Foundation, the amount of the various IgG subclasses varies with age as well as with genetic factors: the IgG in the bloodstream will include ranges of 70% IgG1, 20-30% IgG2, 5-8% IgG3 and 1-3% IgG4 (2000). The reference ranges of IgG subclass level in Caucasians is shown in table II.

Table II. Reference ranges (g/l) of IgG subclasses in healthy Caucasian children and adults: (Meulenbroek et al., 2000).

	IgG1	IgG2	IgG3	IgG4
age in months
0-1	2.4-10.6	0.87-4.1	0.14-0.55	0.04-0.56
1-4	1.8-6.7	0.38-2.1	0.14-0.70	<0.03-0.36
4-6	1.8-7.0	0.34-2.1	0.15-0.8	<0.03-0.23
6-12	2.0-7.7	0.34-2.3	0.15-0.97	<0.03-0.43
age in years
1-1.5	2.5-8.2	0.38-2.4	0.15-1.07	<0.03-0.62
1.5-2	2.9-8.5	0.45-2.6	0.15-1.13	<0.03-0.79
2-3	3.2-9.0	0.52-2.8	0.14-1.20	<0.03-1.06
3-4	3.5-9.4	0.63-3.0	0.13-1.26	<0.03-1.27
4-6	3.7-10.0	0.72-3.4	0.13-1.33	<0.03-1.58
6-9	4.0-10.8	0.85-4.1	0.13-1.42	<0.03-1.89
9-12	4.0-11.5	0.98-4.8	0.15-1.49	0.03-2.10
12-18	3.7-12.8	1.06-6.1	0.18-1.63	0.04-2.30
adults	4.9-11.4	1.50-6.4	0.20-1.10	0.08-1.40

Depending on whether the nature of the antigen is protein or polysaccharide and the frequency and duration of stimulation by the antigen, an antibody response may exhibit changes in the distribution of IgG subclasses in plasma, and cause increased or diminished levels of one or more IgG subclasses (Meulenbroek et al., 2000).

"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" (Meulenbroek et al., 2000). Such complete deficiency is rare and is usually due to deletions in chromosome 14 loci. "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" (Meulenbroek et al., 2000).

Many disease conditions are associated with decreased and/or increased levels in single and/or multiple IgG subclasses.  "Patients who suffer recurrent infections because they lack, or have very low levels of, one or two IgG subclasses, but whose other immunoglobulin levels are normal (or near normal), are said to have a selective IgG subclass deficiency" (Immune Deficiency Foundation Patient/Family Handbook, 2000). According to Meulenbroek and Zeijlemaker, clinicians must determine IgG subclass levels when diagnosing, since a lower level of one IgG subclass may accompany an increase in other IgG subclasses; the patient may have a normal total IgG level (2000). Since patients with IgG1 and/or IgG3 lack antibody responses to protein antigens, they are likely to experience chronic and recurrent infections of the bronchi and lungs. However, patients with IgG2 subclass deficiencies may be prone to infections such as pneumococci, meningococci and Haemophilus influenza type B, since encapsulated bacteria are polysaccharide antigens and IgG2 is one of the primary defenses to them (Meulenbroek et al., 2000). Although IgG4 subclass deficiency is often found in healthy individuals, decreased IgG4 levels may be associated with severe recurrent pulmonary infections (Meulenbroek et al., 2000).

IgG subclass deficiencies may occur in primary and secondary immunodeficiency diseases which result in recurrent or continual infections (table III) (Meulenbroek et al., 2000).

Table III. Decreased or increased levels of IgG subclasses in primary and secondary immunodeficiency syndromes (Meulenbroek et al., 2000).
 

Primary immunodeficiency:	IgG subclass deficiencies
IgA deficiency	frequently associated with IgG2 and IgG4 deficiencies but IgG3 deficiencies may also occur
Common Variable Immunodeficiency  (CVID)	associated with decreased levels of IgG1, IgG2, and IgG4
Wiskott-Aldrich Syndrome (WAS)	IgG3 and IgG4 deficiencies are observed
Ataxia telangiectasia	IgG2 and IgG4 levels are usually very low,  sometimes also associated with IgG3 deficiency
Chronic Mucocutaneous Candidiasis	some patients have IgG2 and IgG4 deficiency, isolated IgG2 and IgG3 deficiencies are also observed
Secondary immunodeficiency:
HIV-infection (stages III and IV)	IgG2 and IgG4 levels are often decreased, while levels of IgG1 and IgG3 are increased
Radiation exposure, chemotherapy (bone-marrow transplantation)	often associated with low levels of IgG2 and IgG4

Different assays are used for "diagnostic testing of pediatric and adult patients with recurrent infections in whom an immunodeficiency is suspected." (Meulenbroek et al., 2000) Such assays include radial immunodiffusion, nephelometry and turbidimetry, radio immune assay (RIA), enzyme-linked immunosorbent assay (ELISA), immuno-affinity chromatography, and agglutination techniques (Meulenbroek et al., 2000).

Treatment of patients with IgG subclass deficiencies who develop clinical symptoms such as recurrent infections usually involves anti-microbial therapy, immunoglobulin substitution and vaccinations. First line of treatment should include antibiotic therapy early in infections, supportive symptomatic therapy, and prophylactic antibiotic treatment in some individuals. Intravenous immunoglobulin is indicated "in patients with primary specific immunodeficiency who have significantly diminished serum IgG levels and/or demonstrated defects in antibody production, since ... administration of immunoglobulins will reduce the incidence of bacterial and viral infections" (Meulenbroek et al., 2000).

One example of an intravenous immunoglobulin injection is Immune Globulin Intravenous (Human) Sandoglobulin, which is an "immunoglobulin preparation produced by cold alcohol fractionation from the plasma of over 16,000 volunteer US donors," that is administered to replace or boost immunoglobulin G (Immune Globulin Intravenous (Human) Sandoglobulin package insert, 1996).

According to a WHO-report, some "patients with selective IgG subclass deficiency may benefit from IgG replacement" (Meulenbroek et al., 2000). Similar to childhood  immunization against polysaccharide antigens, where the polysaccharide antigens are coupled with protein carrier conjugate-vaccines, the poor responsiveness in IgG2 deficient patients can be partially bypassed by using conjugate-vaccines. But "active vaccination procedures may fail, due to a deficient humoral immunity" (Meulenbroek et al., 2000).

Sherrie Hickson, the IgG subclass deficient patient, relates that she has faced more than just severe illness. She has suffered a loss of income since she can no longer work. Furthermore, each of the intravenous immunoglobulin treatments she must take every three weeks costs $2000, which has decimated her family's savings. What other choice does she have? Other patients with severe IgG subclass deficiency, the prognosis is grim.

Hickson, Sherrie. Personal interview. March 11, 2000.

Immune Deficiency Foundation Patient/Family Handbook: for the Primary Immune Deficiency Diseases. 1993. <http://www.ipopi.org/idf/pfhandbk/page39.html>. Accessed 2000 Mar 20.

Immune globulin intravenous (human) Sandoglobulin package insert. Sandoz Pharmaceuticals Corporation: 1996.

Janeway, C.A., Jr., Travers, P., Walport, M., Capra, J.D. Immunobiology: the immune system in health and disease. New York: Elsevier Science Ltd./Garland Publishing: 1999 p.325.

Meulenbroek A.J., Zeijlemaker W.P., Human IgG Subclasses: useful diagnostic markers for immunocompetence. <http://www.researchd.com/rdikits/rdisubbk.htm>.  Accessed 2000 Apr 18.