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Allergen-specific IgG4 has often been regarded as a two-headed phenomenon: potentially harmful as well as potentially protective However, when more is found out about IgG4 antibodies, the harmful effects are hard to substantiate. The protective effects are still debated, but particularly from the field of parasitology the evidence is accumulating that IgG4 does, under certain conditions, effectively interfere with allergen-induced, IgE-medical effector cell triggering, i.e. IgG4 acts as a blocking antibody. Recent data indicate a striking similarity with respect to the type of antigen that triggers the IgG4 and IgE immune responses. Since a marked difference in epitope specificity exists between the IgG4 and IgE antibodies, only a fraction of the allergen-specific IgG4 can interfere effectively with IgE binding. The use of IgG4 antibody assays to monitor immunotherapy is justifiable, but its value should not be overrated. However, if no IgG4 antibody is induced by conventional immunotherapy, the therapy is likely to have been ineffective. An immunotherapy may be considered to be immunologically effective if a substantial increase (10 to 100 fold) in allergen-specific IgG4 is induced (89).

4.4 IgG subclasses in other diseases

Decreased or increased levels of IgG subclasses in serum are associated with several other diseases, examples of which will be given here (90).

4.4.1 Infectious diseases (6)

In most infections the first antibodies to appear will be of the IgM class, while those of the IgG class will be produced later. In general, microbial protein antigens will mainly evoke antibody responses of the IgG1 and IgG3 subclasses, with a minor contribution of IgG2 and IgG4. On the other hand, polysaccharide antigens will predominantly induce IgG2 antibodies.

Some disease-specific observations:

- Pneumococcal otitis media in children is associated with a decreased level of IgG2.
- Patients with recurrent infections by encapsulated bacteria often show decreased levels of IgG2 and IgG4.
- Recurrent respiratory infections with bronchiectasis are often associated with decreased levels of IgG2, IgG3 and IgG4.
- Cystic fibrosis with chronic Pseudomonas aeruginosa infection is associated with an increased level of IgG2 and IgG3, the latter of which seems to be of prognostic significance.

4.4.2 Autoimmunity

In autoimmune diseases the levels of IgG subclasses do mostly not differ from those in healthy individuals, but specific autoantibodies show variable subclass restrictions: frequently, autoantibodies are of the IgG1 and IgG3 subclasses (91,92,118).
- Human rheumatoid factors (RF) are defined as IgG, IgA or IgM antibodies against the Fc fragment of immunoglobulin. In most cases, RF have been found to bind to the Fc fragments of IgG. As for their subclass specificity, most RF have been shown to react with IgG1, followed by IgG2 and IgG4. Binding of RF to IgG3 is rare.

- Abnormal IgG1: IgG2 ratios have been reported in patients suffering from connective tissue diseases. In case of a selective polyclonal increase of IgG1, one should be alert for the possibility of Sjögren's syndrome. It has been suggested that this immunoglobulin abnormality is the product of a restricted oligoclonal B cell response and may thus be the consequence of a benign B cell lymphoma (93,94,95,96).

- Autoantibodies to neutrophil cytoplasmic antigens (ANCA) are predominantly of the IgG1 and IgG4 subclass (97,98). Autoantibodies of the IgG3 subclass almost exclusively occur in patients with renal involvement(98).

 

4.4.3 Hemolytic disease of the newborn

Hemolytic disease of the new-born (HDN) is a disease in which new-born babies show an anemia caused by breakdown of the erythrocytes. This is triggered by maternal (IgG) antibodies, which have passes the placental barrier and bind to the foetal erythrocytes. During pregnancy, but most pronounced during childbirth, erythrocytes exchange between foetus and mother. If the foetal erythrocytes express antigens which are not present on the maternal erythrocytes (e.g. Rhesus D antigen), antibodies directed against these blood groups can be produced by the mother.
Antibodies to blood group antigens show a more or less IgG subclass-distinct profile. The influence of the IgG subclass of anti-Rhesus D antibodies on the severity of hemolytic disease of the newborn has been examined by many groups (99,100,101,102). In the majority of samples tested, both IgG1 and IgG3 antibodies were detected and the hemolytic disease was more severe than when only IgG1 was present. The significance of IgG3 antibodies is controversial. Some authors have suggested that IgG3 is always associated with overt hemolysis, but others could not confirm this. Blood group antibodies of the IgG4 subclass, in contrast to those of IgG1, IgG2 and IgG3 subclasses, are known not to cause clinical problems (hemolysis), which finding is mainly explained by the inability of such antibodies to activate complement(22,103,104,105).The determination of IgG subclasses is indicated especially when there is a clear discrepancy between serological findings and signs of increased red cell destruction in vivo (106).

4.5 Indications for measuring IgG subclass levels

As already mentioned in the previous sections, several studies indicate that (selective) IgG subclass deficiencies may be associated with disease. Specific examples are: bronchiectasis and severe, recurrent stages of otitis media, sinusitis, pneumonia and bronchitis. The possibility of an IgG subclass deficiency should be considered in all children with recurrent infections and chronic obstructive bronchitis. The association between IgG2 deficiency and severe recurrent infections of the respiratory tract in young children, caused by encapsulated bacteria, have led to an increasing demand for the determination of IgG subclasses in sera from children. However, it should be kept in mind that IgG subclass deficiencies in children may be transient. The levels of IgG2 increase relatively late in childhood. Thus, when low IgG2 levels are found in children below the age of 2-3 years, it is advisable to monitor this level in the course of time, since it may be due to a temporary maturation block. Obviously, IgG subclass deficiencies may also occur in all patients at risk for infections due to immunodeficiency, such as occurs e.g. in haematopoietic stem cell transplantation.

In general, IgG subclass levels should be measured whenever the total IgG level is decreased. However, and IgG subclass deficiency is not excluded by a normal or even high total IgG concentration (62). Therefore, it is essential to measure individual IgG subclass levels (107). A correct diagnosis is essential in choosing the appropriate therapy (108). There are several specific disease conditions in which measurement of IgG subclasses is recommended:

- Several specific infections, such as meningitis caused by pneumococci, Haemophilus influenzae (B) and meningococci or osteomyelitis and severe pneumonia;
- Recurrent purulent infections of the upper and lower respiratory tract (it is advisable to assess the actual causative agent(s) by means of serology and culture of the micro-organisms in vitro);
- Bronchiectasias and/or purulent infections of unclear etiology, such as cystic fibrosis, immotile cilia syndrome (Kartagener syndrome), or a history of earlier infections like measles-pneumonia;
- IgA-deficiency associated with infectious disease (pneumonia, sinusitis, etc.);
- Diseases mentioned in chapters 4.2 and 4.4.

4.5.1 Assessment of immune status

The determination of IgG subclass levels is included in the routine laboratory tests for the assessment of the immune status. It is used as a parameter of humoral immunity. For diagnostic testing of pediatric and adult patients with recurrent infections in whom an immunodeficiency is suspected, the following protocol has been developed by the Netherlands Working Party for Immunodeficiencies (109). A characteristic feature of this protocol for the assessment of immunological competence is a graduation in stages of tests with more or less increasing complexity.

A. Patient's history

-Infections: Localization, frequency, duration, reaction to antibiotic therapy, nature of the infectious micro-organism(s): viruses, bacteria, fungi, protozoa
-Allergy: asthma, eczema, diarrhea
-Family: early deaths of other children, occurrence of severe or unusual infections, malignancies, auto-immune diseases

B. Physical examination

- assessment of sites of infection (ear/nose/throat, lungs, abdomen, urogenital, skin)
- swelling or absence of lymphoid tissue (lymph nodes, adenoid, tonsils, spleen)

C. Non-specific immunity

- differential leucocyte count (basophils, eosinophils, neutrophils, lymphocytes, monocytes)
- haemolytic complement (classical and alternative pathway: CH50 and AP50
- opsonic activity of patient's serum
-phagocytic activity of patient's granulocytes

D. Specific immunity

Humoral:

- serum levels of total IgG,IgM,IgA and IgE
- serum levels of IgG subclasses
- titres of isohaemagglutinins
- levels of IgA and IgM in saliva

Cellular:

Determination of lymphocyte subpopulations:

- T cells (CD3+)
- B cells (CD19+)
- T helper/inducer cells (CD3+, CD4+)
- T suppressor/cytotoxic cells (CD3+, CD8+)
- activated T cells (CD3+, HLA-DR+)
- NK cells (CD3-, CD16+, CD56+)

- Specific antibody responses before and after vaccination (Diphtheria/Tetanus/Polio, Haemophilus influenzae B conjugate, Pneumovax, Meningovax type A/C). Since patients with IgG subclass deficiencies frequently suffer from infections with pneumococci and Haemophilus bacteria, it is important to measure specific antibodies against these micro-organisms, before and after vaccination, using the polysaccharide- or conjugate vaccines now commercially available.

- Delayed type hypersensitivity skin tests (Tuberculin, Candida, Trichophyton, Proteus, Tetanus, Diphteria, Streptococcal antigens)

- T cell stimulation in vitro by mitogens and antigens.

4.5.2 Therapeutic considerations

For individuals with IgG subclass deficiencies who also develop clinical symptoms (e.g. recurrent infections), treatment should be considered. Treatment of such patients will generally consist of anti-microbial therapy, immunoglobulin substitution and vaccinations.

Conservative treatment, comprising early antibiotics treatment during infections, prophylactic antibiotic treatment in selected individuals and supportive symptomatic therapy should be the first line of treatment, sometimes supplemented with intravenous immunoglobulin. In patients with primary specific immunodeficiency who have significantly diminished serum IgG levels and/or demonstrated defects in antibody production, intravenous immunoglobulin replacement therapy is currently most often used, since administration of immunoglobulins will reduce the incidence of bacterial and viral infections.
Patients with selective IgG subclass deficiency may benefit from IgG replacement (WHO-report)(110).

The maturation of an immune response can be enhanced by repeated vaccination. Vaccination with Diphtheria/Tetanus/Polio proteins (T cell-dependent antigens) from the age of three months is generally performed. Active immunization against polysaccharide antigens (T cell-independent antigens) is ineffective until about the age of 18 months, because of the slow ontogeny of the anti-polysaccharide immune response. By coupling the polysaccharide antigens to protein carriers conjugate-vaccines), the T cell-independent response is changed into a T cell-dependent one, leading to an effective response against polysaccharide antigens in young children (111, 112, 113, 114). In IgG2-deficient patients, only a marginal compensating mechanism exists, as illustrated by the impaired anti-polysaccharide response in all other immunoglobulin isotypes. This poor responsiveness can be partly bypassed by using conjugate-vaccines.
Nevertheless, it should be kept in mind that active vaccination procedures may fail, due to a deficient humoral immunity.