Immunoglobulin g4

IgG4 immunoglobulins represent a subclass of immunoglobulins G.

Immunoglobulin G (IgG) can be divided into 4 subclasses:

• IgG1, the largest IgG subclass, like IgG3, mediates the immune response to protein and polypeptide antigens
• IgG2 mediates the immune response to polysaccharide antigens
• IgG4 can block an IgE response and is found to be elevated in various allergic and infection-induced immune responses. However, the role of allergen-specific IgG/IgG4 in the pathogenesis of immediate-type allergic reactions is unknown.
• In contrast, IgG4 plays a significant role in IgG4-associated autoimmune diseases.

Class G IgG4 antibodies represent the smallest proportion of IgG subclasses in the blood of healthy people. IgG4 antibodies are mainly produced in allergic reactions, especially food allergies. IgG4 can block an IgE response and is found to be elevated in various allergic diseases. It increases to varying degrees with various immunotherapies (hyposensitization). It increases to varying degrees during various immunotherapies (hyposensitization) and allows statements to be made about the biological value of the measure carried out.

IgG4 and COVID-19: It has recently been shown that spike antigens can directly activate the complement system via its lectin and alternative pathway. The spike antigen occupied by complement degradation products such as C3b, iC3b, C3dg and C3d can bind B cells (expressing complement receptors such as CD21) more strongly. The missing link to IgG4-CSR (class switch reaction) may have been found when it was demonstrated that FDCs (follicular dendritic cells) in germinal centers produce local interleukin-7, leading T cells to prefer a class switch reaction over IgG4 (Jeannin P et al. 1998).

IgG4 production typically occurs during long-term antigen exposure, such as chronic parasitic infections or allergen immunotherapy (Aalberse RC et al. 2009).

Apparently, when the reservoir of FDC cells(follicular dendritic cells) is "saturated", the introduction of further antigens leads to a CSR (class switch reaction) and to IgG4. This is intended to prevent the formation of an excessive number of inflammatory antibodies such as IgG1 and IgG3. The presence or absence of IgG4 does not necessarily mean protection against infection or an excessive immune response (this is known from chronic parasitic infections and IgG4-associated diseases/Kadkhoda K 2023)

The so-called IgG4-associated diseases are rare, autoimmunologic (allergic?) multi-organ diseases affecting the pancreas, kidney, lung, lymph nodes, thyroid, liver, eyes, naso-pharynx and skin. Clinically, pseudotumorous swellings can be impressive.

IgG4 increased:

• Infections, multiple myeloma, lymphomas, malignancies, autoimmune diseases (see also immunoglobulins). High IgG4 concentration is an indication of an IgG4-associated autoimmune disease (e.g. IgG4-associated pancreatitis) in appropriate clinical settings.

IgG4 decreased:

• Primary immunodeficiencies; association with: atopic diseases, autoimmune diseases (SLE, Sjögren's syndrome, vasculitis), chronic active hepatitis, diabetes mellitus, nephrotic syndrome

Expensive and useless is the determination of IgG4 in food allergies. Such "screening tests" are used by various companies. Institutions offer such "screening tests". The high costs involved are justifiably not reimbursed by German health insurance companies (see the corresponding position papers of the professional associations).

1. Aalberse RC et al (2009) Immunoglobulin G4: an odd antibody. Clin Exp Allergy 39:469-477
2. Bookhout CE et al (2016) Immunoglobulin G4-Related Lymphadenopathy. Surg Pathol Clin 9:117-129.
3. Freiberger SN et al. (2016) IgG4 but no IgG1 antibody production after intralymphatic immunotherapy with recombinant MAT-Feld1 in human. Allergy doi: 10.1111/all.12946.

4. Jeannin P et al. (1998) Interleukin-7 (IL-7) enhances class switching to IgE and IgG4 in the presence of T cells via IL-9 and SCD23 Blood 91:1355-1361).

5. Kadkhoda K (2023) Post-COVID mRNA-vaccine IgG4 shift: worrisome? mSphere 8:e0008523).

6. Kollmann D et al. (2016) The quantity and quality of α-gal-specific antibodies differ in individuals with and without delayed red meat allergy. Allergy doi: 10.1111/all.12948.
7. Renz H et al. (2002) In vitro allergy diagnostics. Position paper of the German Society for Allergology and Clinical Immunology (DGAKI). Working group "In vitro allergy diagnostics" of the Immunology Section. Allergo J 11: 492-506
8. Stapel SO et al (2008) EAACI Task Force. Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report. Allergy 63: 793-796
9. Zeng G et al. (2016) Longitudinal profiles of serum specific IgE and IgG4 to Dermatophagoides pteronyssinus allergen and its major components during allergen immunotherapy in a cohort of southern Chinese children. Mol Immunol 74:1-9.

Age-adapted standard values for IGG4:

Age group (years) Value (mg/dl)

• 0 - 1 < 0.8 mg/dl
• 1 - 2 < 40.8 mg/dl
• 2 - 3 0.6 - 68.9 mg/dl
• 3 - 4 1.2 - 93.8 mg/dl
• 4 - 6 1.7 - 115.7 mg/dl
• 6 - 9 3.0 - 157.7 mg/dl
• 9 - 12 4.3 - 190.0 mg/dl
• 12 - 18 5.2 - 196.1 mg/dl
• 18 - 120 5.2 - 125.0 mg/dl