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Abstract
Among the four immunoglobulin G (IgG) subclasses, IgG4 is the least represented in serum of a healthy human and it is considered an “odd” antibody. The IgG4 antibody has unique structural features that affect its biological function. These include the ability to undergo antigen-binding fragment (Fab)-arm exchange, to create fragment crystallizable (Fc) – Fc binding with other IgG4 and other IgG subclass antibodies, have a unique affinity profile for Fc gamma receptors (FcγRs) and no binding to complement component C1q. Altogether, these characteristics support anti-inflammatory roles of IgG4 leading to immune tolerance. Under conditions of chronic antigenic stimulation and Th2-type inflammation, both tissue and serum IgG4 levels are increased. This review seeks to highlight how in allergen immunotherapy IgG4 can confer a protective role as a “blocking” antibody and safeguard from subsequent allergen exposure, while IgG4 can confer immunomodulatory functions to support malignancy. While Th2 conditions drive polarization of macrophages to the M2a subtype, chronic antigen stimulation drives B cell class switching to IgG4 to further support phenotypical macrophage changes towards an M2b-like state. M2b-like macrophages can secrete chemokine (C-C motif) ligand 1 (CCL1) and interleukin-10 (IL-10) to support regulatory cell recruitment and to further shape a tolerogenic microenvironment. Thereby, IgG4 have a Janus-faced role, favorable in allergy but detrimental in cancer.
Highlights
Since fragment crystallizable (Fc)–Fc binding may be possible with other immunoglobulin G (IgG) subclasses suggests that IgG4 can act as a scavenger to IgG molecules with impaired structural integrity [17]
The comparison between IgG4 and IgG1 subclass shows that the affinity of IgG4 for FcγRI is of the same order of magnitude as that of IgG1, while it is lower for FcγRIIa (Arg/His131) and FcγRIIIa (Phe/Val158) in comparison to that calculated for IgG1
Blocking mechanisms exploit all typical IgG4 characteristics: (1) high affinity to the allergen as a result of the affinity maturation process, thereby effectively trapping the allergen; (2) its ability for Fab arm exchange (FAE) resulting in bi-specific antibody that cannot be crosslinked ; (3) the lack of binding pro-inflammatory complement; (4) high affinity for the inhibitory FcγRIIb expressed on effector cells and antigen presenting cells (APCs) [37]; (5) inhibition of IgE-facilitated allergen presentation (IgE-FAP) by direct competition with the allergen binding to IgE-CD23 complexes high affinity [38]
Summary
The four human immunoglobulin (IgG) subclasses, defined IgG1, IgG2, IgG3, and IgG4 following their descending order of abundance, were discovered in the 1960s following extensive studies using specific rabbit antisera against human myeloma IgG proteins. Two identical heavy chains and two identical light chain subunits interconnected by intramolecular disulfide bonds form the IgG as heterotetrameric glycoproteins. There are only two types of light chains (κ or λ) with a size of about 25 kDa, and they are composed of a variable N-terminal domain (VL) and a constant domain (CL). The light and heavy chains join with the VL–VH and CL–CH1 domains to form two “Fab arms” that bind the antigen [2]. The region comprising the CH2 and CH3 domains is defined as fragment crystallizable (Fc). This region is responsible for the effector function, while the Fab binds antigens through the variable domains. A flexible hinge region, between the CH1 and CH2 domains, connects the Fab to the Fc region [3,4]
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