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.