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『JANEWAY’S 免疫生物学』

 

◆Class switch toward noninflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination【Science Immunology　2022年12月22日】

Anti-spike IgG4 rises from obscurity

The four human IgG subclasses have distinct effector properties due to differences in binding Fc receptors and activating complement. The serum concentration of human IgG4 is normally lower than either IgG1, IgG2, or IgG3. Irrgang et al. did a longitudinal analysis of the level of spike-specific antibodies from each IgG subclass in recipients of the SARS-CoV-2 BNT162b2 mRNA vaccine. Anti-spike IgG4 as a fraction of total anti-spike IgG rose by 6 months after the second vaccination and increased further after a third vaccine dose. Serum antibody effector activity assessed by antibody-dependent phagocytosis or complement deposition was less after the third dose than after the second dose. Further studies are needed to determine how emergence of an IgG4 anti-spike response influences vaccine-induced protection from SARS-CoV-2 infection. —IRW

Abstract

RNA vaccines are efficient preventive measures to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. High levels of neutralizing SARS-CoV-2 antibodies are an important component of vaccine-induced immunity. Shortly after the initial two mRNA vaccine doses, the immunoglobulin G (IgG) response mainly consists of the proinflammatory subclasses IgG1 and IgG3. Here, we report that several months after the second vaccination, SARS-CoV-2–specific antibodies were increasingly composed of noninflammatory IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough infections. IgG4 antibodies among all spike-specific IgG antibodies rose, on average, from 0.04% shortly after the second vaccination to 19.27% late after the third vaccination. This induction of IgG4 antibodies was not observed after homologous or heterologous SARS-CoV-2 vaccination with adenoviral vectors. Single-cell sequencing and flow cytometry revealed substantial frequencies of IgG4-switched B cells within the spike-binding memory B cell population [median of 14.4%; interquartile range (IQR) of 6.7 to 18.1%] compared with the overall memory B cell repertoire (median of 1.3%; IQR of 0.9 to 2.2%) after three immunizations. This class switch was associated with a reduced capacity of the spike-specific antibodies to mediate antibody-dependent cellular phagocytosis and complement deposition. Because Fc-mediated effector functions are critical for antiviral immunity, these findings may have consequences for the choice and timing of vaccination regimens using mRNA vaccines, including future booster immunizations against SARS-CoV-2.

 

◆The Role of IgG4 in the Fine Tuning of Tolerance inIgE-Mediated Allergy and Cancer【ResearchGate　2020年7月16日】

Abstract:

Among the four immunoglobulin G (IgG) subclasses, IgG4 is the least represented in serumof a healthy human and it is considered an “odd” antibody. The IgG4 antibody has unique structuralfeatures that affect its biological function. These include the ability to undergo antigen-bindingfragment (Fab)-arm exchange, to create fragment crystallizable (Fc) – Fc binding with other IgG4 andother IgG subclass antibodies, have a unique affinity profile for Fc gamma receptors (FcγRs) and nobinding to complement component C1q. Altogether, these characteristics support anti-inflammatoryroles of IgG4 leading to immune tolerance. Under conditions of chronic antigenic stimulation andTh2-type inflammation, both tissue and serum IgG4 levels are increased. This review seeks to highlighthow in allergen immunotherapy IgG4 can confer a protective role as a “blocking” antibody andsafeguard from subsequent allergen exposure, while IgG4 can confer immunomodulatory functionsto 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 phenotypicalmacrophage changes towards an M2b-like state. M2b-like macrophages can secrete chemokine (C-Cmotif) ligand 1 (CCL1) and interleukin-10 (IL-10) to support regulatory cell recruitment and to furthershape a tolerogenic microenvironment. Thereby, IgG4 have a Janus-faced role, favorable in allergybut detrimental in cancer.