Post-COVID mRNA-vaccine IgG4 shift: worrisome?

ABSTRACT COVID-19 vaccines play a key role in ending the pandemic. Unraveling the immunological phenomena involved in offering protective immunity is the cornerstone of achieving such success. This perspective evaluates the possible mechanisms and implications of IgG4 production in response to mRNA-based COVID-19 vaccines.

these B cells to undergo class-switch recombination (CSR) in GCs in an autocrine fashion (5).
Even months after vaccination, the key to retaining GC reaction seems to rely on the immune complex reservoir on the surface of FDCs as produced through the mechanisms mentioned earlier. Maintaining and replenishing FDC surface reservoir is much more efficiently accomplished when complement components opsonize the Ag. It has recently been shown that spike Ag can directly activate complement via its lectin and alternative pathways (6,7). Spike Ag, studded with complement degradation products such as C3b, iC3b, C3dg, and C3d, can more avidly bind B cells (that express complement receptors such as CD21). CSR requires activation-induced cytidine deaminase, which relies on CD21 (B cell) interaction with immune-complex bearing FDCs (8). The spatial organization of FDCs within the light zone of GCs is such that all FDC network captures and keep immune complexes. Still, the central, not the peripheral, FDCs function as long-term Ag reservoirs due to their higher expression of CD21 (9). The latter reservoir is replenished every time a booster is given, filling the memory B cell pool. The last requires rounds of "cyclic reentry" in the GCs, more somatic hypermutation, and CSR. The missing link to IgG4 CSR was possibly found when it was demonstrated that FDCs produced local interleukin-7 in GCs, which led T cells to favor CSR over IgG4 (10). IgG4 production typically occurs where there is long-term Ag exposure, such as in chronic parasitic infections or allergen immunotherapy (11)(12)(13)(14)(15) in the context of a conducive cytokine milieu, such as IL-4 and IL-10. It appears that when the FDC reservoir is "saturated" and memory cell frequency is adequate, introducing more Ag results in CSR to IgG4 to prevent making too many inflammatory antibodies, such as IgG1 and IgG3, both with efficient complement-fixing and FcR binding capabilities. Through Fab arm exchange and the so-called functional monovalency, IgG4 can block Ag surplus. So, the concern that mRNA-based vaccines trigger IgG4 after multiple boosters having implications for efficacy is not backed up by large-scale clinical trials; therefore, one cannot conclude that these vaccines are inferior to Ad-based ones merely due to a shift to IgG4. More importantly, it would be intuitive to speculate that class switching to IgG4 would happen where there is "enough" antigenic similarity between the incoming Ag and that of "complexed" on the surface of FDCs (from past exposures), obviating the need for undue rounds of cyclic reentry (original antigenic sin-like phenomenon). An emerging (sub)variant (be it from the virus or a vaccine), however, with relatively significant antigenic distance, would forgo IgG4 CSR and allow replenishing (reloading) of FDC surface repertoire and more efficient cyclic reentry leading at least to a reasonable cross-protection as expected to see from the boosters. This notion is further supported by lack of a large shift to IgG4 after repeated rounds of tetanus vaccination for whom no such antigenic variability is recognized (2). The shift to IgG4 also correlated with the overall observed increase in anti-spike IgG avidity, both strongly suggest repeated rounds of cyclic reentry (2).
At this evolutionary juncture, IgG4 is probably still figuring out its role in the immune response. The presence of IgG4, or lack thereof, does not necessarily insinuate protec tion from an infection or an exuberant immune response, a notion that is learned DCs at the injection site (macro)pinocytose the shed Ag, migrate to the regional draining lymph nodes and present to naïve T cells.
Lymph drainage Soluble Ag in interstitium enters lymph, then it is drained to the regional draining lymph nodes via afferent lymphatics. After entering the subscapular sinus, Ags reach the deeper parts of the lymph nodes, and again cognate B cells take them to GCs.
Perspective mSphere from chronic parasitic infections and IgG4-related diseases. Despite IgG4's high levels in certain circumstances, the clinical picture remains not significantly different than when levels are within normal limits, as it appears that IgG4 is a by-product of another ongoing process. Undoubtedly, more in-depth research would shed light on the role of this new evolutionary member of the immune response.