mRNA vaccine-induced IgG4 class switch: What it means for cancer and IgG4-related diseases


A recent study, published in the prestigious journal Science Immunology, has sparked a lot of debate on the efficacy and safety of repeated mRNA vaccinations, especially regarding a set of autoimmune diseases known as IgG4-related diseases (IgG4RD) and cancer.

In brief, the study found that IgG (synonymous with antibody) class switch to IgG4 occurs after the second and third mRNA vaccine (Pfizer) doses, but not with AstraZeneca DNA vaccine, as I previously covered on Newsbreak here. (IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4, of which IgG4 is the least abundant and least effective in mediating antibody-dependent functions).

But importantly, the IgG4 class switch only occurs to anti-spike IgG, where anti-spike IgG4-expressing memory B cells constitute up to 37% of all IgG subclasses. This number is only 1–8% for IgG4-expressing memory B cells that are not anti-spike. (B cells are antibody-producing cells, and memory cells are responsible for the formation of long-term immunity.)

The anti-vaccine community claims that IgG4-related diseases (IgG4RD) will occur after mRNA vaccines based on Irrgang et al.’s findings. In IgG4RD, IgG4 antibodies infiltrate various organs, for unclear reasons, resulting in autoimmunity. Examples of IgG4RD include autoimmune pancreatitis, Riedel thyroiditis, and interstitial pneumonitis, among others.

But the logic that vaccines increasing IgG4 will lead to IgG4RD is flawed, as popular pro-vaccine voices on Twitter have also pointed out. For example, Edward Nirenberg and Sabina Vohra-Miller have written threads arguing that IgG4RD is caused by abnormal B-cell and T-cell responses, and IgG4 may actually be a control or protective mechanism against IgG4RD.

Also, by the same logic, beekeepers and allergic individuals on immunotherapy with dominant IgG4 response will suffer from IgG4RD.* By the same logic, vaccines that increase T-cell responses (for immunity formation) will also lead to T-cell-mediated autoimmune diseases.

* IgG4 is known to promote anti-inflammatory activities. For example, beekeepers have increased IgG4 antibodies against bee venom, thus preventing chronic inflammation from repeated antigen (i.e., bee venom) exposure from bee stings. Immunotherapy for allergies also induces IgG4 class switch, so that symptoms don’t flare when exposed to the antigen (i.e., allergen).

That said, there were four hits in the PubMed database when I entered the relevant keywords. But only three of those were relevant, which are all case reports.

  • Patel et al. describe a 63-year-old man who developed IgG4-related autoimmune pancreatitis 2 months after the 2nd mRNA vaccine dose.
  • Tasnim et al. detail a 71-year-old man who got two doses of mRNA vaccine and developed IgG4-related lung disease two weeks later.
  • Masset et al. describe a 66-year-old man whose IgG4-related nephritis relapsed two weeks after getting the mRNA vaccine.

But such temporal (time) association does not prove causation, for it could also be a coincidence, unless larger cohort studies support it.

More importantly, the timeframe doesn't match. Irrgang et al. showed that the IgG4 class switch only occurs at least 3 months after the 2nd mRNA vaccine dose. But those case reports reported the development of IgG4RD within weeks or 2 months of mRNA vaccination.

Another argument the anti-vaccine community raised is that the IgG4 class switch from mRNA vaccines could cause cancer recurrence. Because antibody-dependent phagocytic activities are needed for removing foreign cells like virus-infected or cancerous cells, the IgG4 class switch that weakens this activity may allow cancerous cells to proliferate.

This argument is convincing as it’s acknowledged as a potential concern in the scientific literature. As Crescioli et al. stated in a 2016 review of research, “Reports of IgG4 antibodies and IgG4+ B cells in different cancers suggest the involvement of IgG4 in tumor escape from immune surveillance through a number of potential mechanisms, including IgG4 blockade of IgG1-mediated effector functions.” (Figure 1).
Photo byCrescioli et al. (2016).
Figure 1. Mechanisms of IgG4 blockage in cancer. Left: tumor suppression where IgG1-mediated responses such as ADCP (antibody-dependent cellular phagocytosis) are working properly to suppress cancer. Right: tumor progression where IgG4 is blocking IgG1’s ability to suppress cancer.

But this mRNA vaccine-IgG4-cancer argument has one critical flaw. It conveniently ignores the antibody-antigen specificity concept, where an antibody only has a receptor specific to one antigen.

So, anti-spike IgG (synonymous with antibody) has a receptor that only binds to the spike protein and thus neutralizes it. Anti-spike IgG won’t and can’t do anything to cancer cells because they don’t have the receptor for a specific antigen of cancer cells. And Irrgang et al. found that the IgG4 class switch only happened to anti-spike IgG, not IgG in general.

The same counterargument also applies to IgG4RD, where IgG4 antibodies dominated the other IgG subclasses. But again, Irrgang et al. only showed an increase in anti-spike IgG4, which is just a small fraction of total IgG4 or IgG in general — whom Mobeen Syed, MD, MS, a medical communicator and educator, has also pointed out.

In other words, the rise in anti-spike IgG4 Irrgang et al. found did not rise to sufficiently high levels that it began to trigger IgG4RD; else, we would see some incidence of IgG4RD (or cancer) within the study itself.

So, anti-vaxxers will reason that the IgG4 class switch after repeated mRNA vaccination (Irrgang et al.) will cause IgG4RD (Patel et al., Tasnim et al., and Masset et al.) and cancer (Crescioli et al.), without telling you that the IgG4 class switch only applies to anti-spike IgG, not all IgG.

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MSc Biology | 8x first-author academic papers | 280+ articles on coronavirus | Independent science writer


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