If you have been following my posts, you know that for the better part of the past year I have been focused on the observation that COVID-19 and its sequelae look VERY MUCH like Graft vs Host disease. We see identical endothelial/multisystemic destruction in both COVID-19 and GvHD.

However, as you know, I have been working to find  the mechanism for this parallel.

I believe I can now explain why COVID-19 and GvHD are intimately related. In both diseases, the body deposits c3 complement (and most likely other immune complexes/antibodies) into the endothelium. Except, in the case of COVID-19, the “Graft” and the “Host” are virtually synonymous as the “reaction” is replicated sans transplant.

This progressive deposition of IgM, IgG, C3, and prominent infiltration of cytotoxic T cells and macrophages, with a small number of NK cells is behind the progressive destruction of the MICROVASCULATURE. It also leads to the  Thrombotic Microangiopathy we are observing and may contribute to the deaths of healthy young people throughout the world.

Another major contributing factor is the induction of AT1 Receptor Antibodies. It is suggested that AT1-receptor antibodies have similarities to anti–endothelial-cell antibodies since endothelial cells have one AT1 receptor, and AT1-receptor antibodies induced phosphorylation of ERK 1/2 in endothelial cells. It is further suggested that binding of AT1-receptor antibodies to the AT1 receptor is a critical step for activating the downstream signaling cascade, mimicking the action of angiotensin II and inducing damage to the allograft. Emerging information has established that angiotensin II acts as an inflammatory cytokine participating in various vascular disorders.

In conclusion, at the heart of both diseases is the induction of multiple autoantibodies. In GvHD the body rejects a foreign substance with immense molecular mimicry. In COVID-19 the body rejects a foreign substance with immense molecular mimicry.

Referenced/Related Papers

Angiotensin II Type 1–Receptor Activating Antibodies in Renal-Allograft Rejection

https://www.nejm.org/doi/full/10.1056/NEJMoa035717

Acute Humoral Xenograft Rejection: Destruction of the Microvascular Capillary Endothelium in Pig-to-Nonhuman Primate Renal Grafts

https://www.nature.com/articles/3780086

Deposition of IgM and complement at the dermoepidermal junction in acute and chronic cutaneous graft-vs-host disease in man

https://pubmed.ncbi.nlm.nih.gov/26718/

Non-HLA agonistic anti-angiotensin II type 1 receptor antibodies induce a distinctive phenotype of antibody-mediated rejection in kidney transplant recipients

https://www.kidney-international.org/article/S0085-2538(19)30173-5/fulltext

COVID-19 Severity Is Associated with Differential Antibody Fc-Mediated Innate Immune Functions

https://journals.asm.org/doi/10.1128/mBio.00281-21

Angiotensin II receptor I auto-antibodies following SARS-CoV-2 infection

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259902