Wolfgang Miesbach: How a Single Mutation Can Flip Immunity into VITT
Wolfgang Miesbach, Professor of Medicine at Frankfurt University Hospital, shared a post on LinkedIn, about a recent article by Jing Jing Wang et al, published in The New England Journal of Medicine։
”How a single mutation can flip a normal anti‑adenovirus response into a rare autoimmune clotting syndrome.
New NEJM paper on VITT after adenoviral COVID‑19 vaccines:
Genetics + somatic ‘hit’
Using antibody proteomics and germline sequencing in 100 VITT patients, the authors show that essentially all pathogenic anti‑PF4 antibodies come from B cells with the light‑chain allele IGLV3‑21*02/*03 and a stereotyped mutation at position 31 (lysine → glutamic acid, K31E) in the light‑chain CDR1. This charge flip, together with acidic motifs in LCDR2 (DDSD) and HCDR3 (ED), creates a strongly negatively charged paratope that binds tightly to positively charged PF4.
The adenoviral trigger
They identify molecular mimicry between PF4 and a highly basic epitope on adenoviral core protein VII (pVII). Only pVII‑purified antibodies carried the “VITT fingerprint”, and recombinant VITT antibodies bound both PF4 and this pVII peptide. When K31E was back‑mutated to germline K31, binding shifted back to pVII, PF4 binding dropped, and thrombosis in a human PF4/FcγRIIa mouse model was almost abolished.
Mechanistic model and implications
In IGLV3‑21*02/*03 carriers, prior adenovirus exposure seeds anti‑pVII memory B cells; on re‑exposure (ChAdOx1‑S, Ad26.COV2.S, or natural infection), rare clones acquire K31E, switch specificity from pVII to PF4, expand mono/oligoclonally, and produce high‑avidity anti‑PF4 IgG that form platelet‑activating PF4–IgG immune complexes.
This nicely explains: rapid ‘secondary’ onset (from day 5), stereotyped antibodies, and restriction to adenoviral vectors.
For future adenoviral platforms: engineer or replace pVII to remove this mimicking epitope, preserving vector function while further reducing an already extremely rare VITT risk — and providing a roadmap for dissecting other boosted autoimmune complications.”
Title: Adenoviral Inciting Antigen and Somatic Hypermutation in VITT
Authors: Jing Jing Wang, Linda Schönborn, Theodore E. Warkentin, Luisa Müller, Thomas Thiele, Lena Ulm, Uwe Völker, Andreas Greinacher
Read the Full Article on The New England Journal of Medicine․
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