The presence of the TTR V30M variant affects the expression of members of the S100 family of calcium-binding proteins, thus likely contributing to the impaired immune response in patients with hereditary transthyretin amyloidosis (hATTR), according to a study published in Amyloid.
The study was conducted by a research team from Portugal who found decreased levels of S100A8 (also known as calgranulin A or myeloid-related protein 8) in plasma samples from patients with hATTR harboring the TTR V30M variant when compared with those of control subjects.
Human TTR V30M failed to trigger the expression of S100A8 and S100A9 (also known as calgranulin B or myeloid-related protein 14) in Schwann cells from transgenic hATTR-V30M mice.
Moreover, the expression of S100A8 upon stimulation of bone marrow-derived macrophages with a toll-like receptor (TLR) 2 or 4 agonist was lower in hATTR-V30M mice than in wild-type mice. These results suggest that macrophages derived from TTR V30M mice might have a compromised response to TLR2 and TLR4 stimulation.
Read more about hATTR genetics
“These findings implicate variant TTR microenvironments with limited innate responses which in turn likely hamper immune cell recruitment to the site of disease. It will be of importance and interest to in the future continue to investigate which reprogramming alterations occur in different cells and how mutated TTR promotes them,” the authors wrote.
In addition, the study found decreased levels of S100A8 and S100A9 in hATTR-V30M mice compared with control mice.
The levels of S100A8 were similar between healthy controls and asymptomatic carriers.
The authors analyzed human plasma samples from 10 patients with hATTR harboring the TTR V30M variant, 10 asymptomatic carriers, and 10 control subjects.
The hATTR-V30M mouse model used in the study carries the V30M variant in a heterozygous background for heat shock factor 1 and deposits transthyretin nonfibrillar constituents in the peripheral nervous system.
Reference
Moreira J, Martins S, Saraiva M, Saraiva MJ. Decreased expression of S100A8/A9 in V30M related ATTRv amyloidosis. Amyloid. Published online March 22, 2023. doi:10.1080/13506129.2023.2185755
