Background and Aims

Proteins in their native state have the hydrophobic amino acid sequences buried (e.g., within the core of their globular structure). Protein misfolding exposes hidden hydrophobic residues and makes proteins immunogenic. Misfolded proteins such as Abeta, Alpha-synuclein, etc. acumulate in neurodegenerative diseases. Antibodies, including the anti-tau antibodies, anti α-synuclein, anti-Aβ, etc., were repeatedly found in neurodegenerative diseases. In Alzheimer´s disease, new study has revealed that the number of plasma B cells producing anti-Aβ42 antibodies is significantly higher in AD patients when compared to healthy controls. Are neurodegenerative diseases autoimmune conditions in origin?

Methods

original article & review

Results

The structural homology in molecular mimicry has traditionally been related to the primary structure of proteins (i.e., amino acid sequence). A new concep, however, has emerged of molecular mimicry that include the secondary and tertiary structures of proteins. In conformational diseases nonself molecular patterns can be afforded by the tertiary and quaternary structures of misfolded proteins. A modified self that exhibits new hydrophobic patches can be recognized as non-self by the immune system. Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. The exposed hydrophobic portions in proteins serve as endogenous ligands for receptors such as Toll-like receptors (TLRs) and others, activating them. The TLR4 itself has a large hydrophobic región and a variety of apparently unrelated molecules that signal through TLR4 have in common important hydrophobic regions.

Conclusions

From: Butnaru D, Chapman J. “The impact of self-replicating proteins on inflammation, autoimmunity and neurodegeneration-An untraveled path”. Autoimmun Rev. 2019 Mar;18(3):231-240

https://www.ncbi.nlm.nih.gov/pubmed/30639644