Under certain conditions, some soluble endogenous proteins can form ordered oligomeric structures leading to the assembly of stable insoluble amyloids, a process that increases with age. The presence of such structures is associated with cellular toxicity and diseases development, e.g. Alzheimer disease, type II diabetes. Recent studies clearly show that the primary toxic species in such pathologies is the soluble oligomers of proteins, precursors of amyloids. Yet, it is unknown if such aberrant forms of proteins would elicit any immune reaction. Here we obtained oligomers derived from several human endogenous proteins and characterized their biochemical and immunological functions. The oligomeric proteins preferentially bind to both DNA and RNA and can be effectively internalized by cells. Surprisingly, the soluble protein oligomers enable prominent IFNα production by PBMCs to self-DNA, self-RNA and necrotic cell debris in a pDC-dependent manner. Consistently, peptides from amyloid β and prion protein, two known etiological agents associated with amyloid diseases, display similar innate immune functions by complexing with nucleic acids and inducing IFN production by pDCs. Therefore, oligomers of endogenous proteins formed during the aging process may strongly promote the host’s type I IFN response to self-nucleic acids, a reaction likely favoring the development of autoimmunity, such as SLE where strong type I IFN presence correlates with disease pathology.
- Copyright © 2011 by The American Association of Immunologists, Inc.