Posttranslationally modified self-peptides promote hypertension in mouse models

Area of Science:

• Immunology
• Cardiovascular Research
• Biochemistry

Background:

• Posttranslational modifications can increase self-protein immunogenicity.
• Isolevuglandins (IsoLGs), products of lipid peroxidation, bind to proteins in conditions like hypertension.

Purpose of the Study:

• To investigate the role of IsoLG-modified peptides in hypertension.
• To identify structural features enabling Major Histocompatibility Complex class I (MHC-I) presentation of IsoLG-adducted peptides.

Main Methods:

• Utilized a computational pipeline to identify MHC-I binding features for modified peptides.
• Identified IsoLG-adducted peptides from renal proteins in hypertensive mice.
• Assessed CD8+ T cell recognition and proliferation in response to these peptides.
• Investigated antigen restriction patterns in human leukocyte antigens (HLAs).

Main Results:

• The murine MHC-I variant H-2Db uniquely presents IsoLG-modified peptides.
• Identified specific IsoLG-adducted renal protein peptides recognized by CD8+ T cells.
• These peptides induced T cell proliferation and primed hypertension upon adoptive transfer.
• Found similarities in IsoLG-adducted antigen restriction between murine and human MHC-I molecules.

Conclusions:

• IsoLG-adducted peptides from renal proteins are likely antigens in hypertension.
• These peptides are recognized by CD8+ T cells and contribute to hypertension pathogenesis.
• The findings provide a basis for understanding IsoLG-mediated immune responses in hypertensive disease.