MHC molecules in health and disease: At the cusp of a paradigm shift

Area of Science:

• Immunogenetics
• Molecular Biology
• Evolutionary Biology

Background:

• The functional roles of the major histocompatibility complex (MHC) in health and disease are not well understood despite its discovery 50 years ago.
• Existing paradigms fail to explain MHC's evolution, structure-function properties, and allele-specific disease associations.
• A deeper understanding of MHC-health/disease associations is crucial, impacting millions of lives.

Purpose of the Study:

• To propose a novel, testable theory explaining the functional role of MHC molecules in health and disease.
• To investigate the significance of a conserved structural feature within MHC molecules.

Main Methods:

• Analysis of structural, functional, and evolutionary data of MHC molecules.
• Consideration of recent experimental findings.
• Focus on a specific conserved structural prominence ('kink') within MHC molecules.

Main Results:

• Identification of an evolutionarily-conserved, tri-dimensional cusp-like prominence ('kink') in MHC molecules.
• The MHC cusp region is proposed to be rich in allele-specific signal transduction ligands.
• These ligands interact with non-MHC cell surface receptors, initiating signaling events.

Conclusions:

• The MHC cusp region plays a critical role in signal transduction pathways.
• Aberrations in these MHC-mediated signaling pathways may contribute to disease development or severity.
• This new theory offers a potential framework for understanding MHC-health/disease associations.