During aging, changes in proteins occur that alter their function and render them immunogenic.
These "neoantigens" are recognized by physiologic autoantibodies.
Physiologic autoantibodies and their corresponding antigens offer therapeutic strategies for disease intervention through the innate immune response.
Early studies done in the 1970s showed humans and animals to have physiologic antibodies that bind to a neoantigen called senescent cell antigen (SCA), which appears on senescent and damaged cells and initiates their removal by macrophages.
Generation of SCA results from oxidation.
This was determined in studies of erythrocytes from vitamin E–deficient rats.
These studies led to the discovery that oxidation can generate a new antigen in situ.
Oxidation accelerated aging of red cells, generated SCA and IgG binding, and triggered removal of red cells by macrophages.
Since then, a number of laboratories have found that oxidation can generate other neoantigens.
For example, oxidized LDL (OxLDL) induces antibodies that can modify the natural progression of atherosclerosis.
Apoptotic cells express oxidatively modified moieties on their surfaces that are involved in macrophage recognition and phagocytosis.
Physiologic autoantibodies were used to isolate SCA from brain tissue.
HPLC and fast atom bombardment ionization mass spectrometry (FAB-MS) of the isolated antigen suggested that the aging antigen is a subset of band 3, a family of proteins also called anion exchange proteins (AE1-3).
FAB-MS results indicate that residues matching all three band 3 isoforms (AE1, AE2, and AE3) are detected in aging antigen fractions.
Summary of cellular aging changes
- Decreased anion transport
- Decreased glucose transport
- Generation of "aged"
- Band 3 degradation
- Appearance of senescent cell antigen
- IgC binding
- Phagocytosis of cell
- Enzyme alterations
Molecular recognition of senescent cells involves oxidation of a crucial membrane protein leading to generation of a neoantigen and binding of physiologic autoantibodies.
These autoantibodies trigger macrophage removal of the cell prior to its lysis at a time when anion transport has decreased but the membrane is still grossly intact.
Autoantibodies such as this one contribute to the maintenance of homeostasis either by performing regulatory functions like cellular removal and/or protective ones such as removal of antigen or cells before they cause a problem either by disintegration or the evoking of a potentially damaging immune response.
The physiologic autoantibody response to neoantigens generated by oxidation is a protective one.
SCA offers the potential for the development of specific interventions in aging by targeting the regions of band 3 that are affected.
It also offers the possibility of treating other proteins that are damaged during aging since they are probably similarly affected.
SCA epitopes and SCIgG also have the potential for altering the natural progression of diseases.
Manipulation of the natural immune response to SCA would be expected to prevent or alter the course of certain diseases.