Pathophysiological Consequences of Protein N-Homocysteinylation - Homocysteine in Protein Structure/Function and Human Disease - page 111

patients and in controls, consistent with the etiology of these autoantibodies.
Furthermore, a subgroup of hemodialysis patients who survived myocardial infarc-
tion (n ¼ 14) had significantly higher levels of anti-N-Hcy-protein IgG

autoantibodies than a subgroup of hemodialysis patients without a history of
CAD (n ¼

29) [379]. Taken together, these data suggest that an autoimmune
response against N-Hcy-proteins contributes to the development of CAD in hemo-
dialysis patients.
In general, antibodies protect against exogenous pathogens and endogenous
altered neo-self molecules to maintain homeostasis by neutralization and clearance.
Similar to other autoantibodies [376], the anti-N-Hcy-protein autoantibodies can be
beneficial or deleterious. For example, the clearing of N-Hcy-protein from the
circulation by anti-N-Hcy-protein autoantibodies would be beneficial. On the
other hand, binding of the autoantibodies to N-Hcy-protein [134, 172, 310] in
tissues may contribute to the deleterious effects of hyperhomocysteinemia on
many organs [20, 29, 30]. For instance, if the neo-self Nε -Hcy-Lys epitopes were

present on endothelial cell membrane proteins, anti-N-Hcy-protein autoantibodies
would form antigen-antibody complexes on the surface of the vascular wall.
Endothelial cells coated with anti-N-Hcy-protein autoantibodies would be taken
up by the macrophage via the Fc receptor, resulting in injury to the vascular surface.
Under chronic exposures to elevated Hcy, the neo-self epitopes Nε -Hcy-Lys, which

initiate the injury, are formed continuously, and the repeating attempts to repair the
damaged vascular wall would lead to an atherosclerotic lesion [69, 134].
The involvement of an autoimmune response in CAD is further supported by
findings showing that lowering plasma tHcy by folic acid supplementation for 3 and
6 months lowers anti-N-Hcy-protein autoantibodies levels in control subjects but
not in patients with CAD [173]. These findings show that lowering plasma tHcy
normalizes anti-N-Hcy-protein IgG autoantibody levels within 3 months, but only
in healthy subjects. Plasma tHcy, Hcy-thiolactone, and N-Hcy-protein levels are
also reversibly modified by the diet in mice [113]. These findings suggest that while
primary Hcy-lowering intervention by B-vitamin supplementation is beneficial,
secondary intervention may be ineffective and may explain at least in part the
failure of B-vitamin therapy [51, 52] to lower cardiovascular events in myocardial
infarction patients.

6.3 N-Hcy-Protein and Innate Immune Responses

Innate immune responses play an important role in etiology of thrombosis and
atherosclerosis [374-376]. These responses are mediated by cytokines and
chemokines produced by multiple cell types. Proinflammatory cytokines are typi-
cally produced in response to the injury (inflammation) and subsequently induce a
variety of target cell to release further cytokines and chemokines in order to
mobilize the innate system to promote reparative processes that involve recruitment
of circulating leukocytes to the injury site. While acute induction is protective, the