Pathophysiological Consequences of Protein N-Homocysteinylation - Homocysteine in Protein Structure/Function and Human Disease - page 108

responses. Phospholipid peroxidation generates reactive aldehydes, such as
malondialdehyde, 4-hydroxynonenal, and 1-palmitoyl-2-(5-oxovaleroyl)-sn-
glycero-3-phosphocholine that can modify lysine residues in LDL and in other
proteins. The resulting oxidized lipid-protein adducts, e.g., malondialdehyde-LDL,
carry neo-self epitopes, which are recognized by specific innate and adaptive
immune responses. That inflammation is important is supported by studies showing
that increased plasma concentration of markers of inflammation, such as C-reactive
protein (CRP), interleukin-1, serum amyloid A, and soluble adhesion molecules, is
an independent predictor of vascular events [377]. Autoantibodies against modified
LDL are elevated in vascular disease patients in some, but not all, studies [378]. As
discussed in the following paragraphs, accumulation of N-Hcy-protein in

hyperhomocysteinemia also leads to autoimmune responses.

6.2.2 N-Hcy-Protein Is Immunogenic in Rabbits

Details of the mechanism underlying the role of Hcy in adaptive immune response
are beginning to emerge. The modification by Hcy-thiolactone, like other chemical
modifications, such as glycation, acetylation, methylation, ethylation, and
carbamylation [376], renders LDL highly immunogenic [356]. Furthermore, immu-
nization of rabbits with Hcy-thiolactone-modified keyhole limpet hemocyanin
(KHL) leads to the generation of anti-N-Hcy-protein antibodies [172, 310]. Of
considerable interest are the observations that antisera from such immunizations
bind not only to the N-Hcy-KHL but also to a variety of other proteins on which the
N-linked Hcy epitope is present, such as N-Hcy-LDL, N-Hcy-albumin, N-Hcy-
hemoglobin, N-Hcy-transferrin, and N-Hcy-antitrypsin. These data suggest that
autoantibodies, once formed in vivo in response to N-Hcy-LDL or any other
N-Hcy-protein, would be capable of binding to other endogenous N-Hcy-proteins.

6.2.3 N-Hcy-Protein Is Autoimmunogenic in Humans

In humans, Hcy incorporation into proteins triggers an adaptive immune response,
manifested as the induction of IgG autoantibodies recognizing Nε -Hcy-Lys

epitopes on N-Hcy-proteins. These autoantibodies react with any N-Hcy-protein,
including N-Hcy-hemoglobin, N-Hcy-albumin, N-Hcy-transferrin, and N-Hcy-
antitrypsin [172]. The antigen specificity of the human anti-N-Hcy-protein
autoantibodies is essentially identical to the specificity of rabbit anti-N-Hcy-protein
antibodies generated by inoculations with N-Hcy-LDL [356] or N-Hcy-KLH [172,
310] (Fig. 6.2 ). Plasma levels of anti-N-Hcy-protein autoantibodies [135, 172, 173,
310] and protein N-linked Hcy [76, 79, 96, 139] vary considerably among
individuals and are strongly correlated with plasma Hcy (Fig. 6.3 ). In contrast,
the titers of anti-N-Hcy-protein autoantibodies are not correlated with plasma