Biomedical Engineering Reference
In-Depth Information
Oxidative modification of proteins has been implicated in the immune
mechanism of various diseases like rheumatoid arthritis, multiple sclerosis,
autoimmune antiphospholipid antibody syndrome, diabetes mellitus (42,43),
and, lately, arteriosclerosis, in which epitopes generated in the process of
atherogenesis, such as those produced by the oxidation of low-density lipo-
proteins, have been implicated as targets of autoimmunity (44,45). This is, to
date, the most clear and unexpected example of how modified self-proteins
can become antigenic and produce disease, a common disease.
Other external and xenobiotic agents have been implicated in the mod-
ification of self-proteins to be recognized as antigenic material. Importantly,
xenobiotics, of which cigarette smoke is abundant, can interact with self-
proteins and generate immunogenic determinants through various mechan-
isms, including covalent binding or noncovalent modifications (43). Induc-
tion of organ-specific autoimmune disease following tissue inflammation,
and
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or trauma has been frequently reported and likely occurs via tissue
damage that results in the availability of previously isolated antigens, as is
the case in ophthalmia following eye injury (46) or orchiditis following
vasectomy (42). Infections with tissue tropic pathogens such as viruses
may induce a similar autoimmune phenomenon, and also provide abundant
cytokines and costimulatory molecules, the additional stimulus important in
the perpetration of the immune response. This is exemplified in rodents and
humans who develop diabetes after infection with Coxsackie B viruses and
rheumatic fever after streptococcal infections (42,47).
Cigarette smoke could easily follow the same mechanisms. The tissue
injury and potential modification of self-proteins could generate antigens
and the associated innate immune inflammation associated with smoking
could provide the necessary soluble mediators and co-stimulatory molecules
for the initiation and perpetration of an adaptive immune response. It is
important to recognize that in a disease like COPD, in which multiple
mechanisms could induce different antigens (e.g., release of cryptic antigens,
modified proteins, necrotic cells, apoptotic cells, etc.), more than one anti-
gen could be involved in the generation of an immune response, and more
than one might be responsible for the T-cell activation. This phenomenon
has been described in insulin-dependent diabetes, where large numbers of
autoantibodies and autoantigens have been found (48).
Besides the breakdown of elastin and collagen, cell injury mediated by
proteinases could also be a source of antigenic material. Cellular survival
seems to depend on signals from the integrin family of adhesion receptors
continuously sensing the extracellular milieu (49,50), and a major signal
for cellular apoptosis is loss of extracellular matrix contact that can be
induced by proteases (51). Therefore, it is likely that lung injury in cigarette
smokers involves apoptosis and
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or necrosis of cells in the alveolar wall
(epithelial and endothelial) following focal proteolytic damage to their
underlying matrix (apoptosis) or directly to the cells themselves (necrosis)
