Biomedical Engineering Reference
In-Depth Information
and consequent production of antigenic molecules that would reach the DC
by the mechanisms reviewed before. However, not all smokers seem to react
to these antigens and develop the disease, and even when disease develops
the severity varies for the same amount of smoking. A careful review of
the published data on inflammatory cell infiltration in the lung shows a large
variability in the number of T-cells and other inflammatory cells in smokers'
lungs, probably accounting for the variable degree of lung damage. Possible
reasons for these differences could be that the T-cell repertoire of those
patients who develop COPD includes autoreactive clones that have escaped
thymic deletion to some lung proteins not expressed in the thymus (not all
proteins are), or that a break in immunological tolerance has occurred.
Tolerance, the ''immunologist's Holy Grail'' (197), is a poorly under-
stood, ever changing, and continuously evolving concept, comprising central
and peripheral tolerance. In today's concept of central tolerance, immature
T-cells randomly rearrange their TCR genes and proliferate at high rates,
eventually migrating to the medulla of the thymus, where they are exposed
to autoantigens in the presence of self-MHC molecules. Those cells with
very low or very high affinity to self-antigens undergo negative selection
succumbing to apoptosis. However, cells with receptors with intermediate
affinity to such complexes undergo a positive selection and migrate to the
periphery (10,200).
Today's paradigm is that a low level of autoreactivity (i.e., reactivity to
self-antigens) is physiologic (201), that autoantigens help to form the reper-
toire of mature lymphocytes, and that the survival of na¨ve T-cells in the
periphery requires continuous exposure to autoantigens (202). Thus, the
lymphocyte evolved not to distinguish itself from a foreign substance, as
it was believed, but to respond to antigen only in certain microenvironments
(203). As autoreactivity is physiological, the challenge is to understand how
it becomes a pathological process.
One important point that has emerged in the studies of tolerance is
that tolerance is not an all or nothing phenomenon—various degrees of
tolerance, thus disease can occur (204). If COPD was due to different
degrees of failure in tolerance to self or modified self-antigens, it could
explain the variable responses of the lung to cigarette exposure, the variabil-
ity in the number of T-cells in the lungs of smokers, the wide range of FEV
1
found in smokers and the correlation found between the level of FEV
1
and
extent of emphysema with the number of T-cells in the airways and lung
parenchyma (7,88).
The emphasis of immunological tolerance has recently switched from
central to peripheral, and the interactions of T-cells with DCs might be the
most important factor in determining peripheral tolerance (205). Antigen
stimulation can lead to divergent T-cell responses that range from the dele-
tion of antigen-specific lymphocytes and tolerance to the generation of a
large number of effector cells followed by establishment of immunological
