The Influence Of Cigarette Smoke On The Effectors Of The Immune System

Cigarette smoke has been, and is, a major risk factor for lung carcinoma, cardiovascular disease and chronic obstructive lung disease (reviewed in ref. [9]. Although, the entire spectrum of effects of cigarette smoking on the immune system are not fully realized, it appears that smoking influences nearly any cellular component.

Growing evidence implicates immune mechanisms in the breakdown of the normal pulmonary architecture in smokers, with the subsequent replacement of the alveolar cells by connective tissue. The number of neutrophils present in the bronchial lavage fluid of smokers was claimed to be increased by some [10, 11], whereas, others failed to detect quantitative differences between smokers and nonsmokers [12, 13]. Recruitment of neutrophils mediates local adhesion molecule expression [14] and therefore induces chemotaxis of inflammatory cells to the airway mucosa [15], The effects of cigarette smoking is not limited to the number of the neutrophils or to their functional state but also to their physical properties. Accordingly, neutrophils have been shown to be sequestered in the lung capillaries [10, 16] due to reduced deformability [17, 18], This effect is probably exerted by oxidants (aldehydes, epoxides, peroxides, HO2O2 and O2-) present in cigarette smoke and could be ameliorated by prior use of antioxidants [18,19],

Alveolar macrophages from cigarette smokers exhibit reduced responsiveness towards lipopolysacharide (LPS) [20]. This observation was attributed to an inhibited production of TNF-a and IL-6 resulting in a hampered resistance towards foreign invading pathogens [20, 21]. Furthermore, cigarette smoking decreases the production of other cytokines such as IL-1 and IL-8 (observed only in some smokers) [21, 22], which are known to contribute to the pathogenesis of the inflammatory reaction.

Polyphenol rich glycoprotein (termed TGP) is isolated from cured tobacco leaves and is present in cigarette smoke condensate [23]. This protein stim ulates the proliferation of peripheral T lymphocytes in murine models and in humans [24]. TGP (in contrast to the classical T-cell mitogens PHA and con-A that provoke significant proliferation of the T cells) activates only approximately 3% of the T cells and therefore exerts an antigenic rather than a mitogenic effect [24], These effects of TGP, an inherent component of cigarette smoke may aid in understanding the link to autoimmunity which will later be explained.

Specific subpopulation of T cells are increased in cigarette smokers. Thus, yS T cells [25] are more common in bronchial the trees of smokers. They constitute a significant part of the inflammatory response in the bronchial glands of smokers and could represent an enhanced cellular response in these subjects.

TGP also contributes to activation of factor XII-dependent pathways [26] (with the subsequent generation of active serine proteases), and inhibition of the classical pathway of complement activation by binding to the rate limiting protein C2 [27].

TGP has been shown to stimulate the proliferation of B cells from the LPS nonresponders C3H\HeJ mice [28] and to induce the differentiation of B cells into IgM, IgG and IgA secreting cells.

The immune responses triggered following immunization with TGP in animals consists also of a predominant IgE response in mice [29], neonatal rabbits [30] and guinea pigs [31], An IgE mediated "wheal and flare" response has also been demonstrated in human volunteers injected intradermally with TGP, suggesting effects of smoking on the humoral immune system.

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