4.1. Smoking and Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic degenerative joint disease known to be of an autoimmune nature. Heliovaara et al.  investigate the association of cigarette smoking with the incidence of rheumatoid arthritis (either seropositive or seronegative) in a cohort of adult Finns. The study engaged 24,445 woman and 28,364 men, followed consecutively from 1966 to 1989. Five hundred and twelve subjects were found at some time to develop RA, 119 of whom were men and 229 were seropositive. A close association was found between smoking and seropositive RA. It was evident that the relative risk for developing seropositive RA was 2.6 in male ex-smokers and 3.8 in current smokers, compared to men who never smoked.
In a recent paper by Silman et al. , the susceptibility to RA was evaluated by interview questionnaires on the smoking history among 71 monozygotic and 79 dizygotic twin-pairs discordant for RA. The authors found that a strong association existed between smoking history and the incidence of RA in monozygotic twin-pairs (odds ration 12.0, 95% confidence interval 1.78-513), most of whom were concordant for RA and discordant for smoking. Similar trend was obtained with dizygotic twin- pairs (odds ratio 2.5, 95% confi dence interval 0.92- 7.87). This study provided further support for the assumption that smoking predisposes individuals with similar genetic susceptibility to RA to develop a clinically overt disease.
In an additional study conducted by Symmons et al.  in the UK, the authors sought to examine the clinical risk factors for the development of RA, employing a population-based case control patients aged 18-70 years old. The results indicated that smoking obesity and blood transfusions were important environmental triggers for RA.
Data presented in an additional paper  provided further support for the association of smoking with RA. The authors performed clinical evaluation of 857 subjects and found that smokers with RA were 3.1 times more likely to exhibit rheumatoid factor seropositivity, and 2.4 more likely to have radiographic erosions.
Although the association between smoking and RA can still not be explain it is possible that a nonspecific activation of the immune system (a state of polyclonal activation). Thus, IgM rheumatoid factor constitutes only a part of a heterogeneous set of antibodies generated by the immune system in response to cigarette smoking. This effect resembles "nonspecific" polyclonal activation induced following exposure to bacterial LPS.
4.2. Smoking and Goodpasture's Syndrome
Goodpasture's syndrome is defined by the combination of hemoptysis and glomerulonephritis. This clinical picture is observed in 75% of the patients harboring antibodies to glomerular basement membrane (GBM) , Anti-GBM antibodies are thought to be actively involved in the generation of pulmonary lesions due to the presence of linear deposits of IgG and complement in the alveolar septa of the affected lungs [39, 40]. The "Goodpasture's antigen" towards which anti-GBM antibodies form has been found to reside in the a3 chain of type IV collagen , The corresponding epitope has also been characterized and located within the globular noncollageneous (NCI) domain of the a3 chain . Recently, it was further sublocalized to the last 36 amino acid residues of its carboxyl terminus.
Donaghy et al.  investigated the association of cigarette smoking with pulmonary hemorrhage in these patients. Among 51 patients examined, 43 had lung hemorrhage. Forty-seven patients were either current or previous smokers, 37 smokers were found to suffer from subsequent pulmonary hemorrhage, compared to only 2 out of 11 nonsmokers. No significant difference was evident between the titers of circulating anti-GBM antibodies in smokers and nonsmokers. Moreover, in one patient, resumption of smoking was closely followed by reappearance of lung hemorrhage.
It seems probable that pulmonary bleeding is enhanced by smoking regardless of the absolute titers of anti-GBM antibodies. It may be speculated that the mechanical damage precipitated by cigarette smoke results in exposure of the previously concealed anti-gen/s that could simultaneously induce the production of autoantibodies and allow for the binding of those already present in the circulation. Both effects could result in progression an immune mediated damage (by mechanisms such as complement activation) resulting in pulmonary hemorrhage.
Ophthalmopathy occurs in 25-50% of the patients with Graves' disease and its disfiguring propreties may result in complete blindness , The pathogenesis of this yet unpreventable condition is uncertain to date. However, several points regarding its interplay with the immune system deserve emphasis.
The involvement of the humoral immunity in Graves' ophthalmopathy has been recognized by the findings of antibodies to crude preparations of eye muscle and orbital connective tissue . The autoantigen to which the antibodies bind has been characterized as a 64 kD extraocular muscle protein .
Evidence for the participation of cellular immunity in the pathogenesis of Graves' ophthalmopathy is the increased serum concentrations of soluble IL-2 receptors marking a T-cell activation , Furthermore, endomysial fibroblasts found in the fatty connective tissue of the orbits express HLA-DR molecules (involved in antigen recognition by T cells) as well as intracellular adhesion molecules 1 (ICAM-1) .
The 72 kD heat shock protein is known to induce cellular proliferation and confer protection from stressful stimuli , Indeed, its expression on the cell surface was detected in cultured orbital fibroblasts from patients with severe Graves' ophthalmoathy , however, since it is a stress protein it cannot be determined with certainty whether it represents a reaction to the local pressure (i.e., an epiphenomenon) or plays a causal role.
It has been proposed  that circulating T cells directed against an antigen on thyroid follicular cells, enter the orbit and interact with fibroblasts leading to the production of cytokines. The cytokines are thought to enhance the expression of immunoregulatory proteins such as the 72 kD heat shock protein, ICAM-1 and HLA-DR, to further maintain the ongoing autoimmune process. Additionally, several cytokines (i.e., TGF-/3, IFN-y and insulin-like growth factor I) induce production of glycosaminoglycan leading to the emergence of the ophthalmopathy , In this respect, it is interesting to mention the study by Prummel et al.  showing that antibodies to hsp-72 were increased both in the sera of Graves' disease patients and in smoking control subjects suggesting that the antibodies may be a marker for autoimmune susceptibility.
The association between smoking, Graves' disease and endocrine ophthalmopathy has recently been examined in a case control study of newly diagnosed patients with Graves' disease . Furthermore, a retrospective survey was carried out among 72 patients treated for Graves' disease and admitted due to endocrine ophthalmopathy. Although no effect of smoking on the thyroid hormone levels or the autoantibody titers could be observed, a positive correlation was evident, between smoking and the severity of the ophthalmopathy. The authors have shown that smoking was accompanied by an increased risk of Graves' disease and it enhanced the severity of the ocular manifestations in cases that subsequently developed endocrine ophthalmopathy during the course of treatment.
Hypothyroidism due to Hashimoto thyroiditis (HT) is also of clear autoimmune nature. In a ret-roscpective study by Fukata et al. , 387 women with Hashimoto's thyroiditis were evaluated for smoking history and thyroid functions. The prevalence of hypothyroidism in smokers with HT was 76.4%, whereas only 34.8% of the nonsmokers with HT were hypothyroid. The authors have also tested serum levels of thiocyanate (an antithyroid substance generated by smoking). They found that the highest serum levels of thiocyanate were in patients with HT who smoked and had hypothyroid suggesting that the increase of thiocyanate may contribute to the development of hypothyrodism in HT.
The immense impact of cigarette smoking on cancer is highlighted by the observation that 30% of all cancer deaths can be attributed to cigarette smoking. When observed collectively it appears that smokers are twice as likely to die in comparison to nonsmokers, whereas heavy smokers are 4 times more likely.
The most important malignancies associated with smoking are within the lung. Over 80% of deaths caused by lung malignancies are directly attributed to smoking and the relative risk of death from lung cancer is 15 in smokers. There is a 22-fold increased risk of lung cancer in current male smokers, and a 12-fold increased risk in current female smokers. An important trend observed in recent years demonstrates an increase in the risk of lung cancer among women, suggesting an increase in the total smoking per years in women. All four types of lung cancer (squamous cell, small cell, large cell and adenocarcinomas) are increased due to cigarette smoking.
A second malignancy strongly associated with smoking is the laryngeal carcinoma (10 times more common in male smokers in comparison with non-smokers), also due to the direct contact with the carcinogenic elements in tobacco smoke.
The spectrum of malignancies thought to be causally associated smoking is extending. Currently, it is considered that apart from lung cancer, malignancies of the larynx, hypopharynx, esophagus, bladder, renal pelvis, pancreas andstomach, renal body as well as myeloid leukemia are caused by smoking. Confounding data exists regarding the association between smoking and cancers of the colon and cervix.
The strength of data supporting a causal role for smoking in the pathogenesis of cancer derives from the "dose response effect", namely, the increased risk for cancer with increasing exposure extent (total number of smoked cigarette) and time (duration of smoking). Moreover, cessation of smoking is associated with a reduction in the risk for cancer.
The major tumorogenic factors found in cigarette smoke include the polyaromatic hydrocarbon subtractions contained in the particulate matter ("tar"). Cigarette tar exerts a dose-dependent effect on carcinogenesis. Whereas tar acts as an initiator of carcinogenesis, other components in cigarette smoke act as promoter that enhance the process. These factors include the weekly acidic and neutral portions of tobacco smoke condensates.
The maximal carcinongenic effect of tobacco smoke occurs in the tissues directly exposed, such as the airway lining epithelium, although additional remote organs are not spared. As an example of the remote cancerous effect, the 2-naphthylamine can be brought, that is concentrated in the urinary bladder and probably by direct exposure, increases the risk for transitional cell carcinoma.
As mentioned above, cigarette smoke can exert the carcinongnic effect by a remote effect in the cases of kidney and bladder cancer. In this respect it is important to note that other chemicals (found in rubber, paint and leather) may act to synergize with smoking and increase the likelihood of contracting cancer.
Recent data implies that cigarette smoking can also influence the occurrence of liver, gastrointestinal and prostatic cancers.
In conclusion, cigarette smoking has been recognized as a major cause of malignancies of various origins. This effect is exemplified in the fact that the extent of exposure determines the magnitude of the risk for cancer. However, cessation of smoking, despite reducing the risk, cannot completely reverse the increased tendency to develop malignancies.
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