Received 16 May 2016; accepted 24 July 2016; published 27 July 2016
Immunoglobulin A (IgA) against chemical carcinogens plays a critical role in mucosal immunity. According to our previous publication  , it was assumed that serum IgA could modulate carcinogenesis by binding chemical carcinogens and endogenous steroids and delivering them into the epithelium cells through membrane Fc-rece- ptor. These types of antibodies against benzo[a]pyrene (IgA-BP) and estradiol (IgA-Es) could stimulate the pro- cesses of cancer initiation and promotion. However, antibodies against progesterone (IgA-Pg) could inhibit process of promotion in the steroid-depending cells. The possibility of tumor transformation (cancer risk) was increased or decreased depending on ratio stimulating/inhibiting antibodies. Here the confirmations of these suppositions based on the latest studies of antibodies against Bp, Es, and Pg in the lung and breast cancer patients (LCP and BCP, respectively) are presented. Additionally, the possible functions of appropriate anti-idi- otypic antibodies were discussed. It was necessary for the further development of cancer immune-prevention strategy.
2. Effects of IgA Antibodies against Environmental Carcinogen and Sex Steroids onto Lung and Breast Cancer Risk
There were many experimental data in vivo and in vitro about immunomodulation of carcinogenesis and tumor growth by antibodies against the chemical carcinogens and sex steroid hormones  -  . It was well known that levels of antibodies against carcinogen-DNA adduct and carcinogen-protein conjugates increased in human after carcinogen influence and in cancer patients  -  . However the functional significance of these antibodies in human remain to be elucidated. It was postulated that antibodies could stimulate or inhibit carcinogenesis in the certain conditions    .
To confirm the supposition about immunomodulation of chemical carcinogenesis in humans the serum IgA against Bp, Es and Pg in LCP and BCP were studied    . It was found that high level of IgA against Bp and Es revealed more frequently in LCP and BCP than in healthy people (Table 1). In contrast there were no any differences in IgA-Pg in analyzed groups of people. The high IgA-Bp/IgA-Pg and IgA-Es/IgA-Pg ratios were found in cancer patients than in healthy donors. The LC and BC risks increased significantly. These data mean that domination of IgA-Bp and IgA-Es over IgA-Pg stimulates the carcinogenesis in lung and mammary gland.
All the men and women were separated on to 8 subgroups in consideration of the combinations of high and low antibodies levels against Bp, Es and Pg (Table 2). It was revealed, that absence or low IgA levels to all three compounds (group 1) took place in LCP (20.3%) and BCP (27.6%) more rarely than in healthy donors (36.4% and 36.8%,respectively). Cancer risks decreased to 0.4 - 0.6 in these cases.
High levels of IgA-Bp along or IgA-Es along (groups 2 and 3, respectively) were found in the same frequency both in BCP and healthy women and odds ratio (OR) did not increase. It means that IgA-Bp and IgA-Es separately did not effect on carcinogenesis in lung and mammary gland. High levels of IgA-Bp only or IgA-Es were
Table 1. Amount of cases (N), amount of cases in each group (n) and frequency of occurrence (%) for high levels antibodies and antibodies ratios in the blood serum of men and postmenopausal women. Immunoglobulin A against Bp (IgA-Bp), Es (IgA-Es), and Pg (IgA-Pg). Ratios immunoglobulin A against Bp and Pg (IgА-Bp/Pg), immunoglobulin A against Es and Pg (IgА-Es/Pg). The groups with significant differences between healthy donors and sick people are in bold.
Table 2. Lung and breast cancer risks (OR) for high (>) and low (≤) antibodies levels in the blood serum of men and postmenopausal women   . Immunoglobulin A against Bp (IgA-Bp), Es (IgA-Es), and Pg (IgA-Pg). The groups with significant difference between healthy donors and sick people are in bold.
revealed in LCP more frequently than in healthy men and OR increased to 4.1 - 2.5, respectively. There were no significant differences between comparable groups in case of IgA-Pg along (group 4).
It was interesting that high levels of IgA-Bp in combination with IgA-Es (group 5) revealed in cancer patients significantly more frequently than in healthy donors. LC and BC ricks increased to 16.2 and 6.2, respectively. So, simultaneous IgA-formation to Bp and Es without to Pg stimulated carcinogenesis in lung and mammary gland much more than they acted separately. The mutual amplification of IgA-Bp and IgA-Es effects means that these antibodies act as co-initiators and co-promoters according to classical chemical-induced carcinogenesis model.
LC and BC risks were not increased when IgA-Pg formed together with IgA-Bp or with IgA-Es (groups 6 and 7). Moreover the cancer risks were lower when IgA-Pg were formed together with IgA-Bp and with IgA-ES (group 8; LC OR = 2.7; BC OR = 2.5) compared with IgA-Bp and IgA-Es without IgA-Pg (group 5). It means that IgA-Pg acted as co-inhibitor.
The revealed actions of IgA against the chemical carcinogens and sex steroids could explain by: 1) binding of these compounds in blood serum; 2) transport immune complexes into the epithelium cell though membrane Fc-receptor; 3) interaction of carcinogens and steroids with intracellular receptors with the known subsequent biological effects.
The stimulation of IgA synthesis against environmental carcinogens according to cancer immune-prevention strategy could be not acceptable because these antibodies revealed mainly together with Es-antibodies and cancer risk increased in these cases  . That why, it was necessary to examine the inhibition of IgA-Es and stimulation of IgA-Pg syntheses as possible components of cancer immune-prevention strategy.
3. Immunomodulation of Human Carcinogenesis by Antiidiotypic Antibodies against the Chemical Carcinogens and Endogenous Steroids
Previously antibodies against the polycyclic aromatic hydrocarbons (Ab1) and corresponding antiidiotypic antibodies (Ab2) were detected in the serum of BCP and LCP   . It was shown that Ab2 levels exceeded Ab1 levels (Ab1/Ab2 ≤ 0/5) in healthy donors, but not in LCP (Ab1/Ab2 ~ 1.0). We supposed that Ab2 blocked the protection functions of Ab1. It was postulated the Ab2 formation against endogenous steroids in analogy to Ab2 to chemical carcinogens with the same anti-protection actions  .
At the same time another effects of Ab2 on the carcinogenesis initiation and promotion were possible. In a few works, the ability of monoclonal Ab2 (clone 1D5) directed against the binding site of a monoclonal anti-Es Ab1 to interact with the estrogen receptor (ER) was investigated. It was shown the Es-like effects of Ab2 1D5 (increase in creating kinase activity) in vivo in epiphyseal cartilage, diaphyseal bone, uterus, prostate, thymus of immature female models  -  and in vitro in female human and rat osteoblasts  . Rabbit polyclonal R4 antibodies against ER hinge region sequence increased prolactin release from rat pituitary cells. But monoclonal H 151 antibodies against a different hinge region epitope decreased prolactin release and blocked the stimulatory action of Es  . Another two monoclonal antibodies against the ligand binding domains of ER (H 222) and PR (C 262) were blocked of the calcium response to Es and Pg in human spermatozoa  .
Taken together, all these experimental data support the ability of antibodies against membrane steroid receptors to mimic the effects of corresponding steroids. If Ab2-formation against Es and Pg really takes place in human, these Ab2 could bind to their membrane receptors on target cells and stimulate or inhibit the promotion of carcinogenesis. If aryl hydrocarbon-like receptor could express in the cell surface membrane, the Ab2-Bp could mimic the Bp effects on the initiation of carcinogenesis. Anyway the Bp-initiation would be modulated by antibodies against steroid hormones through the known mechanisms of aryl hydrocarbon receptor-steroid receptor crosstalk   .
The speculative character of those suppositions was obvious as well as previously described    . But the functions of Ab2 against environmental carcinogens and endogenous steroids have to explain by different types of research in details.
Sources of support: the program No. 0355-294-0001 FNI state academic science on Siberian Branch of the Russian Academy of Sciences, “Genetic basis of immune responses to chemical carcinogens and steroid hormones in lung cancer in humans”; the grant of Russian Science Foundation No. 16-15-00034, “Development of the test-systems for cancer risks preclinical diagnostics among workers in the coal industry”.
Conflict of Interests
Authors have declared that no competing interests exist.
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