**4. Exogenous factors: Epitope spreading and bystander effect**

Multiple exogenous factors of diverse origin may contribute to trigger MAABD, e.g. druginduction of malignancy in ABD patients and, contrarily, self-antigen drug/virus/bacteriainduced alteration. Drug-induced immunosuppression in ABD (e.g. with methotrexate) was considered a prospective triggering factor for lymphoproliferative disorders [132]. Viral/ microbial factors could serve both as a trigger for autoimmunity and risk factor for malignancy. It was hypothesized, that foreign antigens (e.g. viral, fungal, bacterial) may act as a superan‐ tigen in ABD induction or take part in epitope spreading phenomenon [133,134]. HBV, HCV, H. pylori, T. gondii and CMV were reported to contribute to elicit ABD [135]. Viral infection (TTV, HSV2, HHV6, HHV8, HSV1, HSV2, EBV, HBV, HIV-1, Coxsackie virus) [136–143] has been put forward as a causative agent of ABD-type autoimmunity in PV, PF, BP and pemphi‐ gus vegetans. There has been multiple factors suspected of prostatic cancerogenesis, including viruses (BK, HSV2, HSV6, HSV11, HSV16, HSV18, HSV31, HSV33, HHV8, XMRV, CMV) and microbial agents (Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, Neisseria gonorrhoeae and Treponema pallidum), yet data was inconclusive or supported no relation [144–151]. Surprisingly, Epstein-Barr virus infection has been found statistically associated with increased breast carcinoma risk [152]. It was speculated that the virus itself may play a role in ABD induction [153,154]. The data covering the issue of exogenous factors contributing to both malignancy and ABD is yet generally inconclusive.

link between the production of pathogenic autoantibodies in ABD and the development of the associated neoplasy should facilitate the development of more specific diagnostic tests and

Malignancy in Relation to Autoimmune Blistering Dermatoses: Molecular and Clinical Aspects

http://dx.doi.org/10.5772/55240

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Pemphigus group is characterized by presence of autoantibodies against desmosomal cadherins. Research on human and animal models indicated that alternation in desmosomes components may lead to tumor progression and metastasis. However, little is known about the role of desmosome during cancer development [161]. It is clear, that the origin and maintenance of epidermis requires the coordinated regulation of proliferation, adhesion, migration and differentiation. Conceptually, desmosome complexes form when desmosomal cadherins – DCs (desmogleins – DSGs and desmocollins – DSCs) participate in heterotypic interactions that bring the plasma membranes of adjacent cells in close apposition [161]. The

The data describing desmosome protein expression during human cancer progression are conflicting [161–163]. Molecular abnormalities of desmosomal proteins (DPs) are observed in ABD and epithelial malignancies. However, in malignancy, where cells may separate, detach and metastasize, it is possible that alterations in DPs expression may be the reason of carcino‐ genesis process. Several studies demonstrated that downregulation of DCs occurs during the progression of cancers and is often correlated with and predictive of tumor metastasis [161,162]. On the other hand, other studies reported overexpression of DCs during the cancer progression, and this pattern is associated with poor prognosis [163]. The regulatory mecha‐ nism controlling DCs expression are scanty explained. As known, gene expression may be modulated by genetic and/or epigenetic mechanisms and in this way may contribute to the development of pathologic autoimmunity or malignancies. Genetic changes as mutation, deletion, and gene rearrangement of DCs have been poorly found in cancer and ABD. Possible mechanism may also involve post-translational modification of protein, like phosphorylation, acetylation or methylation. In light of this, some data reported methylation of DCs, e.g. methylation of DSC3 in breast cancer. It was showed, that DSC3 is downregulated in colorectal cancer by DNA methylation [164]. Thus, further analysis of methylation status of DCs DNA

Alternatively, the possible link between desmosomal components and malignancy may be the Perp protein. The Perp tetraspan membrane protein was originally identified as a transcrip‐ tional target of the p53 tumor suppressor upregulated during apoptosis [161,165]. However, Perp may have function as a target of the p53-related transcription factor (p63) involved in maintaining epithelial integrity by promoting desmosomal cell-cell adhesion. Electron microscopy and biochemical analyses showed that the blistering phenotype observed in the Perp-deficient epithelia is accounted for by both a reduction in desmosome number and compromised desmosome complex formation. It is suggested, that pemphigus autoantibodies may trigger internalization of Perp, which enhances adhesion defects [166]. Perp's position downstream of p63 and p53, as well as its essential role in normal desmosome function, suggest

**5.1. Malignancy in relation to the autoimmunity in pemphigus group: The role of**

cytoplasmic tails of these cadherins interact with plakoglobin and plakophilins.

may be useful to predict clinical outcomes in patients with malignancy.

therapeutic strategies [160].

**desmosomes components**

Constant activation of immune system in ABD sustains chronic inflammation leading to tissue degeneration by proinflammatory molecules. As a result, the risk of the neoplasy increases [3]. However, that relation could be two-sided. Inflammation in tumor nest stimulates and modifies the immunity mechanisms. Furthermore, there is a hypothesis that the multiplicity of target antigens in ABD may result from intra- and intermolecular epitope spreading. The effect of epitope spreading in ABD is well-known fact and it seems to be a constitutional compound of autoimmunity. Structural similarities between autoantigen epitope and to-beautoantigen epitope may lead to production of autoaggresive cross-reacting immunoglobulins [9,155]. This phenomenon, which represents a broadening of the immune response from a single epitope to additional epitopes, is also described in cancer and recent findings suggests that epitope spreading may be a more significant predictor of effective immunity [156].

The initial anti-cancer immunity may ricochet to autoaggresion by epitope spreading and bystander effect alike [157]. Local inflammation in the course of malignant tumor or chemo‐ therapy/radiotherapy treatment may result in enhanced autoantigen presentation that causes T-cell priming, activation and expansion of additional specificity [158]. Therefore, in situations where immunosuppressive/anti-cancer treatment is absent or ceased, anti-cancer response may be responsible for development of autoimmunity to self-antigens characteristic for ABD.
