**3. Endogenous factors leading to breakage of self-tolerance in malignancy**

Endogenous factors seem to be crucial for development of autoimmunity, as they form the organism reaction to external threat.

#### **3.1. Development of paraneoplastic immunity**

The autoimmunity in cancer is developed by distortion of immune system, arising from central tolerance disruption, peripheral immunity rearrangement and altering of self-antigens. Cancer-associated impairment of the function of immune system may take place at many stages. Rearrangement of T-cell receptor (TCR) genes proceeding in thymus cortex promotes T-cell education to recognize major histocompatibility complex (MHC) molecules of self-cells. It is a necessary condition for a T-cell to pass the positive selection process. The negative selection, being the following stage, is conducted in thymus medulla, where T-cells are exposed to plethora of tissue specific self-antigens (TSAs) by medullary thymic epithelial cells. Selfantigens presented to T-cells are previously processed, thus some T-cells expressing TCR with high affinity to poorly presented antigens may evade negative selection achieving maturation [88]. The process is controlled by autoimmune regulator (AIRE) transcription factor [89]. Autoaggressive thymocytes are being terminated in apoptosis. Impairment of any of these stages – positive selection, negative selection, antigen processing, antigen presentation by malignancy, might have impact on T-cell set and scope of activity in periphery. Thymoma is the most common neoplasm of thymus, outrunning lymphomas, germ cell tumor, thymic carcinoma, carcinoid tumors and others [90]. One of the syndromes in relation to thymoma is paraneoplastic pemphigus, where diverse autoantibodies target diverse structural autoanti‐ gens. While pemphigus vulgaris (PV) and paraneoplastic (PNP) pemphigus may both target the same antigen, the difference is within the range of them and difference in epitopes bound (e.g. mucocutaneus PV preferably targets DSG3 N-terminal determinant, while PNP binds multiple epitopes). Another distinctive feature is IgG subclass – predominant PV IgG autoan‐ tibody subclass is IgG4, while in PNP – subclass is IgG1 and IgG2 [1].

As far as anti-enzyme ABD is concerned, association of DH with subsequent development of lymphoma seems well-documented [18,24,25]. It is possible that gluten intolerance is the factor associated with malignancies. Some data suggested, that following a strict gluten-free diet is protective against malignancy [26]. Moreover, researchers postulate that the risk of malignancy decreases with time from diagnosis of gluten-sensitive enteropathy to nearly the same as occurs in the general population. In light of above, it is postulated that the increased risk of malignancy in patients with DH may be the result of a polyclonal stimulation of lymphocytes by gluten that causes transformation into a malignant clone [18]. Still, in our over 20 years of clinical/laboratory experience as a clinician/clinical researchers we do not recall a DH-

There is a wide group of malignancies concomitant with ADB. Lung cancer has been reported in coexistence with wide range of ABD: PV [17,27,28], PNP [29], pemphigus vegetans [30,31], pemphigus herpetiformis [32], IgA pemphigus [33], BP [34] and MMP [35]. In some BP cases, tumor resection led to complete recovery [36] supporting the thesis of close interrelation of the diseases. Gastrointestinal tumors have been reported in association with BP [17,37], PNP [38], pemphigus vegetans [39], PV [40–45] and MMP [46] sometimes with post-excisional remission [47,48]. Both chronic leukemia and lymphoma have been reported with DH [49–51] and PNP [52–54]. Based on few case reports, MMP [55–57] is not rare finding in leukemia. There has been only one case of BP reported in patient with leukemia [58]. Thymoma and PV appears in numerable patients [43] with post-excisional remissions not uncommon [59]. Among reported thymoma-related ABD, there are also cases of PF [60,61], BP [62] and MMP [63]. Malignant tumor of the pancreas seem to be generally connected to MMP [64,65] and sometimes PNP [66]. Renal neoplasm has been reported to occur in with BP [67–70] and occasionally with MMP [71], PNP [72] and PF [73]. Ovarian cancer was incidentally described in relation with BP [74], antilaminin gamma1 pemphigoid [75] and MMP [76]. Concerning prostatic cancer, single cases of PNP [77], pemphigus herpetiformis [78], PF [79] and MMP [80] were described in literature. There are numerous case reports on ABD and breast cancer including predominantly BP [20,81–85] and PV [86,87] with well-documented BP-lesion induction with radiotherapy.

**3. Endogenous factors leading to breakage of self-tolerance in malignancy**

Endogenous factors seem to be crucial for development of autoimmunity, as they form the

The autoimmunity in cancer is developed by distortion of immune system, arising from central tolerance disruption, peripheral immunity rearrangement and altering of self-antigens. Cancer-associated impairment of the function of immune system may take place at many stages. Rearrangement of T-cell receptor (TCR) genes proceeding in thymus cortex promotes T-cell education to recognize major histocompatibility complex (MHC) molecules of self-cells. It is a necessary condition for a T-cell to pass the positive selection process. The negative

associated lymphoma patient.

164 Highlights in Skin Cancer

organism reaction to external threat.

**3.1. Development of paraneoplastic immunity**

Some authors hypothesized that tumor cells alone may produce the autoantibodies [91,92]. The thesis of in-tumor immature T-cell improper maturation, without negative selection, leading to autoaggression may be supported by findings in patient with follicular dendritic cell sarcoma [93]. Malignancy is based on breakage of cell cycle guarding and dysregulation of gene expression resulting in over- or underexpression of proteins. Via gene mutation, the neoplastic cell changes the antigen suit, by exposing altered self-antigens or "hiding" those already known. The reaction of immune system to cancer growth is immune cells recruitment (T-cells, NK cells, mast cells) and inflammation by various mediators causing apoptosis of both neoplastic and non-neoplastic cells. One T-cell can recognize many antigens presented by different MHC molecules. The condition of recognition is the compatibility of antigen fragment with lymphocyte TCR. Along with antigen sequestration theory, the determinants of cell proteins released in tumor necrosis can be exposed by antigen presenting cells to matured Tcells that migrate to lymph nodes. B-cells in response start to produce polyclonal antibodies against novel tumor epitopes. However, T-cells may also react with cancer antigens starting the chain of events leading to production of certain antibody cross-binding both neoplastic antigens and self-antigens [90].

The role of immune system protection against malignancy can be exemplified by noticeable higher cancer incidence in patients given immunosuppressive drugs impairing self/foreignantigens recognition. Hence hypothetically, the distortion in immune system function in ABD may contribute to further susceptibility to the development of malignancy. Naive T-cell activation in the periphery alone is thought to be insufficient for autoimmunity induction and co-stimulation by CD28, a co-stimulatory molecule activating T-cells, seem to be necessary [94]. CD28 is able to bind CD80 molecule and CD86 molecule, constitutionally expressed on B-cells, subsequently enhancing IgG antibody production [95]. CD80 molecule appear also scantly on other antigen-presenting cells (APC – primarily B-cells, macrophages and dendritic cells) and is upregulated after APC activation. Active APC present CD40, a ligand for CD40L expressed on active T helper cells. Ligation of CD40 on APC cells leads to increase co-stimulatory capacity and antigen presentation ability enhancement. It is worth noticing that, CD80/CD86 is also expressed on cells of diverse lymphomas (e.g. non-Hodgkin lymphoma and chronic lyphocytic leukemia), that can act on behalf of APC, evading being recognized by the immune system. It was suggested that T-cells may omit the "APC guarding stations" in lymph nodes and directly infiltrate the tumor. Thus, the tumor itself may act as a "T-cell kidnapper" and support naive T-cell infiltration, activation and differentiation into effector cells [96], hypothetically pro‐ gramming or "indoctrinating" T-cells to achieve autoimmune potential. Moreover, the study based on collective incubation of non-malignant regulatory and cytotoxic T-cells with chronic lymphocytic leukemia cells showed non-malignant T-cells cytoskeleton remodeling decrease and vesicle trafficking decrease resulting in impaired synapse formation [97,98].

functions [119]. Polarization to Th1-mediated immunity via IL-1, IL-4, IL-5, IL-6, IL-8 and IFNgamma was observed in BP [120], while Th2-mediated reaction via IL-10 and IL-4, in conjunc‐ tion with decrease in IL-2 and IFN-gamma levels, were shown in PV [119]. The cytokines that promote cancer growth (e.g IL-8 for colon and gastric cancer) [121,122] may collaterally initiate Th population shift to the profile promoting ABD. Likewise, a proliferation inducing ligand (APRIL) of TNF family plays an important role in several autoimmune diseases, including ABD, and in several malignancies. Soluble APRIL level was reported to be raised in e.g. lung, thyroid, lymphoid and gastrointestinal tumors [123,124], thus supposedly contribute to dysregulation of immunity in cancer. B-cell activating factor (BAFF/BLyS), belonging to TNF family, regulates B-lymphocyte proliferation and survival, also in B-cell lymphoproliferative disorders [125]. Interestingly, serum of BP-, but not PV-patients, showed high titers of BAFF [126]. It seems rational, that molecular mechanisms leading to increase of BAFF level in BP

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

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

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As some entities of ABD have sex-predisposition, just as some malignancies, the role of sex hormones on development of MAABD need to be investigated. Certain tumors prevail in female (breast cancer, non-Hodgkin lymphoma), in man (gastrointestinal tumor, laryngeal cancer, Hodgkin lymphoma or kidney cancer) or are typical for one sex for anatomical reasons (prostate cancer, ovarian cancer) [15]. Sex-associated distribution of PV and BP seems equal with slight female dominance, while other ABD promote males (DH – 2:1) or are exquisitely female domain (PG) [5,127]. Both T and B cells have estrogen, testosterone and prolactin receptors. Furthermore, androgens and estrogens have an impact on the Th1/Th2 balance [128]. Therefore, menopause may be followed by change in cytokine profile affecting immune response. Interestingly, studies on endocrine hormones in PV- and BP-patients have revealed increased serum levels of both adrenocorticotropic hormone (ACTH) and hydrocortisone [129]. It was hypothesized, that slight female predominance of women in PV may be contrib‐ uted to hormone replacement therapy (HRT) [130]. HRT is known risk factor for ovarian cancer, yet the impact on neoplasm induction in breast cancer and endometrial cancer is

**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

patients may favor pathological lymphoproliferation.

**3.4. Sex hormones**

uncertain [131].

Fc receptors (FcRs) play essential role in the activation/inhibition of various cells in antibodymediated immune responses. Thus, FcRs function may be a key purpose in the treatment with monoclonal antibodies (mAbs) therapy. Probably, FcRs may be a molecular link between ABD and malignancies [99,100]. FcRs-targeting therapies are used for ABD and cancer, e.g. rituxi‐ mab, which is used in ABD and is the first anti-tumor mAb drug admitted by the US Food and Drug Administration. It was demonstrated that Fc-receptor-dependent mechanisms contrib‐ ute substantially to the action of cytotoxic antibodies against tumors and indicated that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcγRIIB [101]. Interestingly, rituximab – the chimeric monoclonal IgG1antibody specific for the B-cell marker CD20 – was recently approved for the treatment of B-cell lymphoma. In vitro studies with rituximab have indicated that a direct proapoptotic activity may be associated with this antibody [102].

### **3.2. Genetic predisposition**

There seems to be a causative relation between HLA-association and autoimmunity in ABD, especially in pemphigus [103–109] and pemphigoid [110], yet these observations may vary geographically. HLA-DQB1\*0301 allele, associated with MMP [111–114], was reported in patients with esophageal squamous cell carcinoma [113], gastric cancer [115], HPV-associated cervical neoplasia [116]. It was hypothesized, that the gene may have a role in T-cell recognition of basement membrane antigens resulting in production of IgG autoantibodies binding basement membrane antigens [117]. It is also possible, that the link exists between certain malignancies and HLA or autoimmunity predisposition connected to defective apoptotic genes. Nonetheless, there are few studies covering that field, so coexistence may also be purely coincidental.

#### **3.3. The role of cytokines**

There is eventuality of oversecretion of certain cytokines regulating the mRNA expression and polarization of certain T helper (Th) cell population [118,119], as the most common neoplasms in relation to ABD seem to be lymphoproliferative malignancies. It has been reported that qualitative as well as quantitative alterations in cytokine production can result in activation of inefficacious effector mechanisms and therefore, complex and severe impairment in immune functions [119]. Polarization to Th1-mediated immunity via IL-1, IL-4, IL-5, IL-6, IL-8 and IFNgamma was observed in BP [120], while Th2-mediated reaction via IL-10 and IL-4, in conjunc‐ tion with decrease in IL-2 and IFN-gamma levels, were shown in PV [119]. The cytokines that promote cancer growth (e.g IL-8 for colon and gastric cancer) [121,122] may collaterally initiate Th population shift to the profile promoting ABD. Likewise, a proliferation inducing ligand (APRIL) of TNF family plays an important role in several autoimmune diseases, including ABD, and in several malignancies. Soluble APRIL level was reported to be raised in e.g. lung, thyroid, lymphoid and gastrointestinal tumors [123,124], thus supposedly contribute to dysregulation of immunity in cancer. B-cell activating factor (BAFF/BLyS), belonging to TNF family, regulates B-lymphocyte proliferation and survival, also in B-cell lymphoproliferative disorders [125]. Interestingly, serum of BP-, but not PV-patients, showed high titers of BAFF [126]. It seems rational, that molecular mechanisms leading to increase of BAFF level in BP patients may favor pathological lymphoproliferation.

#### **3.4. Sex hormones**

on active T helper cells. Ligation of CD40 on APC cells leads to increase co-stimulatory capacity and antigen presentation ability enhancement. It is worth noticing that, CD80/CD86 is also expressed on cells of diverse lymphomas (e.g. non-Hodgkin lymphoma and chronic lyphocytic leukemia), that can act on behalf of APC, evading being recognized by the immune system. It was suggested that T-cells may omit the "APC guarding stations" in lymph nodes and directly infiltrate the tumor. Thus, the tumor itself may act as a "T-cell kidnapper" and support naive T-cell infiltration, activation and differentiation into effector cells [96], hypothetically pro‐ gramming or "indoctrinating" T-cells to achieve autoimmune potential. Moreover, the study based on collective incubation of non-malignant regulatory and cytotoxic T-cells with chronic lymphocytic leukemia cells showed non-malignant T-cells cytoskeleton remodeling decrease

Fc receptors (FcRs) play essential role in the activation/inhibition of various cells in antibodymediated immune responses. Thus, FcRs function may be a key purpose in the treatment with monoclonal antibodies (mAbs) therapy. Probably, FcRs may be a molecular link between ABD and malignancies [99,100]. FcRs-targeting therapies are used for ABD and cancer, e.g. rituxi‐ mab, which is used in ABD and is the first anti-tumor mAb drug admitted by the US Food and Drug Administration. It was demonstrated that Fc-receptor-dependent mechanisms contrib‐ ute substantially to the action of cytotoxic antibodies against tumors and indicated that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcγRIIB [101]. Interestingly, rituximab – the chimeric monoclonal IgG1antibody specific for the B-cell marker CD20 – was recently approved for the treatment of B-cell lymphoma. In vitro studies with rituximab have indicated that a direct pro-

There seems to be a causative relation between HLA-association and autoimmunity in ABD, especially in pemphigus [103–109] and pemphigoid [110], yet these observations may vary geographically. HLA-DQB1\*0301 allele, associated with MMP [111–114], was reported in patients with esophageal squamous cell carcinoma [113], gastric cancer [115], HPV-associated cervical neoplasia [116]. It was hypothesized, that the gene may have a role in T-cell recognition of basement membrane antigens resulting in production of IgG autoantibodies binding basement membrane antigens [117]. It is also possible, that the link exists between certain malignancies and HLA or autoimmunity predisposition connected to defective apoptotic genes. Nonetheless, there are few studies covering that field, so coexistence may also be purely

There is eventuality of oversecretion of certain cytokines regulating the mRNA expression and polarization of certain T helper (Th) cell population [118,119], as the most common neoplasms in relation to ABD seem to be lymphoproliferative malignancies. It has been reported that qualitative as well as quantitative alterations in cytokine production can result in activation of inefficacious effector mechanisms and therefore, complex and severe impairment in immune

and vesicle trafficking decrease resulting in impaired synapse formation [97,98].

apoptotic activity may be associated with this antibody [102].

**3.2. Genetic predisposition**

166 Highlights in Skin Cancer

coincidental.

**3.3. The role of cytokines**

As some entities of ABD have sex-predisposition, just as some malignancies, the role of sex hormones on development of MAABD need to be investigated. Certain tumors prevail in female (breast cancer, non-Hodgkin lymphoma), in man (gastrointestinal tumor, laryngeal cancer, Hodgkin lymphoma or kidney cancer) or are typical for one sex for anatomical reasons (prostate cancer, ovarian cancer) [15]. Sex-associated distribution of PV and BP seems equal with slight female dominance, while other ABD promote males (DH – 2:1) or are exquisitely female domain (PG) [5,127]. Both T and B cells have estrogen, testosterone and prolactin receptors. Furthermore, androgens and estrogens have an impact on the Th1/Th2 balance [128]. Therefore, menopause may be followed by change in cytokine profile affecting immune response. Interestingly, studies on endocrine hormones in PV- and BP-patients have revealed increased serum levels of both adrenocorticotropic hormone (ACTH) and hydrocortisone [129]. It was hypothesized, that slight female predominance of women in PV may be contrib‐ uted to hormone replacement therapy (HRT) [130]. HRT is known risk factor for ovarian cancer, yet the impact on neoplasm induction in breast cancer and endometrial cancer is uncertain [131].
