Review

Vitamin D in autoimmune bullous diseases*

Stefan Tukaj✉

Department of Molecular Biology; Faculty of Biology; University of Gdańsk; Gdańsk, Poland

Numerous epidemiological studies have suggested a link between vitamin D deficiency and the development of various autoimmune diseases, including diabetes mellitus type 1, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis or systemic lupus erythematosus. More recently, such a link has been also proposed for autoimmune bullous diseases (AIBD). This is a relatively rare and potentially life-threatening, organ-specific group of inflammatory skin diseases characterized by the presence of tissue-bound and circulating autoantibodies against various molecules present in desmosomes (in pemphigus diseases) or hemidesmosomes (in pemphigoid diseases). In addition to the well-known role of vitamin D in calcium and phosphate homeostasis, the hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (calcitriol), exerts potent effects on cellular differentiation and regulation of immune responses via binding to the vitamin D receptor present in most cells of the immune system. Since cells of both, the innate and adaptive immune systems, are known to be relevant in AIBD, the role of vitamin D analogues in the treatment of patients with these disorders deserves much attention. This mini-review summarizes recent epidemiological and experimental studies on vitamin D involvement in the autoimmune bullous diseases.

Key words: calcitriol; 1,25(OH)2D3; vitamin D; 25(OH)D; autoimmune bullous diseases

Received: 05 November, 2019; revised: 09 January, 2020; accepted: 29 January, 2020 available on-line: 12 February, 2020

✉e-mail: stefan.tukaj@biol.ug.edu.pl

*Acknowledgments of Financial Support: This study was supported by the Polish National Science Centre (NCN) grant no. 2017/25/B/NZ6/00305.

Abbreviations: AIBD, autoimmune bullous diseases; 1,25(OH)2D3, 1α,25-dihydroxyvitamin D3; 25(OH)D, 25-hydroxyvitamin D3; VDR, vitamin D receptor; APC, antigen presenting cell; IVIG, intravenous immunoglobulin; PV, pemphigus vulgaris; PF, pemphigus foliaceus; BP, bullous pemphigoid; EBA, epidermolysis bullosa acqusita; COL17, collagen type XVII; COL7, collagen type VII

Vitamin D: production, metabolism, and mechanisms of action

In a canonical metabolic pathway, the cholesterol-derived vitamin D is present in two major forms: ergocalciferol (D2) and cholecalciferol (D3), the latter being synthesized in the skin upon sunlight exposure (UV radiation) and converted to 25-hydroxyvitamin D3 [25(OH)D; calcidiol] and 1,25-dihydroxyvitamin D3 [1,25(OH)2D, calcitriol] in the liver and kidneys, respectively, by the vitamin D-25-hydroxylase (CYP2R1 and CYP27A1) and the 25(OH)D-1α-hydroxylase (CYP27B1) (Holick et al., 2011; Bikle, 2014). Active form of vitamin D3 [1,25(OH)2D] binds to the vitamin D binding protein (DBP) in circulation and is delivered to the target tissues, such as the intestine, bone and kidneys, to regulate the calcium and phosphate homeostasis (Bikle, 2012). In addition, 1,25(OH)2D is also synthesized locally in the epidermis and various immune cells (Bikle, 2012; 2014). Alternatively, vitamin D2 and D3 can be supplemented by a balanced diet of plant and animal origin, respectively. Vitamin D, whether produced in the skin from 7-dehydrocholesterol or absorbed from the diet, must be activated first to 25(OH)D and then to 1,25(OH)2D (Bikle, 2014). Nevertheless, numerous agencies and scientific organizations highly recommend vitamin D supplementation to maintain health and prevent development of metabolic, cancerous, and immune-related diseases (Pludowski et al., 2018). Recent studies have revealed that the vitamin D metabolites can be also synthetized and activated through a CYP11A1-driven non-canonical metabolic pathway (Slominski et al., 2012; Slominski et al., 2014a; Slominski et al., 2015a; Slominski et al., 2015b).

While 25(OH)D is the major (inactive) circulating form of vitamin D, commonly used as a serological indicator to evaluate the vitamin D status in patients (Holick et al., 2011), calcitriol represents the biologically active vitamin D metabolite which serves as the primary ligand for the vitamin D receptor (VDR) expressed in the bone, gastrointestinal tract, skeletal muscle or skin, as well as in various immune cells, including dendritic cells, monocytes/macrophages or lymphocytes (Yang et al., 2013; Mazzaferro et al., 2014; Mostafa & Hegazy 2015). The 1,25(OH)2D/VDR complex binds to the vitamin D response elements (VDREs) in the genome to activate or suppress transcription of hundreds of genes in a cell-specific manner. In general, the functions of vitamin D analogues are characterized as genomic, i.e. mediated through VDR transcriptional effects inside the cell nucleus, and non-genomic, when VDR induces rapid signaling, including the ability to stimulate calcium transport across the plasma membrane (Bikle, 2014).

Apart from the classic role of vitamin D in the calcium and phosphate homeostasis, many in vivo studies have shown that active vitamin D metabolites regulate several physiological processes, such as the cell proliferation, differentiation, and immune modulation. Active vitamin D metabolites display immunomodulatory activity manifested by reduction in the antigen presenting cells’ (APC) activity or pro-inflammatory T helper 1 (Th1) and T helper 17 (Th17) frequencies, as well as expansion of the T- and B-regulatory cells (Takeda et al., 2010; Bikle, 2014; Alhassan Mohammed et al., 2017; Tukaj et al., 2018).

In addition, it has been proven that CYP11A1-derived vitamin D metabolites serve as ligands for VDR or can act as inverse agonists on retinoic acid orphan receptors (ROR) α and γ (Slominski et al., 2014b; Slominski et al., 2017), which are known to play key roles in regulation of the immune and metabolic pathways. More recently, the top signaling pathways for CYP11A1-driven analogues, such as 20,23(OH)2D, were linked to activation of the aryl hydrocarbon receptor (AhR), representing an alternative receptor to VDR (Slominski et al., 2018). It is worth to mention that despite the importance of UVB radiation in the 25-hydroxyvitamin D3 synthesis, this radiation is also a key agent that induces DNA damage in the skin. Both, 1,25(OH)2D and CYP11A1-derived vitamin D analogues, protect the epidermal keratinocytes against UVB-induced damage via activation of the Nrf2-dependent antioxidant response and p53-phosphorylation, as well as by induction of the DNA repair system (Chaiprasongsuk et al., 2019). In addition, both - the classical 1,25(OH)2D and non-calcemic CYP11A1-driven analogues, exert anti-inflammatory effects on keratinocytes by inhibiting the nuclear factor-κB (NF-κB) activity (Janjetovic et al., 2009; 2010; Tukaj et al., 2016).

Because regulatory effects of vitamin D analogues on proliferation and differentiation have been also confirmed for cells outside the immune system, topical application of vitamin D analogues has been considered and approved for the treatment of psoriasis - one of the most common chronic inflammatory skin disease which affects approximately 2% of the general human population (Umar et al., 2018). In addition, some reports indicate that topically applied vitamin D analogues are also effective in vitiligo (Xing & Xu, 2012). Because skin is the main source of vitamin D in our body (approximately 90%) and most of the available data point to this vitamin’s significant impact on the health of skin and other organs (Mostafa & Hegazy, 2015), the potential impact of hypovitaminosis D on the development of dermatological diseases, including autoimmune bullous skin diseases, deserves special attention.

Autoimmune bullous diseases

Autoimmune bullous diseases (AIBD) are characterized by the presence of tissue-bound and circulating autoantibodies that are directed against different structural molecules present in the skin and adjacent mucous membranes. AIBD are divided into three different subgroups, such as the pemphigoid, pemphigus, and dermatitis herpetiformis, the last being the cutaneous manifestation of the celiac disease with autoantibodies directed against the tissue and the epidermal transglutaminase (Witte et al., 2018). Pemphigus is a group of autoantibody-mediated autoimmune diseases of the skin and oral mucosa, in which the loss of cell adhesion (acantholysis) causes blisters and erosions. Patients with pemphigus are characterized by the presence of autoantibodies directed against desmoglein 1 and desmoglein 3, which are cell-cell adhesion molecules found in desmosomes in the epidermis. There are two major subtypes of pemphigus diseases: pemphigus vulgaris (PV) and pemphigus foliaceus (PF), the first being the most common form of pemphigus (Kasperkiewicz et al., 2017). While the etiology of pemphigus diseases is largely unknown, the genetic and environmental risk factors have been proposed. Both, the PV and PF are frequently associated with other (auto)inflammatory diseases, such as psoriasis, neurological and psychiatric disorders or some malignancies. In the case of PV, genetic risk factors include either HLA alleles DRB1*04:02 and DQB1*05:03 or non-HLA genes, i.e. DSG3, TAP2, IL6, and ST18. In addition, environmental risk factors, in particular use of penicillamine and captopril, as well as exposure to pesticides, metal vapor, UV, ionizing radiation, burns, undergoing surgery or stressful life events have been noted. In genetically susceptible individuals, the autoimmune reaction is driven by autoreactive T and B lymphocytes. Autoreactive T cells are educated by antigen presenting cells (APC) that present Dsg peptides via HLA class II molecules. Consequently, autoreactive T helper cells specific for Dsg molecules drive generation of autoreactive B cells and secretion of the tissue-bound and circulating autoantibodies to Dsg (Kasperkiewicz et al., 2017; Schmidt et al., 2019). Pemphigus can be treated with systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin (IVIG) and plasmapheresis. In addition, rituximab, a monoclonal antibody against the CD20 molecule (B cells’ marker), is another promising therapeutic option (Kasperkiewicz et al., 2017).

Pemphigoid is another well-defined subgroup of AIBD that is characterized by the presence of tissue-bound and circulating autoantibodies directed against different structural molecules present in hemidesmosomes at the cutaneous basement membrane (Schmidt & Zillikens, 2013). Bullous pemphigoid (BP), where autoantibodies to BP180 (collagen type XVII or COL17) and BP230 are observed, is the most common autoimmune subepidermal blistering disorder, whose incidence, similarly to other autoimmune diseases, is constantly increasing (Witte et al., 2018). By contrast, epidermolysis bullosa acquisita (EBA), a subepidermal blistering disease with autoantibodies to type VII collagen (COL7), is one of the rarest AIBD, with an incidence rate of 0.2–0.5 per million per year (Vorobyev et al., 2017). The etiology of pemphigoid seems to be unclear, nevertheless either environmental or genetic risk factors have been described. Numerous data found an association between pemphigoid and other immunological disorders, including psoriasis (Schmidt & Zillikens, 2013; Ohata et al., 2015). In addition, BP has been strongly associated with neurological disorders, including cognitive impairment, Parkinson’s disease, stroke, epilepsy or multiple sclerosis (Schmidt & Zillikens, 2013). Several trigger factors, such as penicillin, vancomycin, gentamycin, trauma, burns, radiotherapy, UV-radiation, vaccination and contact allergy to metals have been described (Schmidt & Zillikens, 2013; Vorobyev et al., 2017). In addition, an association between HLA-DQB1*0301 and BP or mucous membrane pemphigoid (MMP), as well as the risk allele HLA-DRB1*15:03 or association between HLA-DR2 and EBA, have been reported (Schmidt & Zillikens, 2013; Kasperkiewicz et al., 2016). The majority of studies concerning the pathophysiology of pemphigoid are based on experimental animal models and numerous evidences pointed to pathogenic importance of both, the local and systemic innate and adaptive autoimmune responses against structural proteins of the dermal–epidermal junction (Schmidt & Zillikens, 2013; Kasperkiewicz et al., 2016).

As in the case of pemphigus, the pemphigoid diseases can be controlled medically by using corticosteroids, high-doses of IVIG, rituximab, plasmapheresis, and immunoadsorption (Schmidt & Zillikens, 2013; Koga et al., 2019).

Vitamin D status in THE autoimmune bullous diseases

Several epidemiological studies demonstrated that the vitamin D deficiency leads to an increased prevalence of autoimmune diseases, such as the multiple sclerosis, diabetes type 1, rheumatoid arthritis or systemic lupus erythematosus (Yang et al., 2013, Dankers et al., 2017). More recently, the role of vitamin D has been also investigated in AIBD and the emerging evidence suggests an increased frequency of vitamin D deficiency/insufficiency in patients with pemphigus and pemphigoid, such as the PV and BP or EBA, respectively (Marzano et al., 2012 and Marzano et al., 2015; Tukaj et al., 2013; El-Komy et al., 2014; Joshi et al., 2014; Zarei et al., 2014; Moravvej et al., 2016; Sarre et al., 2016; Tukaj et al., 2018) (Table 1). In addition, in some reports, lower concentrations of 25(OH)D have been associated with AIBD activity, pointing towards a possible causative role of hypovitaminosis D in the disease process (Zarei et al., 2014; Marzano et al., 2015; Moravvej et al., 2016). The role of vitamin D deficiency in AIBD, however, is still a matter of debate because other studies have found no difference in the 25(OH)D levels between patients and healthy subjects, possibly due to concomitantly observed low vitamin D levels in the corresponding controls and/or limited number of patients and controls involved in the study (Tukaj et al., 2013; Joshi et al., 2014; Moravvej et al., 2016; Sarre et al., 2016).

Experimental therapies using vitamin D analogues in THE autoimmune bullous diseases

The efficacy of vitamin D supplementation in experimental models of arthritis, lupus, multiple sclerosis, encephalomyelitis, diabetes type 1, and atherosclerosis has been confirmed in various studies (Deluca & Cantorna, 2001; Takeda et al., 2010; Dankers et al., 2017). Moreover, several clinical trials have been performed to investigate the therapeutic value of vitamin D supplementation in multiple sclerosis, rheumatoid arthritis, Crohn’s disease, type I diabetes, and systemic lupus erythematosus (Dankers et al., 2017). While patients with the autoimmune bullous skin diseases suffer from vitamin D deficiency (Marzano et al., 2012 and Marzano et al., 2015; Tukaj et al., 2013; El-Komy et al., 2014; Joshi et al., 2014; Zarei et al., 2014; Moravvej et al., 2016; Sarre et al., 2016; Tukaj et al., 2018), a direct link between hypovitaminosis D and the development of autoimmune bullous diseases has not been proven.

It is hypothesized that binding of bullous pemphigoid (BP)-specific IgG autoantibodies to BP180 initiates the Fc receptor-independent events leading to the excessive expression and secretion of pro-inflammatory IL-6 and IL-8 from basal keratinocytes (Schmidt et al., 2000; Schmidt & Zillikens, 2013). Activation of complement at the dermal–epidermal junction (DEJ), together with the mast cells’ degranulation and inflammatory chemokines result in the infiltration of inflammatory cells, including granulocytes, in the upper dermis. The reactive oxygen species (ROS) and matric metalloproteinases (MMP) released by the activated granulocytes induce dermal-epidermal splitting and blister formation (Schmidt & Zillikens, 2013). We have recently found that bullous pemphigoid (BP) IgG-induced IL-6 and IL-8 secretion from the human keratinocytes HaCaT cells was reduced in the presence of calcitriol via inhibition of STAT3 phosphorylation and NFκB activity (Tukaj et al., 2016) (Fig. 1a). Effectiveness of the calcitriol treatment was confirmed in vivo by using a well-established EBA mouse model which offers an elegant tool to study the pathogenesis of autoantibody-induced and immune cell-mediated blistering, as well as enables investigators to identify new therapeutic targets for EBA and other AIBD (Bieber et al., 2016; Kasperkiewicz et al., 2016). We have found for the first time that orally administrated calcitriol modulated the clinical course of experimental EBA through induction of the T and B regulatory cells, as well as down-regulation of neutrophil activity and blockade of proinflammatory Th17 cell population (Tukaj et al., 2018). Because both, the immunosuppressive Treg and Breg, or proinflammatory Th1, Th17, and neutrophils are associated with the AIBD development (Hammers et al., 2011; Tukaj et al., 2014; Tukaj et al., 2018; Bieber et al., 2017a; Bieber et al., 2017b; Chakievska et al., 2019), targeting these cell populations is an important therapeutic approach in the described disorders (Fig. 1b).

Conclusion

Despite growing understanding of AIBD pathogenesis, treatment of this group of skin disorders remains challenging. This is because of frequent relapses, numerous side effects due to corticosteroid usage, or simply due to lack of effective treatment (Koga et al., 2019; Izumi et al., 2019). In addition, the incidence of AIBD is constantly increasing (Witte et al., 2018), and therefore there is a growing urgency for discovering an effective treatment or prophylactic regimen in order to reduce the incidence of these autoimmune disorders. Despite the usage of topical vitamin D analogues in the treatment of autoimmune skin conditions, such as psoriasis and vitiligo (Xing & Xu, 2012; Umar et al., 2018), there is a limited number of epidemiological and experimental studies on vitamin D involvement in the autoimmune bullous diseases. This requires further research and clinical trials involving the pemphigus and pemphigoid patients. In fact, several case reports have described that the Hailey-Hailey disease, also known as a familial benign chronic pemphigus, can be successfully controlled with vitamin D analogues applied either orally or topically (Bianchi et al., 2004; Rajpara & King, 2005; Megna et al., 2019). Finally, because there are many case reports describing the coexistence of AIBD and psoriasis (Ohata et al., 2015), the role of topically applied vitamin D analogues in the treatment of these disorders needs to be properly evaluated.

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