The hormonally active, UVB-induced vitamin D metabolite, 1,25-dihydroxyvitamin D3 (calcitriol), participates in regulation of immune responses through binding to the vitamin D receptor expressed in multiple cells of the immune system . There are several lines of evidence indicating vitamin D involvement in AIBD. A meta-analysis of 9 case–control studies revealed that the vitamin D level of patients with AIBD including BP was significantly lower than that in controls . On an experimental level, we previously showed that calcitriol inhibited BP180-NC16A IgG-induced secretion of pro-inflammatory cytokines in a human keratinocyte culture . In addition, calcitriol promoted regulatory T and B cells, inhibited pro-inflammatory Th17 cells and neutrophils, and attenuated autoantibody production in a mouse model of the BP-like pemphigoid disease epidermolysis bullosa acquisita . Moreover, previous studies observed that vitamin D inhibited the expression of pemphigus and pemphigoid autoantigens [13, 14]. In line with these reports, our current work showed that anti-BP180-NC16A IgG-reactive healthy individuals have significantly lower plasma vitamin D levels and about a two-fold higher percentage of vitamin D deficiency compared to anti-BP180-NC16A IgG-negative healthy persons. These findings are intriguing in two ways, as previously discussed in a similar context of ANA-positive healthy individuals . First, the observation that both BP autoantibody-positive healthy individuals and BP patients have reduced vitamin D indicates that the molecular mechanisms by which hypovitaminosis D would predispose to autoimmunity operate early in BP development, prior to the possible onset of clinical symptoms. Second, considering that AIBD patients possess some risk factors for hypovitaminosis D (i.e., skin lesions and pain may limit outdoor activities, where sun exposure may in turn trigger the disease), whereas BP180-NC16A IgG-positive healthy individuals do not , it can be therefore assumed that an abnormal vitamin D status is not solely the result of disease-associated lifestyle changes. Nevertheless, it needs to be mentioned that more than half of anti-BP180-NC16A IgG-negative healthy individuals also had inadequate plasma vitamin D levels, confirming that hypovitaminosis D is common in the general population (irrespective of subclinical autoimmune disease phenomena) [9, 15, 16].
A potential pathogenic relevance of the detected anti-BP180-NC16A autoantibodies in healthy individuals has been proposed . We could previously show that these autoantibodies formed immune complexes with recombinant antigen and dose-dependently stimulated neutrophils in vitro, although fine-epitope mapping within NC16A revealed differences in the binding pattern between healthy individuals and BP patients . BP is considered a Th2-mediated disease in which the presence of autoreactive T cells with increased, therapeutically relevant Th2-associated cytokines (e.g., IL-5, L-10, and IL-13) in serum and blister fluid has been reported [5, 17]. Our observation that these Th2 cytokines were predominantly elevated in the blood of anti-BP180-NC16A IgG-reactive compared to anti-BP180-NC16A IgG-negative individuals further suggests a subclinical, BP-like pathogenic environment which may potentially turn into full-blown disease by additional yet-to-be-defined factors.
In contrast, we did not find a direct correlation between the low vitamin D status and the upregulated Th2 cytokines in anti-BP180-NC16A IgG-reactive individuals, which may at least partly be explained by the fact that we analyzed normal blood donors without any known immunological diseases. In fact, different studies indicated variable correlations between vitamin D levels and the cytokine output by Th2 cells, with mostly allergic disorders showing an inverse relationship while some autoimmune diseases (e.g., systemic lupus erythematosus) or healthy subjects were lacking associations [18,19,20]. Interestingly, we observed a series of positive cross-correlations between the studied cytokines (i.e., IL-2, IL-5, IL-9, IL-10, and IL-13). The presence of these associations may either suggest a physiological interplay or a convergent pathway toward Th2 polarization characteristic of the autoimmune process in BP patients.
Limitations of this study include lack of information regarding demographic data and long-term follow-up of the blood donors.