Vitamin D deficiency and lower TGF-β/IL-17 ratio in a North Indian cohort of pemphigus vulgaris

Abstract

BackgroundPemphigus vulgaris (PV) is an autoimmune bullous disease caused by acantholysis of keratinocytes due to pathogenic desmoglein-3 autoantibodies. Role of vitamin D has been recently implicated in various autoimmune conditions due to its immunomodulatory effects on innate and adaptive immune responses. One of the key mechanisms of the immune regulation by vitamin D is through its anti-inflammatory effects by suppression of Th17 functions. Thus, vitamin D may be involved in pathogenesis of PV. In this study, the serum vitamin D, IL-17 and TGF-β levels in PV patients as well as healthy controls were estimated in order to understand the underlying immune mechanism involved in disease pathogenesis.ResultsThis retrospective study included 30 biopsy proven PV patients’ sera. Ten age matched volunteers without any cutaneous or autoimmune conditions were recruited as healthy control (HC). Serum Vitamin D levels were measured using chemiluminescence, whereas IL-17 and TGF-β levels were determined using ELISA. All patients showed deficient vitamin D levels (11.1 ± 5.8 ng/ml). Moreover, all the PV patients had elevated serum IL-17 levels (210.7 ± 105.3), whereas it was not detectable in any (n = 10) of the healthy controls sera (ELISA sensitivity ≥ 8 pg/ml). The mean serum TGF-β concentration was also lower in patient sera as compared to healthy control, and the TGF-β/IL-17 ratio was drastically reduced in patients (30.30 ± 28), as compared to healthy controls (1363.34 ± 559.52).ConclusionsHypovitaminosis is common in North India, as ascertained by deficient levels in healthy controls, and was also consistently observed in PV patient. These low levels were not related to age or gender. The increased serum IL-17 and dramatic reduction in TGF-β/IL-17 ratio in diseased patients further indicate that dysregulation of the Treg/Th-17 axis of T effector cells may be of significance in pathogenesis of PV. Thus, the study indicates that vitamin D insufficiency may be a predisposing factor in PV, contributing through its role in any of the various adaptive immune mechanisms that regulate T cell functions in vivo. Thus, there is a need to further evaluate the Treg/Th-17 axis, as it may have an important role in disease progression.

Vitamin D in autoimmune bullous disease

“…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 andMarzano 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).…”

“…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).…”

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

“…VDR expression on monocytes and T cells allows vitamin D to exert immunomodulatory effects on a transcriptional level and downregulate proinflammatory cytokines . Hypovitaminosis D can thus result in immune dysregulation and is associated with an increased prevalence of autoimmune diseases . Notably, pemphigoid patients have hypovitaminosis D which correlates with increased disease severity .…”

“…208 Hypovitaminosis D can thus result in immune dysregulation and is associated with an increased prevalence of autoimmune diseases. [209][210][211] Notably, pemphigoid patients have hypovitaminosis D which correlates with increased disease severity. 212 In preclinical trials, mice receiving prophylactic oral calcitriol experienced milder skin lesions and histologically less intense dermal infiltration of neutrophils.…”

Immune cellular regulation on autoantibody production in pemphigus

“…Joshi et al . examined the serum IL‐17 and TGF‐β levels of PV patients by enzyme‐linked immunoassay and found that all the PV patients had elevated serum IL‐17 levels, whereas it was not detectable in any healthy controls . The mean serum TGF‐β concentration was also lower in patient sera as compared with healthy control, and the TGF‐β/IL‐17 ratio was drastically reduced in patients.…”