Dipeptidyl Peptidase 4 Inhibitor‒Associated Bullous Pemphigoid Is Characterized by an Altered Expression of Cytokines in the Skin

Tuusa, Jussi; Kokkonen, Nina; Mattila, Anja; Huilaja, Laura; Varpuluoma, Outi; Rannikko, Sirpa; Glumoff, Virpi; Miettunen, Jouko; Tasanen, Kaisa

doi:10.1016/j.jid.2022.07.006

Cited by 1 publication

(3 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DPP4i may exhibit various immune-modulatory functions in BP progression [52]. Although our in vitro laboratory data on IL-6 are in line with recent reports [22], the highly complicated in vivo pathogenic mechanisms involved are still largely unexplored. Finally, we only treated HaCaT cells with vildagliptin, the consistently reported most common culprit of DPP4i.…”

Section: Discussionsupporting

confidence: 81%

“…The surrounding increased IL-6 may feedback to stimulate more IL-6 production from keratinocytes and drive the downstream inflammatory cascades of DBP [47]. In support of this, a recently published article demonstrated comparably elevated IL-6 mRNA and protein levels in both lesional and non-lesional skin tissues of either IBP or DBP patients [22]. Importantly, it has also been reported that BP disease activity can be controlled by the modulation of IL-6 production by keratinocytes [51].…”

Section: Discussionmentioning

confidence: 86%

“…Izumi et al [20] identified autoantibodies that targeted the mid-portion of Collagen 17 but not the NC16A region of BP180 in non-inflammatory BP cases. Controversially, a recently published paper reported higher levels of eosinophil-attractive cytokines in DBP skin samples, which correlated with serum anti-BP180 NC16A IgG autoantibody titers [22]. These emerging study results make the underlying pathogenic mechanisms of DBP more intriguing; however, they remain unclear [23].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dipeptidyl Peptidase-4 Inhibitor-Related Bullous Pemphigoid: Clinical, Laboratory, and Histological Features, and Possible Pathogenesis

Hung

Chang

Wang

2022

IJMS

View full text Add to dashboard Cite

Dipeptidyl peptidase-4 inhibitor (DPP4i) is a widely used antidiabetic agent. Emerging cases of DPP4i-associated bullous pemphigoid (DBP), whose pathogenesis remains unclear, have been reported. Thus, a retrospective study was conducted from January 2016 to June 2021 to determine the clinical, laboratory, and histopathological features of DBP and idiopathic bullous pemphigoid (IBP). We set up in vitro experiments using vildagliptin-treated HaCaT keratinocytes to validate what we found by analyzing published RNA sequencing data about the genes related to the dermal–epidermal junction. We also observed IL-6 expression by HaCaT cells treated with vildagliptin. We enrolled 20 patients with DBP and 40 patients with IBP. The total Bullous Pemphigoid Disease Area Index (BPDAI) score was similar in both groups. However, the BPDAI score of erosions and blisters in DBP was significantly higher than that in IBP (24.6 vs. 16.68, p = 0.0189), and the score for urticaria and erythema was lower in DBP (12 vs. 19.05, p = 0.0183). The pathological features showed that the mean infiltrating eosinophil number per high-power field was significantly lower in DBP than in IBP (16.7 vs. 27.08, p = 0.023). The expression of LAMA3, LAMB3, LAMC2, DST, and COL17A1 decreased significantly in vildagliptin-treated human keratinocytes. On the other hand, IL-6, the hallmark cytokine of bullous pemphigoid (BP) severity, was found to be upregulated in HaCaT cells by vildagliptin. These experimental findings imply less of a requirement for eosinophil infiltration to drive the inflammatory cascades in DBP blistering. Both immunologic and non-immunologic pathways could be employed for the development of DBP. Our findings may help explain the higher incidence of non-inflammatory BP that was observed in DBP.

show abstract

Section: Discussionsupporting

confidence: 81%