Increased expression of NLRP3 inflammasome components and interleukin-18 in patients with bullous pemphigoid

Fang, Hui; Shao, Shuai; Cao, Tianyu; Lei, Jie; Dang, Erle; Zhang, Jieyu; Wang, Gang

doi:10.1016/j.jdermsci.2016.04.009

Cited by 30 publications

(32 citation statements)

References 34 publications

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“…New studies have revealed a complex interplay between innate and adaptive immunity behind the formation of blisters, however not yet well understood. Overexpression of nod‐like receptor P3 inflammasome components and IL‐18 seems to correlate with the titre of serum autoantibodies, as well as disease severity . It is also suggested that there is an interaction between periostin and CD163+ skin‐resident macrophages in BP .…”

Section: Pathogenesis Of Bullous Pemphigoidmentioning

confidence: 99%

Glucocorticoids: The mode of action in bullous pemphigoid

Kubin

Hellberg

Palatsi

2017

Experimental Dermatology

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Bullous pemphigoid (BP) is the most common of pemphigoid diseases caused by autoantibodies against the structures of dermoepidermal junction followed by complement activation, innate immune cell infiltration, neutrophil proteinase secretion and subepidermal blister formation. The first-line treatment of BP is topical and systemic glucocorticoids (GC). Regulation of the immune system and inflammatory cells is the main target of GC actions. GCs act through genomic and non-genomic mechanisms.The human glucocorticoid receptor (GR) mediates most of the biologic effects of GC:cytosolic GR binds GCs and is capable to bind to glucocorticoid response elements in DNA and either transactivate or transrepress genes depending on the tissue and cell type. In addition, GR exerts rapid, non-genomic effects possibly mediated by membrane-localized receptors or by translocation to mitochondria. GCs can also interact directly with several enzymes and cytokines. As a target treatment for BP, the production of autoantibodies should be discontinued. GCs, in spite of their wide immunosuppressive actions, are weak to stop immunoglobulin G (IgG) autoantibody formation. However, both systemic and topical GCs are able to reduce the clinical symptoms of BP. GCs are used to inhibit the secondary inflammation and symptoms, such as blistering and pruritus, and it is shown that GC treatment will gradually decrease also the autoantibody formation. Our review article analyses the mode of action of GC treatment in BP, as far it is possible due to paucity of modern immunological studies. K E Y W O R D Sauto-bullous pemphigoid180 antibodies, B-cell-activating factor, bullous pemphigoid, corticosteroids, Interleukin-17

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Section: Pathogenesis Of Bullous Pemphigoidmentioning

confidence: 99%

Glucocorticoids: The mode of action in bullous pemphigoid

Kubin

Hellberg

Palatsi

2017

Experimental Dermatology

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“…Inflammasomes are multi‐protein signalling complexes consisting of NLRP3 domains, caspase‐1 enzymes and immature forms of IL‐1β and IL‐18 . Recent studies have identified upregulation of the NLRP3 inflammasome in the serum and peripheral blood mononuclear cells of BP patients . Aberrant NLRP3 inflammasome activity increases activation of IL‐1β and IL‐18, both known to stimulate proinflammatory cytokine release (IL‐6, IL‐8 and IL‐17) and pushes differentiation of immune effectors such as Th1 and Th17 cells .…”

Section: Evolving Therapeutic Targetsmentioning

confidence: 99%

“…Inflammasome activity has been implicated in development of autoimmune diseases and inflammation‐induced cancer growth . Although its role in BP remains unclear, inhibition using corticosteroids in experimental models decreased expression of NLRP3 and its respective components . Currently, a randomized open label, controlled trial evaluating the efficacy of diacerein in BP (NCT03286582).…”

Section: Evolving Therapeutic Targetsmentioning

confidence: 99%

“…120 Recent studies have identified upregulation of the NLRP3 inflammasome in the serum and peripheral blood mononuclear cells of BP patients. 121 Aberrant NLRP3 inflammasome activity increases activation of IL-1b and IL-18, both known to stimulate proinflammatory cytokine release (IL-6, IL-8 and IL-17) and pushes differentiation of immune effectors such as Th1 and Th17 cells. [121][122][123] Inflammasome activity has been implicated in development of autoimmune diseases and inflammation-induced cancer growth.…”

Section: Small Molecular Inhibitorsmentioning

confidence: 99%

“…121 Aberrant NLRP3 inflammasome activity increases activation of IL-1b and IL-18, both known to stimulate proinflammatory cytokine release (IL-6, IL-8 and IL-17) and pushes differentiation of immune effectors such as Th1 and Th17 cells. [121][122][123] Inflammasome activity has been implicated in development of autoimmune diseases and inflammation-induced cancer growth. 120,124 Although its role in BP remains unclear, inhibition using corticosteroids in experimental models decreased expression of NLRP3 and its respective components.…”

Section: Small Molecular Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

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

Kridin

Kowalski

Kneiber

et al. 2019

Acad Dermatol Venereol

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Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B‐cell depletion, T‐regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases.

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Association of Dipeptidyl Peptidase 4 Inhibitor Use With Risk of Bullous Pemphigoid in Patients With Diabetes

et al. 2019

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IMPORTANCE Recent studies suggest that dipeptidyl peptidase 4 (DPP-4) inhibitors are associated with an increased risk of developing bullous pemphigoid (BP). Population-based studies on the association between DPP-4 inhibitors and BP are limited. OBJECTIVE To characterize the potential association between the use of DPP-4 inhibitors and an increased risk of developing BP. DESIGN, SETTING, AND PARTICIPANTS This retrospective, nationwide, population-based, case-control study using Korean insurance claims data from January 1, 2012, to December 31, 2016, included patients with newly diagnosed BP and diabetes. Control patients with diabetes (and without BP) were randomly obtained after matching for age, sex, and year of diagnosis within the same period. MAIN OUTCOMES AND MEASURES The number of patients with newly diagnosed BP and diabetes per year and annual changes in the proportion of patients with diabetes among all patients with BP were measured. The association between use of DPP-4 inhibitors and risk of developing BP was analyzed using univariate and multivariate logistic regression analyses. RESULTS The study included 670 case patients (with diabetes and BP) and 670 control patients (with only diabetes) (mean [SD] age, 75.3 [10.0] years in each group; 342 [51.0%] male in each group). The number of patients with diabetes and BP more than doubled during the study period (from 77 in 2012 to 206 in 2016). The proportion of patients with diabetes among all patients with BP also increased (from 0.18 in 2012 to 0.33 in 2016). The use of DPP-4 inhibitors was associated with a significant increase in the risk of developing BP (adjusted odds ratio [aOR], 1.58; 95% CI, 1.25-2.00; P < .001); among all DPP-4 inhibitors used in Korea, the highest aOR was associated with the use of vildagliptin (aOR, 1.81; 95% CI, 1.31-2.50; P < .001). Subgroup analyses revealed a significant association in male patients (aOR, 1.91; 95% CI, 1.39-2.63; P < .001) and that vildagliptin was the most high-risk DPP-4 inhibitor (aOR, 2.70; 95% CI, 1.73-4.34; P < .001). CONCLUSIONS AND RELEVANCE The findings suggest that DPP-4 inhibitors are associated with a significantly increased risk of the development of BP in patients with diabetes. Of the DPP-4 inhibitors available in Korea, vildagliptin was associated with the highest risk, particularly in male patients. Practitioners should consider that DPP-4 inhibitors, particularly vildagliptin, may be associated with the development of BP in patients with diabetes. These nationwide, population-based results may serve as a foundation for further studies seeking to understand how DPP-4 inhibitors contribute to the development of BP.

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Increased expression of NLRP3 inflammasome components and interleukin-18 in patients with bullous pemphigoid

Cited by 30 publications

References 34 publications

Glucocorticoids: The mode of action in bullous pemphigoid

Glucocorticoids: The mode of action in bullous pemphigoid

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

Association of Dipeptidyl Peptidase 4 Inhibitor Use With Risk of Bullous Pemphigoid in Patients With Diabetes

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