JAK-STAT pathway, type I/II cytokines, and new potential therapeutic strategy for autoimmune bullous diseases: update on pemphigus vulgaris and bullous pemphigoid

Abstract

Autoimmune Bullous Diseases (AIBDs), characterized by the formation of blisters due to autoantibodies targeting structural proteins, pose significant therapeutic challenges. Current treatments, often involving glucocorticoids or traditional immunosuppressants, are limited by their non-specificity and side effects. Cytokines play a pivotal role in AIBDs pathogenesis by driving inflammation and immune responses. The JAK-STAT pathway is central to the biological effects of various type I and II cytokines, making it an attractive therapeutic target. Preliminary reports suggest that JAK inhibitors may be a promising approach in PV and BP, but further clinical validation is required. In AIBDs, particularly bullous pemphigoid (BP) and pemphigus vulgaris (PV), JAK inhibitors have shown promise in modulating pathogenic cytokine signaling. However, the safety and selectivity of JAK inhibitors remain critical considerations, with the potential for adverse effects and the need for tailored treatment strategies. This review explores the role of cytokines and the JAK-STAT pathway in BP and PV, evaluating the therapeutic potential and challenges associated with JAK inhibitors in managing these complex disorders.

Keywords: JAK inhibitors; JAK-STAT pathway; autoimmune bullous diseases; bullous pemphigoid; cytokines; pemphigus vulgaris.

Figure 1

Activation of the canonical JAK-STAT signaling pathways. (1) Type I//II cytokines act through receptors associated with JAK. The receptors comprise at least two chains, each linked to a specific JAK; (2) Binding of ligand dimerizes the receptor, resulting in phosphorylation and activation of JAK for each other, which then phosphorylates the receptor. The STAT family has an N-terminal structural domain that allows STAT to form inactive dimers; (3) STAT bind to the phosphorylated receptor, which in turn phosphorylates by JAK; (4) STAT detach from the receptor to form activated dimers; (5) STAT dimers enter the nucleus, bind to DNA binding domain (DBD) and regulate transcription, which is involved in cell proliferation, differentiation and apoptosis. Created with Adobe Illustrator2023.

Figure 2

Cytokine involvement in pemphigus vulgaris. Exposed desmogleins (Dsgs) identified by antigen-presenting cells such as dendritic cells and present the antigen to autoreactive naïve CD4⁺T cells. Subsequently, under the influence of various cytokines, these T cells differentiate into distinct subsets, secreting cytokines that predominantly exert their biological effects via the JAK-STAT pathway. Specifically, Th2 differentiation is enhanced, leading to the secretion of Th2 cytokines IL-4, IL-5, and IL-10, while simultaneously suppressing Th1 responses and downregulating Th1 cytokines such as IL-2 and IFN-γ. This shift may be associated with cytokines released by NK cells. Additionally, Th17 and Tfh cell differentiation is amplified, resulting in the secretion of IL-6, IL-17, IL-21, and IL-23. Notably, IL-6 and IL-17 promote inflammatory responses, IL-21 enhances B cell activation into plasma cells, and IL-4 and IL-10 facilitate antibody class switching, prompting plasma cells to secrete IgG4 antibodies against Dsgs, culminating in acantholysis. Furthermore, a reduction in Treg cell differentiation is crucial for the proliferation of autoreactive T cells and antibody production. Figure image created with Adobe Illustrator2023.

Figure 3

Cytokine involvement in bullous pemphigoid (BP). Patient-specific factors and external stimuli lead to the exposure of BPAG antigens, recognized and presented by dendritic cells to naïve CD4+ T cells. These cells differentiate into CD4+ T cell subsets that secrete cytokines inducing pruritus and vesicle formation, predominantly through the JAK-STAT pathway. Specifically, Th2 cells secrete IL-4 and IL-13, which regulates IgG and IgE isotype switching, while IL-5 enhances eosinophil accumulation and activation. Eosinophils secrete IL-31 and toxic proteins, contributing to local inflammation. Th17 cells produce IL-17 and IL-23, activating neutrophils that release neutrophil elastase and MMP-9, degrading the extracellular matrix and disrupting dermal-epidermal junctions. Tfh cells stimulate high-affinity autoantibody production by B cells via IL-21. However, the role of Treg cells in BP remains controversial. Figure image created with Adobe Illustrator2023.