Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis: Focus on Abrocitinib, Baricitinib, and Upadacitinib

Atopic dermatitis (AD) is a clinically heterogenous, inflammatory skin condition with a high impact on patients’ daily activities that remains difficult to treat. The knowledge acquired over the last decade on AD pathophysiology and disease burden led to the development of new targeted therapeutic options that enable clinicians to better manage AD patients. The JAK/STAT signaling pathway modulates several immune pathways (T helper (Th)1, Th2, Th17, and Th22 cells) that have been found to be involved in AD pathogenesis. For this reason, JAK inhibitors emerged as a possible therapy for AD. Baricitinib, upadacitinib, and abrocitinib are the three oral JAK inhibitors already approved or in advanced clinical development for this purpose. The results showed that this drug class is highly effective achieving symptomatic relief (itch control) in the short term, as well as improving disease severity in the short and medium term. However, their efficacy should be balanced with possible side effects, that have been reported in clinical trials. More data on the long-term efficacy and safety, as well as from head-to-head comparisons and from real-world setting will be crucial to position oral JAK inhibitors in the AD therapeutic armamentarium.

Increased Numbers of Circulating Th22 and Th17 Cells in Children With Kawasaki Disease

T-helper (Th) 17 and Th22 cells are critical for the pathogenic process of Kawasaki Disease (KD). A total of 43 children with freshly diagnosed KD and 20 healthy controls (HC) were quantified for the numbers of Th17, Th22 and Th1 cells by flow cytometry. The concentrations of serum IL-17, IL-22, IL-6, IFN-γ and TNF-α were examined by ELISA. Compared to those in the HC, significantly increased numbers of Th17 and Th22 cells, but not Th1 cells, and higher levels of serum IL-17 and IL-22, but not IFN-γ, were found in KD patients. Stratification analysis indicated the numbers of both Th17 and Th22 cells and the concentrations of serum IL-17 and IL-22 in KD patients with coronary artery lesions (CAL) were significantly greater than that in those with noncoronary artery lesions (NCAL). Treatment with the intravenous immunoglobulin (IVIG) therapy significantly decreased numbers of Th22 and Th17 cells as well as the serum concentrations of IL-22 and IL-17 in KD patients. The concentrations of serum IL-22 and IL-17 were correlated positively with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values as well as N-terminal pro-brain natriuretic peptide (NT-proBNP) in those patients respectively. Conclusion: Our study provided direct evidence that Th22 and Th17 cells might contribute to the pathogenesis of KD.

Dendritic Cells and T Cell Subsets in the Development of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with steatosis, inflammation and fibrosis. Liver dendritic cells (DCs) are usually tolerogenic in the sinusoidal milleu composed of immunosuppressive cytokines. In NAFLD and NASH, DCs become pro-inflammatory and modulate hepatic immune response. Murine liver DCs are three major subtypes: classical (lymphoid) cDC1 or the crosspresenters (CD8α+CD103+), classical (myeloid) cDC2 (CD11b+) and plasmacytoid pDCs (PDCA-1+Siglec-H+) and two additional subtypes or lymphoid + myeloid DCs and NKDCs. Similarly, human liver DCs are three subtypes or CD141+CLEC9A+, CD1c+ (BDCA1+) and pDCs (CD303+BDCA2+). Compared to blood human hepatic DCs are less immature and predominantly induce regulatory T cells (Tregs) and IL-4 secreting T cells (Th2). DCs polarize T cells into different Th types that are in interrelations in NAFLD/NASH. T helper 1 (Th1) (T-bet) cells are associated with adipose tissue inflammation. The differentiation of Th2 (GATA3) cells is induced by IL-4 DCs, increased in NAFLD. Similarly, Th17 cells (RORγt/ RORc) are increased in NAFLD and NASH. Tregs (FoxP3) are increased in the liver in steatosis and Th22 cells (AHR) are elevated in diabetes mellitus 2 (DM2) and adiposity. CD8+ T cells γδT cells and MAIT cells also contribute to liver inflammation.

Lithospermum erythrorhizon Alleviates Atopic Dermatitis-like Skin Lesions by Restoring Immune Balance and Skin Barrier Function in 2.4-Dintrochlorobenzene-Induced NC/Nga Mice

The incidence of atopic dermatitis (AD), a disease characterized by an abnormal immune balance and skin barrier function, has increased rapidly in developed countries. This study investigated the anti-atopic effect of Lithospermum erythrorhizon (LE) using NC/Nga mice induced by 2,4-dinitrochlorobenzene. LE reduced AD clinical symptoms, including inflammatory cell infiltration, epidermal thickness, ear thickness, and scratching behavior, in the mice. Additionally, LE reduced serum IgE and histamine levels, and restored the T helper (Th) 1/Th2 immune balance through regulation of the IgG1/IgG2a ratio. LE also reduced the levels of AD-related cytokines and chemokines, including interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor-α (TNF-α), thymic stromal lymphopoietin, thymus and activation-regulated chemokine, macrophage-derived chemokine, regulated on activation, normal T cell expressed and secreted, and monocyte chemoattractant protein-1 in the serum. Moreover, LE modulated AD-related cytokines and chemokines expressed and secreted by Th1, Th2, Th17, and Th22 cells in the dorsal skin and splenocytes. Furthermore, LE restored skin barrier function by increasing pro-filaggrin gene expression and levels of skin barrier-related proteins filaggrin, involucrin, loricrin, occludin, and zonula occludens-1. These results suggest that LE is a potential therapeutic agent that can alleviate AD by modulating Th1/Th2 immune balance and restoring skin barrier function.

Induction of IL-22-Producing CD4+ T Cells by Segmented Filamentous Bacteria Independent of Classical Th17 Cells

The intestinal microbiota modulates IL-22 production in the intestine, including the induction of IL-22-producing CD4+ T helper cells. Which specific bacteria are responsible for the induction of these cells is less well understood. Here, we demonstrate through the use of novel gnotobiotic knock-in reporter mice that segmented filamentous bacteria (SFB), which are known for their ability to induce Th17 cells, also induce distinct IL-17A negative CD4+ T cell populations in the intestine. A subset of these cells instead produces IL-22 upon restimulation ex vivo and also during enteric infections. Furthermore, they produce a distinct set of cytokines compared to Th17 cells including the differential expression of IL-17F and IFN-γ. Importantly, genetic models demonstrate that these cells, presumably Th22 cells, develop independently of intestinal Th17 cells. Together, our data identifies that besides Th17, SFB also induces CD4+ T cell populations, which serve as immediate source of IL-22 during intestinal inflammation.

Hidradenitis Suppurativa: Where We Are and Where We Are Going

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily affecting apocrine gland-rich areas of the body. It is a multifactorial disease in which genetic and environmental factors play a key role. The primary defect in HS pathophysiology involves follicular occlusion of the folliculopilosebaceous unit, followed by follicular rupture and immune responses. Innate pro-inflammatory cytokines (e.g., IL-1β, and TNF-α); mediators of activated T helper (Th)1 and Th17 cells (e.g., IFN-γ, and IL-17); and effector mechanisms of neutrophilic granulocytes, macrophages, and plasma cells are involved. On the other hand, HS lesions contain anti-inflammatory mediators (e.g., IL-10) and show limited activity of Th22 cells. The inflammatory vicious circle finally results in pain, purulence, tissue destruction, and scarring. HS pathogenesis is still enigmatic, and a valid animal model for HS is currently not available. All these aspects represent a challenge for the development of therapeutic approaches, which are urgently needed for this debilitating disease. Available treatments are limited, mostly off-label, and surgical interventions are often required to achieve remission. In this paper, we provide an overview of the current knowledge surrounding HS, including the diagnosis, pathogenesis, treatments, and existing translational studies.

Role of Th22 Cells in Human Viral Diseases

Naive CD4+ T cells can differentiate into different cell subsets after receiving antigen stimulation, which secrete corresponding characteristic cytokines and thereby exert biological effects in various diseases. Th22 cells, a novel subset of CD4+ T cells, are different from Th1, Th2, Th17, and Treg cell subsets, which have been discovered in recent years. They can express CCR4, CCR6, and CCR10 molecules and secrete IL-22, IL-13, and TNF-α. They are not able to secrete IL-17, IL-4, and interferon-γ (IFN-γ). IL-22 is considered as a major effector molecule of Th22 cells whose functions and mechanisms of regulating cell differentiation have been constantly improved. In this review, we provide an overview of the origin, differentiation of Th22 cells. Moreover, we also describe the interrelationships between Th22 cells and Th17, Th1, and Th2 cells. Additionally, the role of Th22 cells were discussed in human diseases with virus infection, which will provide novel insight for the prevention and treatment of viral infection in human.