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Psoriasis Is Characterized by Accumulation of Immunostimulatory and Th1/Th17 Cell-Polarizing Myeloid Dendritic Cells
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Myeloid dermal dendritic cells (DCs) accumulate in chronically inflamed tissues such as psoriasis. The importance of these cells for psoriasis pathogenesis is suggested by comparative T-cell and DC-cell counts, where DCs outnumber T cells. We have previously identified CD11c(+)-blood dendritic cell antigen (BDCA)-1(+) cells as the main resident dermal DC population found in normal skin. We now show that psoriatic lesional skin has two populations of dermal DCs: (1) CD11c(+)BDCA-1(+) cells, which are phenotypically similar to those contained in normal skin and (2) CD11c(+)BDCA-1(-) cells, which are phenotypically immature and produce inflammatory cytokines. Although BDCA-1(+) DCs are not increased in number in psoriatic lesional skin compared with normal skin, BDCA-1(-) DCs are increased 30-fold. For functional studies, we FACS-sorted psoriatic dermal single-cell suspensions to isolate these two cutaneous DC populations, and cultured them as stimulators in an allogeneic mixed leukocyte reaction. Both BDCA-1(+) and BDCA-1(-) myeloid dermal DC populations induced T-cell proliferation, and polarized T cells to become T helper 1 (Th1) and T helper 17 (Th17) cells. In addition, psoriatic dermal DCs induced a population of activated T cells that simultaneously produced IL-17 and IFN-gamma, which was not induced by normal skin dermal DCs. As psoriasis is believed to be a mixed Th17/Th1 disease, it is possible that induction of these IL-17(+)IFN-gamma(+) cells is pathogenic. These cytokines, the T cells that produce them, and the inducing inflammatory DCs may all be important new therapeutic targets in psoriasis.
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... The main role of DCs in psoriasis is to orchestrate the immune response of T cells. Psoriatic DCs strongly induce both T H 17 and T H 1 T cells [178]. Notably, some of the T cells activated by psoriatic DCs simultaneously produce both IFN-γ and IL-17, which is not the case for healthy skin dermal DCs [178]. ...
... Psoriatic DCs strongly induce both T H 17 and T H 1 T cells [178]. Notably, some of the T cells activated by psoriatic DCs simultaneously produce both IFN-γ and IL-17, which is not the case for healthy skin dermal DCs [178]. ...
... DCs in psoriatic lesions are divided into two main groups-CD11c + BDCA-1 + resident DCs that are found also in healthy skin, and CD11c + BDCA-1 − inflammatory DCs that are more common in psoriasis lesional skin and are immature DCs that produce inflammatory cytokines [178]. These inflammatory DCs also include TNF-inducible NO synthase (iNOS)-producing DCs (TipDCs) [53,179]. ...
Psoriasis is one of the most common inflammatory skin diseases with a chronic, relapsing-remitting course. The last decades of intense research uncovered a pathological network of interactions between immune cells and other types of cells in the pathogenesis of psoriasis. Emerging evidence indicates that dendritic cells, TH17 cells, and keratinocytes constitute a pathogenic triad in psoriasis. Dendritic cells produce TNF-α and IL-23 to promote T cell differentiation toward TH17 cells that produce key psoriatic cytokines IL-17, IFN-γ, and IL-22. Their activity results in skin inflammation and activation and hyperproliferation of keratinocytes. In addition, other cells and signaling pathways are implicated in the pathogenesis of psoriasis, including TH9 cells, TH22 cells, CD8⁺ cytotoxic cells, neutrophils, γδ T cells, and cytokines and chemokines secreted by them. New insights from high-throughput analysis of lesional skin identified novel signaling pathways and cell populations involved in the pathogenesis. These studies not only expanded our knowledge about the mechanisms of immune response and the pathogenesis of psoriasis but also resulted in a revolution in the clinical management of patients with psoriasis. Thus, understanding the mechanisms of immune response in psoriatic inflammation is crucial for further studies, the development of novel therapeutic strategies, and the clinical management of psoriasis patients. The aim of the review was to comprehensively present the dysregulation of immune response in psoriasis with an emphasis on recent findings. Here, we described the role of immune cells, including T cells, B cells, dendritic cells, neutrophils, monocytes, mast cells, and innate lymphoid cells (ILCs), as well as non-immune cells, including keratinocytes, fibroblasts, endothelial cells, and platelets in the initiation, development, and progression of psoriasis.
... In this study, we aimed to characterize the circulating molecular profiles in EP patients to define a systemic inflammatory phenotype associated with the disease. One notable finding in our investigation was the significant Th1/Th17 skewing observed in EP patients, indicating an inflammation polarization similar to that seen in plaque psoriasis and EP skin biopsies [51,54]. This aligns with previous research and further supports the notion of shared inflammatory pathways between different forms of psoriasis [51]. ...
Erythrodermic atopic dermatitis (EAD) and erythrodermic psoriasis (EP) are rare yet debilitating inflammatory skin disorders that propose challenges in diagnosis and discovering effective therapeutic targets. Despite their clinical and histological similarities, the underlying molecular mechanisms and systemic biomarkers of these diseases are substantially unclear. In this study, we sought to investigate the differential serum proteome of EP and EAD patients and identify biomarkers for these two subtypes of erythroderma. We recruited 14 EAD patients, 14 EP patients and 14 healthy controls. Serum samples were collected and analyzed using the Olink high-throughput platform to assess the levels of 269 inflammation-/immune response-/cardiovascular-related biomarkers. Both EAD and EP patients exhibited enhanced immune activation and dysregulated cardiovascular profiles compared to healthy controls. EAD demonstrated a more pronounced inflammation tone, characterized by Th1/Th2/Th22/IL-1-dominant patterns, as well as increased TNF superfamily, Th17, and apoptosis markers. Conversely, EP displayed inflammation with Th1/Th17/TNF-skewing and mild Th2 upregulation, along with notable increases in epidermal-development markers. Disease severity in EAD was strongly correlated with apoptosis/Th2 markers, while correlated with Th17 markers in EP. Furthermore, a panel of eight markers (IL-17A/IL-17C/PI3/CCL20/SH2D1A/SIRT2/DFFA/IL-13) was identified that effectively discriminated between EP and EAD, with an Area Under the Curve greater than 0.8. Our study comprehensively characterizes the circulating molecular profiles in EAD and EP patients, providing insights into the similarities and complexities of their inflammation phenotypes. The identified serum biomarkers have the potential to differentiate between EP and EAD, which could aid in the diagnosis and guiding tailored therapeutics.
... Kryczek et al. found that IFN-γ is a potent promoter of human IL-17+ T cell function, induction, and trafficking [24]. IFN-γ synergizing with IL-17 can enhance β-defesin-2 secretion, suggesting that Th1 and Th17 cells can cooperate to contribute to the pathogenesis of psoriasis [25]. IFN-γ injections in the unaffected skin of a patient with psoriasis can cause pathogenic T cell infiltration, dendritic cell infiltration, and IL-23 secretion [26]. ...
Biologics are widely used to treat moderate-to-severe psoriasis. However, we have unmet needs for predicting individual patient responses to biologics before starting psoriasis treatment. We investigate a reliable platform and biomarkers for predicting individual patient responses to biologics. In a cohort study between 2018 and 2023 from a referral center in Taiwan, twenty psoriasis patients with or without psoriatic arthritis who had ever experienced two or more biologics were enrolled. Peripheral blood mononuclear cells obtained from these patients were treated with Streptococcus pyogenes and different biologics. The PASI reduction rate was strongly correlated with the reduction rate in the IL-13 level (p = 0.001) and the ratios of IFN-γ to IL-13 (p < 0.001), IFN-γ to IL-4 (p = 0.019), and IL-17A to IL-13 (p = 0.001). The PASI reduction difference was strongly correlated with the difference in the IFN-γ level (p = 0.002), the difference in the ratios of IFN-γ to IL-4 (p = 0.041), the difference in the ratios of IFN-γ to IL-13 (p = 0.006), the difference in the ratios of IL-17A to IL-4 (p = 0.011), and the difference in the ratios of IL-17A to IL-13 (p = 0.029). The biomarkers IFN-γ, IL-13, IFN-γ/IL4, IFN-γ/IL13, IL-17A/IL-4, and IL-17A/IL-13 are representative of the effectiveness of psoriasis treatment.
... A common route between TNF and IL-17 signaling is the stimulation of NF-κB. Recent studies have shown that TNF-α may activate the T H17 response indirectly by stimulating mDCs [111,115]. Also, the synergistic interaction of TNF-α and IL-17 has been recorded to activate certain genes found in fibroblast and osteoblast cells. Furthermore, a study by Zaba et al. reported the potential of psoriatic dermal DCs to induce T-cell proliferation and polarization, aiding in the differentiation of T H17 and T H1 cells [116]. ...
Autoimmunity is defined as the inability to regulate immunological activities in the body, especially in response to external triggers, leading to the attack of the tissues and organs of the host. Outcomes include the onset of autoimmune diseases whose effects are primarily due to dysregulated immune responses. In past years, there have been cases that show an increased susceptibility to other autoimmune disorders in patients who are already experiencing the same type of disease. Research in this field has started analyzing the potential molecular and cellular causes of this interconnectedness, bearing in mind the possibility of advancing drugs and therapies for the treatment of autoimmunity. With that, this study aimed to determine the correlation of four autoimmune diseases, which are type 1 diabetes (T1D), psoriasis (PSR), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE), by identifying highly preserved co-expressed genes among datasets using WGCNA. Functional annotation was then employed to characterize these sets of genes based on their systemic relationship as a whole to elucidate the biological processes, cellular components, and molecular functions of the pathways they are involved in. Lastly, drug repurposing analysis was performed to screen candidate drugs for repositioning that could regulate the abnormal expression of genes among the diseases. A total of thirteen modules were obtained from the analysis, the majority of which were associated with transcriptional, post-transcriptional, and post-translational modification processes. Also, the evaluation based on KEGG suggested the possible role of TH17 differentiation in the simultaneous onset of the four diseases. Furthermore, clomiphene was the top drug candidate for regulating overexpressed hub genes; meanwhile, prilocaine was the top drug for regulating under-expressed hub genes. This study was geared towards utilizing transcriptomics approaches for the assessment of microarray data, which is different from the use of traditional genomic analyses. Such a research design for investigating correlations among autoimmune diseases may be the first of its kind.
... T-helper 17 cells (Th17) [8][9][10][11]. Th17 expansion in turn is induced by IL-23, which is released by activated myeloid DCs [12,13]. However, IL-17A is also released by other cells in psoriatic skin, including polymorphonuclear neutrophils (PMNs) and mast cells [14][15][16][17]. ...
Targeting of the proinflammatory cytokine interleukin 17A (IL-17A) or tumor necrosis factor alpha (TNFα) with the monoclonal antibodies (mAbs) ixekizumab or adalimumab, respectively, is a successful therapy for chronic plaque psoriasis. The effects of these treatments on immune cell populations in the skin are largely unknown.
In this study, we compared the composition of cutaneous, lesional and non-lesional immune cells and blood immune cells in ixekizumab- or adalimumab-treated patients with psoriasis.
Our data reveal that both treatments efficiently downregulate T cells, macrophages and different subsets of dendritic cells (DCs) in lesional skin towards levels of healthy skin. In contrast to lesional skin, non-lesional areas in patients harbor only few or no detectable DCs compared to the skin of healthy subjects. Treatment with neither ixekizumab nor adalimumab reversed this DC imbalance in non-lesional skin of psoriatic patients.
Our study shows that anti-IL-17A and anti-TNFα therapy rebalances the immune cell repertoire of lesional skin in psoriatic patients but fails to restore the disturbed immune cell repertoire in non-lesional skin.
The skin resident immune cells act as sentinels protecting the host from distinct inflammatory processes. An intricate network of skin-resident immune cells and non-immune cells exist and their appropriate functioning is extremely crucial for host defense as well as tissue homeostasis. Deregulation of immune responses frequently leads to defective healing and poor tissue restoration and function. Herein we provide an overview of the function of skin-resident immune cells in homeostasis and their role in different skin diseases, mainly autoimmunity, allergy, and infections. Further, we discuss the various therapeutics developed so far targeting skin-resident or skin-homing immune cells and their efficacy in keeping cutaneous inflammation at bay.
Curcumin, a polyphenol natural product derived from turmeric, possesses diverse pharmacological effects due to its interactions with various cells and molecules. Recent studies have highlighted its immunomodulatory properties, including its impact on immune cells and mediators involved in immune responses. Th17 cells play a crucial role in promoting immune responses against extracellular pathogens by recruiting neutrophils and inducing inflammation. These cells produce inflammatory cytokines such as TNF-α, IL-21, IL-17A, IL-23, IL-17F, IL-22, and IL-26. Curcumin has been shown to significantly inhibit the proliferation of Th17 cells and reduce the production of inflammatory cytokines, including TNF-α, IL-22, and IL-17. This review aims to assess the effectiveness of curcumin and its underlying mechanisms in modulating Th17 cells.
Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.
Much remains to be learned about the physiologic events that promote monocytes to become lymph-homing dendritic cells (DCs). In a model of transendothelial trafficking, some monocytes become DCs in response to endogenous signals. These DCs migrate across endothelium in the ablumenal-to-lumenal direction (reverse transmigration), reminiscent of the migration into lymphatic vessels. Here we show that the subpopulation of monocytes that expresses CD16 (Fcgamma receptor III) is predisposed to become migratory DCs. The vast majority of cells derived from CD16(+) monocytes reverse transmigrated, and their presence was associated with migratory cells expressing high levels of CD86 and human histocompatibility leukocyte antigen (HLA)-DR, and robust capacity to induce allogeneic T cell proliferation. A minority of CD16(-) monocytes reverse transmigrated, and these cells stimulated T cell proliferation less efficiently. CD16 was not functionally required for reverse transmigration, but promoted cell survival when yeast particles (zymosan) were present as a maturation stimulus in the subendothelial matrix. The cell surface phenotype and migratory characteristics of CD16(+) monocytes were inducible in CD16(-) monocytes by preincubation with TGFbeta1. We propose that CD16(+) monocytes may contribute significantly to precursors for DCs that transiently survey tissues and migrate to lymph nodes via afferent lymphatic vessels.
Psoriasis is a type I-deviated disease characterized by the presence of interferon (IFN)-gamma and multiple IFN-related inflammatory genes in lesions. Because interleukin (IL)-23 is now recognized to play a role in the recruitment of inflammatory cells in a T helper cell (Th)1-mediated disease, we examined psoriasis skin lesions for production of this newly described cytokine. IL-23 is composed of two subunits: a unique p19 subunit and a p40 subunit shared with IL-12. We found a reliable increase in p19 mRNA by quantitative reverse transcription polymerase chain reaction in lesional skin compared with nonlesional skin (22.3-fold increase; P = 0.001). The p40 subunit, shared by IL-12 and IL-23, increased by 11.6-fold compared with nonlesional skin (P = 0.003), but the IL-12 p35 subunit was not increased in lesional skin. IL-23 was expressed mainly by dermal cells and increased p40 immunoreactivity was visualized in large dermal cells in the lesions. Cell isolation experiments from psoriatic tissue showed strong expression of p19 mRNA in cells expressing monocyte (CD14+ CD11c+ CD83-) and mature dendritic cell (DC) markers (CD14- CD11c+ CD83+), whereas in culture, the mRNAs for p40 and p19 were strongly up-regulated in stimulated monocytes and monocyte-derived DCs, persisting in the latter for much longer periods than IL-12. Our data suggest that IL-23 is playing a more dominant role than IL-12 in psoriasis, a Th1 type of human inflammatory disease.
Psoriasis is a complex inflammatory skin disease that is thought to be mediated by T helper (Th)1 cells that secrete interferon-γ. Interestingly, recent advances by cellular immunologists have identified a new distinct type of T cell, called a Th17 cell, that plays an essential pathogenic role in several classic autoimmune inflammatory diseases previously believed to be Th1 diseases. Recent data also suggest that Th17 cells play a key role in psoriasis pathogenesis. Cytokines that are critical to the development, survival, proliferation, and function of Th17 cells include transforming growth factor β1 (initial differentiation), interleukin-23 (survival and proliferation), and interleukin-17A (proinflammatory effector function). If psoriasis is proven to be a Th17 disease and not a Th1 disease, these cytokines will be attractive targets for future therapies for individuals with psoriasis. These new concepts regarding psoriasis pathogenesis and treatment are the focus of this review.
Thus far, the best-studied and most appreciated biopolymers are the proteins. Although the investigation of proteins has been shown to be necessary for understanding of biological phenomena, more and more evidence shows that biological events cannot be explained solely by the functions of proteins. Fine tuning of the system requires the involvement of other biomolecules, such as carbohydrates and lipids. Key to our specific defense against microbial infections are critical interactions between the specific adaptive and relatively non-specific innate part of the immune response. The most critical link between both parts of the immune system is T cell activation by antigen presentation. This report describes the immunological significant role of bacterial-derived carbohydrate structures in T cell activation, as context of antigens as well as antigen itself. This report will expand the concepts of the role of carbohydrates in microbial interactions with the adaptive immune system.
Dendritic cells (DCs) can induce tumor- or pathogen-specific T cell responses in humans. We comprehensively compared the clinically available DC maturation stimuli for their ability to promote uniformly mature DCs that elicit higher levels of T cell responses. We compared the standard maturation stimulus, autologous monocyte-conditioned medium (MCM), with a synthetic double stranded RNA (poly I:C), soluble CD40 ligand trimer, and a defined cocktail of cytokines (TNF-alpha, IL-1 beta, IL-6) and PGE(2) to promote mature phenotype and function in human monocyte-derived DCs. The cocktail was the most efficient despite the lack of induction of IL-12p70. While these results support the use of the MCM-mimic cocktail in clinical DC immunotherapy trials, the roles of it's individual constituents remain to be completely defined.
Dendritic cells (DCs) present microbial antigens to T cells and provide inflammatory signals that modulate T cell differentiation. While the role of DCs in adaptive immunity is well established, their involvement in innate immune defenses is less well defined. We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice. The absence of Tip-DCs results in profound TNF and iNOS deficiencies and an inability to clear primary bacterial infection. CD8 and CD4 T cell responses to L. monocytogenes antigens are preserved in CCR2-deficient mice, indicating that Tip-DCs are not essential for T cell priming. Tip-DCs, as the predominant source of TNF and iNOS during L. monocytogenes infection, orchestrate and mediate innate immune defense against this intracellular bacterial pathogen.
Psoriasis vulgaris is a common inflammatory skin disease that involves infiltration of leukocytes, activation of skin-resident cells and increased production of numerous cytokines, chemokines and inflammatory molecules. This Review presents an integrated view of disease pathogenesis, taking into account immune biology, broad-scale genomic characterization and the response of psoriasis to immune-targeted therapies. Recent studies suggest that activated dendritic cells (DCs) and T cells are central to its pathogenesis, causing ‘inflammation’ through a pathway of sequential interleukin-23 (IL-23) synthesis, interferon-γ (IFN-γ) production, activation of STAT1 (signal transducer and activator of transcription 1) and subsequent transcription of a broad series of IFN- and STAT-1-regulated genes. In situ expression of macrophage inflammatory protein-3β (MIP-3β; CCL19), secondary lymphoid tissue chemokine (SLC; CCL21) and other chemokines normally confined to formal lymphoid tissues, might help to sustain DC accumulation and overall activation of this inflammatory pathway.
Dendritic cells (DCs) are crucial in the immune response during infection. Recent studies have identified a cell population with features of DCs that are recruited to the spleen of Listeria-infected mice in a CCR2-dependent fashion. These cells, which produce tumor necrosis factor-α (TNF-α) and nitric oxide, are named TipDCs. The adaptor for Toll-like receptor signaling, MyD88, is not required for TipDC appearance in the spleen during infection but is required for development of TipDC effector functions. These studies also provide insight into the complexity of the innate immune response to bacteria.