The immunology of psoriasis: from basic research to the bedside

Psoriasis is a frequent, chronic, clinically variable inflammatory disease of unknown etiology, affecting primarily the skin and the joints. A cure for the disease is still missing, and due to the chronic course of the disease, currently available treatments are associated with serious morbidity. Psoriasis is considered to be an (auto)immune disorder, probably initiated by the overactive skin innate immune system, and maintained by immigrating activated type 1 T cells and abnormally proliferating and differentiating keratinocytes. A complex network of cytokines and chemokines mediates the pathological reaction, whereas the abnormal function of psoriatic regulatory T cells is likely responsible for the chronic nature of psoriasis. The most important clinical, histological, and pathogenic characteristics of psoriasis are discussed, and an overview of traditional and novel therapeutic modalities is provided. Based on recently obtained evidence from animal disease models and clinical studies using biological drugs with selective immunological action, a complex model for the immunopathogenesis of psoriasis is outlined. Advances in understanding the immunology of psoriasis have not only provided more insights into the cause and development of the disease, but gave new therapeutic tools into the hands of clinicians to more selectively and (possibly) more effectively treat psoriasis.     

The immune system of the skin and stereotyped reaction patterns in inflammatory skin diseases

The clinical and histological presentation of inflammatory disease in the skin is exceedingly heterogeneous. Nonetheless, most inflammatory dermatoses can be classified according to five stereotypical tissue-reaction patterns: the spongiotic, the lichenoid, the psoriasiform, the vesiculo-bullous and the vasculopathic. By means of potent antigen-presenting cells, cytokine and chemokine cascades and a skin-specific cutaneous lymphocyte antigen (CLA)-positive lymphocyte population, the skin is able to respond very efficiently to pathogens that threaten the individual. Inflammatory skin diseases follow the rules and routes of the physiological reaction to inflammation but however for various reasons the immune response may be inadequate, enhanced or chronic. In allergic contact dermatitis, which is a prototype of the spongiotic reaction pattern, the inflammation is directed against an otherwise harmless antigen, for which the body is sensibilized. Lichenoid dermatitis (like erythema multiforme, graft versus host disease or lupus erythematodes) is based on a primary cytotoxic reaction against the basal epithelial cell, due to alterations in its antigenic make-up or due to an altered immune response. In psoriasis, an example of psoriasiform dermatitis, the interaction between inflammatory cells, antigen presenting cells and epithelial cells is disturbed.     

Gut Microbiota in Psoriasis

Psoriasis is a chronic inflammatory skin disease with autoimmune pathogenic characteristics and is caused by chronic inflammation, which results in uncontrolled keratinocyte growth and defective differentiation. The link between the gut microbiota and immune system regulation opened a novel angle to understand the pathogenesis of many chronic multifactorial diseases, including psoriasis. Current evidence suggests that modulation of the gut microbiota, both through dietary approaches and through supplementation with probiotics and prebiotics, could represent a novel therapeutic approach. The present work aims to highlight the latest scientific evidence regarding the microbiome alterations of psoriatic patients, as well as state of the art insights in terms of microbiome-targeted therapies as promising preventive and therapeutic tools for psoriasis.     

Obesity,Nutrients and the Immune System in the Era of COVID-19

The past year has shown that obesity is a risk factor for severe complications of SARS-CoV-2 infection. Excess fat mass during obesity is known to be a risk factor for chronic diseases but also for severe infections and infectious complications. We have focused here on the elements responsible for this particular susceptibility to infections and more specifically to COVID-19. Excess fat is, in itself, responsible for alterations of the immune system by disrupting the production and function of immune cells. Indeed, hypertrophic adipocytes produce more pro-inflammatory adipokines (including cytokines). The increase in their apoptosis induces a release of pro-inflammatory compounds into the circulation and a recruitment of pro-inflammatory macrophages into the adipose tissue. A chronic systemic inflammatory state is then observed. In addition, diet, apart from its role in the development of adipose tissue, can also affect the immune system, with excess simple sugars and saturated fats exerting pro-inflammatory effects. This inflammation, the adipokines released by the adipocytes, and the infiltration of lipids into the lymphoid organs affects the production of immune cells and, directly, the functions of these cells. The alteration of the immune system increases the risk of infection as well as complications, including secondary bacterial infections and septic states, and increases infection-related mortality. During COVID-19, the chronic inflammatory state promotes the cytokine shock, characteristic of severe forms, caused in particular by excessive activation of the NLRP3 inflammasome. Furthermore, in obese subjects, the already present endothelial dysfunction will render endothelial inflammation (endotheliitis) due to viral infiltration all the more severe. Added to this is a state of hypercoagulability and a decrease in respiratory capacity, leading to a risk of severe COVID-19 with cardiovascular complications, acute respiratory distress syndrome, and disseminated intravascular coagulation, which can lead to multiple organ failure and even death.     

Effects of Dietary Protein Intake on Cutaneous and Systemic Inflammation in Mice with Acute Experimental Psoriasis

Background: Psoriasis is a systemic inflammatory disorder, primarily characterized by skin plaques. It is linked to co-morbidities including cardiovascular disease and metabolic syndrome. Several studies demonstrate that dietary habits can influence psoriasis development and severity. However, the effect of different dietary protein levels on psoriasis development and severity is poorly understood. In this study, we examine the influence of dietary protein on psoriasis-like skin disease in mice. Methods: We fed male C57BL/6J mice with regular, low protein and high protein chow for 4 weeks. Afterwards, we induced psoriasis-like skin disease by topical imiquimod (IMQ)-treatment on ear and back skin. The local cutaneous and systemic inflammatory response was investigated using flow cytometry analysis, histology and quantitative rt-PCR. Results: After 5 days of IMQ-treatment, both diets reduced bodyweight in mice, whereas only the high protein diet slightly aggravated IMQ-induced skin inflammation. IMQ-treatment induced infiltration of myeloid cells, neutrophils, and monocytes/macrophages into skin and spleen independently of diet. After IMQ-treatment, circulating neutrophils and reactive oxygen species were increased in mice on low and high protein diets. Conclusion: Different dietary protein levels had no striking effect on IMQ-induced psoriasis but aggravated the systemic pro-inflammatory phenotype.     

New systemic treatments for psoriasis: etanercept, infliximab, adalimumab, efalizumab and alefacept

The chronic skin disease psoriasis frequently requires long-term systemic treatment with agents that suppresses the immune system with little specificity, which can lead to systemic side effects. Today, using recombinant techniques, it is possible to produce modified proteins, the so-called biologicals, that target specific molecules in the inflammatory process. For the biologicals etanercept, infliximab, adalimumab, efalizumab and alefacept, the clinical efficacy expressed in the rates of partial remission (75% reduction in skin lesions) in patients with plaque psoriasis range from 12 to 88%, compared with 22 to 87% for existing systemic therapies for psoriasis. The side effects of biologicals are usually mild to moderate, but can sometimes be severe. The biologicals should be prescribed with caution, given that they have been on the market for a relatively short period, and because all forms of immune suppression carry an increased risk of oncologic degeneration. The guideline of the Dutch Society of Dermatology and Venereology states that the use of a biological may be considered when a patient cannot tolerate or is unresponsive to conventional systemic therapy, or has an increased risk of adverse events. Biologicals increase the number of options for treatment-resistant plaque psoriasis, which allows therapy to be tailored to the individual patient.     

白介素33与常见自身免疫性疾病

白介素1家族的细胞因子在许多炎性和传染性疾病的宿主防御和免疫调节中都起着重要的作用.白介素33(interleukin-33,IL-33)是白介素1家族的一个新的细胞因子,它可以作为一种分泌性细胞因子参与Th2细胞免疫应答的调节,并且具有前炎性因子的作用.IL-33在自身免疫性疾病中发挥着重要的作用,对其功能的研究,可能会为探索这些疾病的发病机制、寻找治疗靶点提供新的思路.     

Photo dermatology

Photodermatology has become an important part of the dermatologist's area of focus. This subspeciality is not only involved with studying basic biological processes such as the effects of ultraviolet (UV) irradiation on the skin's immune system (photo-immunology), melanocytes or DNA (carcinogenesis), but also with clinical issues such as photoprotection, photosensitive skin diseases (photodermatoses) and phototherapy. Increasing knowledge about the effects of UV irradiation on the skin, with or without photosensitising agents, has led to the development of new forms of photo(chemo)therapy. These allow good therapeutic results to be achieved in the treatment of not only psoriasis, but also other chronic inflammatory skin diseases, with minimal side effects. DNA can absorb UV irradiation. This can lead to irreversible DNA damage and mutations in genes responsible for cell cycle control. These events can lead to skin cancer. The presence of pheomelanin, which is an inferior type of UV light-absorbing melanin, can add to this process of DNA damage. The three most important types of skin cancer are basal cell carcinoma (more than 30,000 new patients per year in the Netherlands), squamous cell carcinoma and melanoma.     

Contributions of neutrophils to the adaptive immune response in autoimmune disease

Neutrophils are granulocytic cytotoxic leukocytes of the innate immune system that activate during acute inflammation. Neutrophils can also persist beyond the acute phase of inflammation to impact the adaptive immune response during chronic inflammation. In the context of the autoimmune disease, neutrophils modulating T and B cell functions by producing cytokines and chemokines, forming neutrophil extracellular traps, and acting as or priming antigen presentation cells. Thus, neutrophils are actively involved in chronic inflammation and tissue damage in autoimmune disease. Using rheumatoid arthritis as an example, this review focuses on functions of neutrophils in adaptive immunity and the therapeutic potential of these cells in the treatment of autoimmune disease and chronic inflammation.     

Anti- and proinflammatory cytokines in the pathogenesis of tissue damage in Crohn's disease

Crohn's disease is a chronic inflammatory bowel disease of unknown origin. The understanding of the pathogenesis of inflammatory bowel diseases has been greatly advanced by manipulations of the immune system in mice using targeted disruptions of genes that encode specific anti- and proinflammatory cytokines, as well as T-cell subsets. The outcome of these experiments has implicated CD4+ lymphocytes and certain proinflammatory cytokines (tumour necrosis factor-alpha, interleukin-12) as playing a central role in the pathogenesis of mucosal inflammation in Crohn's disease. The present review focuses on these recent important immunological observations, and discusses several newly developed therapeutic strategies that are based either on blocking proinflammatory cytokines or on the administration of anti-inflammatory cytokines.     

Obesity, inflammation and the immune system

Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications.     

Inflammatory Mechanisms: The Molecular Basis of Inflammation and Disease

Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of many chronic diseases. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases of many organs. A coordinated series of common effector mechanisms of inflammation contribute to tissue injury, oxidative stress, remodeling of the extracellular matrix, angiogenesis, and fibrosis in diverse target tissues. Atherosclerosis provides an example of a chronic disease that involves inflammatory mechanisms. Recruitment of blood leukocytes characterizes the initiation of this disease. Its progression involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The complications of established atheroma, including plaque disruption and thrombosis, also intimately involve inflammation. Mastery of the inflammatory response should aid the development of novel strategies to predict disease susceptibility, target and monitor therapies, and ultimately develop new approaches to the prevention and treatment of chronic diseases associated with aging, such as atherosclerosis.     

Systemic inflammatory load in young and old ringdoves is modulated by consumption of a jerte valley cherry-based product

Abstract A chronic subclinical inflammatory status that coexists with immune dysfunction is commonly found in the elderly population. Consumption of foods rich in antioxidants (e.g., cherries) is an attractive strategy to reduce risk from chronic diseases. Based on previous studies showing the antioxidant effect of a Jerte Valley cherry derivative product in humans, the objective of this work was to evaluate the effect of the intake of a Jerte Valley cherry-based beverage on inflammatory load in both young and old ringdoves (Streptopelia risoria). To this purpose, circulating levels of pro-inflammatory and anti-inflammatory cytokines as well as serum levels of different acute-phase proteins were measured before and after a 10-day treatment with the Jerte Valley cherry-based beverage. Thus, the 10-day treatment with the cherry-based beverage modulated the balance of pro- and anti-inflammatory cytokines in both young and old ringdoves by down-regulating the levels of pro-inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor-α, and interferon-γ) and up-regulating the levels of anti-inflammatory cytokines (IL-4, IL-2, and IL-10). Moreover, the 10-day treatment with the Jerte Valley cherry-based product reduced the levels of several proteins involved in acute-phase responses, such as C-reactive protein, haptoglobin, α(2)-macroglobulin, and serum amyloid P component. On the other hand, old birds showed imbalanced levels of inflammatory markers toward a pro-inflammatory status, thereby underlining the fact that aging is usually accompanied by systemic inflammation and inflammation-related chronic diseases. To sum up, the data suggest a potential health benefit by consuming the cherry-based beverage, especially in aged populations, through their anti-inflammatory properties.     

The role of CCR5 in Chagas disease - a systematic review

Chagas disease is an infection caused by the protozoan Trypanosoma cruzi. The clinical manifestations result from the chronic forms of the disease: indeterminate, cardiac, digestive or mixed. The pathogenesis of this disease is related to the genetic variability of both the parasite and the host with polymorphisms of genes involved in immune response possibly being involved in the variable clinical course. Cytokines play a key role in regulating immune response, in particular chemokines exert a crucial role in the control of leukocyte migration during the host's response to infectious processes. Furthermore, inflammatory cytokines and chemokines have been implicated in the generation of inflammatory infiltrates and tissue damage. The involvement of the CC Chemokine Receptor 5 (CCR5) in leukocyte migration to sites of inflammation has been elucidated and this receptor has been investigated in Chagas disease. Here we review the role of CCR5 in T. cruzi infection as well as its importance in the pathogenesis of the Chagas disease.     

Immunometabolism in Obese Asthmatics: Are We There Yet?

Obesity is now recognised as a worldwide epidemic. The recent International Association for the Study of Obesity/International Obesity Taskforce (IASO/IOTF) analysis estimates that approximately 1.0 billion adults are currently overweight and a further 475 million are obese. Obesity has huge psychosocial impact with obese children and adolescents facing discrimination and stigmatization in many areas of their lives leading to body dissatisfaction, low self-esteem and depression. Indeed, obesity is recognised as an important risk factor for the development of several chronic diseases such as hypertension, cancer, asthma and metabolic syndrome. Chronic low grade systemic inflammation is considered as a hallmark of obesity and may possibly explain the link between obesity and chronic disease, in particular the increased incidence, prevalence and severity of asthma in obese individuals. There is now strong evidence for infiltration of immune and inflammatory cells into adipose tissue that drives systemic inflammation and subsequent end organ damage. In addition to adipocytes, the key adipose tissue resident immune cells are macrophages and mast cells. Immunometabolism, as an emerging field of investigation, explores the pivotal role of these immune cells in translating immunological changes to metabolic effects in obesity. Abundance of free fatty acids, along with other inflammatory cytokines shift the balance of metabolic homeostasis to pro-inflammatory status by influencing the development of inflammatory cell lineage, which, further exhibits distinct functional phenotypes. There is emerging evidence for macrophage activation and functional polarization of an anti-inflammatory M₂ phenotype towards a pro-inflammatory M₁ phenotype of macrophages in obese adipose tissue. Similarly, studies in both obese humans and murine models reveal the pathognomic presence of an increased number of mast cells in visceral adipose tissue. These suggest a possible contribution of mast cells to the unique metabolome of obese asthma. This review examines proposed multilevel interactions between metabolic and immune systems in obese asthmatics that underlie the negative effects of obesity and may offer significant therapeutic promise.     

肥胖相关代谢性炎症研究进展

肥胖是能量代谢失衡所导致的体脂过度积聚,可引起动脉粥样硬化、胰岛素抵抗和血脂异常等多种代谢综合征的发生。肥胖本身是一种发生在脂肪组织的慢性炎症疾病,伴随着脂肪组织细胞内炎症信号通路的激活、炎性细胞因子的释放和免疫细胞的浸润等病理改变。脂肪组织释放的炎症介质也可以进入循环系统而影响其他器官组织功能,引起相关代谢综合征的发生。因此,研究代谢性炎症与肥胖的关系对肥胖及其相关代谢性疾病的防治具有深远意义,针对肥胖代谢炎症的治疗方法也将为肥胖及其相关代谢疾病的治疗带来新的思路。