This article presents a summary of the evidence for a link between autoinflammatory diseases and psoriasis. The main concepts regarding the disease state of psoriasis are discussed and these lead to a change in the perspective on the clinical and pathophysiologic nature of psoriasis as a chronic, recurrent disease with important genetically defined features, and an associated or concomitant systemic inflammatory state that involves a multifactorial cellular and molecular network, transforming the old perception of psoriasis as a localized autoimmune skin disease, to one of psoriasis as a systemic inflammatory disease with autoinflammatory features and severe associated comorbid conditions.
Key points
- •
Psoriasis immunopathogenesis.
- •
Inflammatory cycle.
- •
Psoriasis causes and genetic and clinical features.
- •
Autoinflammatory versus autoimmune.
- •
Role of Th1-Th2 activation and balance on psoriasis.
- •
T-cell activation.
- •
Pathogenic mechanisms of self-immunity.
- •
Immune links of psoriasis to autoinflammation.
- •
Inflammasome-mediated inflammation.
Introduction
This article presents a summary of the evidence that can be used to establish a link between the recently introduced autoinflammatory diseases (AIDs) and psoriasis, a member of the papulosquamous disorders, the primary lesions of which are characterized by scaly plaques. These entities have some common characteristics among their phenotypic features, genetic components, and the mechanism of tissue damage exerted through intricate immunopathologic pathways and players.
The main concepts regarding the disease state of psoriasis are discussed and these lead to the establishment of a link that can change the perspective on the clinical and pathophysiologic nature of psoriasis as a chronic, recurrent disease with important genetically defined features, and an associated or concomitant systemic inflammatory state that involves a multifactorial cellular and molecular network, transforming the old perception of psoriasis as a localized autoimmune skin disease, to the new perspective of psoriasis as a systemic inflammatory disease with autoinflammatory features and severe associated comorbid conditions.
The extension of the skin lesion to a systemic inflammatory stage, as shown in several studies and publications, manifests in different body systems, creating the need for a more comprehensive approach to the affected patients.
From the point of view of several investigators, the concurrent inflammation seen in the different types of psoriasis compromises innate and adaptive immune system components and has a well-defined network of chemokines and messengers that can be compared with the cellular and chemical networks found in the patient with AID, requiring the identification of the possible links between them and the subsequent potential consideration of psoriasis as an AID.
Several years of intense studies of the pathogenic components, immune mediators, and involved pathways of psoriasis enhanced knowledge about the disease state and its clinical associated conditions. The concept of activated T cells has gained a key role, suggesting autoimmunity as a basic mechanism of the disease. In later publications and discoveries, after evaluating the different psoriasis phenotypes, analysis of the variable course of the disease with periodic outbreaks, as well as results from immunotyping studies, justified an extension of the autoimmunity concept. Current evidence establishes that innate immunity and autoinflammation play significant roles.
Introduction
This article presents a summary of the evidence that can be used to establish a link between the recently introduced autoinflammatory diseases (AIDs) and psoriasis, a member of the papulosquamous disorders, the primary lesions of which are characterized by scaly plaques. These entities have some common characteristics among their phenotypic features, genetic components, and the mechanism of tissue damage exerted through intricate immunopathologic pathways and players.
The main concepts regarding the disease state of psoriasis are discussed and these lead to the establishment of a link that can change the perspective on the clinical and pathophysiologic nature of psoriasis as a chronic, recurrent disease with important genetically defined features, and an associated or concomitant systemic inflammatory state that involves a multifactorial cellular and molecular network, transforming the old perception of psoriasis as a localized autoimmune skin disease, to the new perspective of psoriasis as a systemic inflammatory disease with autoinflammatory features and severe associated comorbid conditions.
The extension of the skin lesion to a systemic inflammatory stage, as shown in several studies and publications, manifests in different body systems, creating the need for a more comprehensive approach to the affected patients.
From the point of view of several investigators, the concurrent inflammation seen in the different types of psoriasis compromises innate and adaptive immune system components and has a well-defined network of chemokines and messengers that can be compared with the cellular and chemical networks found in the patient with AID, requiring the identification of the possible links between them and the subsequent potential consideration of psoriasis as an AID.
Several years of intense studies of the pathogenic components, immune mediators, and involved pathways of psoriasis enhanced knowledge about the disease state and its clinical associated conditions. The concept of activated T cells has gained a key role, suggesting autoimmunity as a basic mechanism of the disease. In later publications and discoveries, after evaluating the different psoriasis phenotypes, analysis of the variable course of the disease with periodic outbreaks, as well as results from immunotyping studies, justified an extension of the autoimmunity concept. Current evidence establishes that innate immunity and autoinflammation play significant roles.
AIDs: a new category
The AIDs, a concept recently introduced in the medical literature, are a category of illnesses characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells, in which, as in the autoimmune diseases, the capability of self-recognition is disturbed, initiating an attack on the body’s own tissues. The distorted and abnormal response generates a cellular network with the implicated chemokine chain reaction that, in turn, generates an inflammatory response. The mechanisms for which the inflammation is generated and the abnormal action of the innate immune system are currently not completely understood. In 2008, Yao and colleagues proposed the new classification, with the identification of the genes underlying hereditary components associated with gene mutations for the periodic fever syndromes. Soon after the new nosology was proposed, Masters and colleagues published an article in which 6 categories of AIDs were defined: interleukin (IL)-1β activation disorders (inflammasomopathies), nuclear factor (NF)-κB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes. More conditions, mostly included because of their clinical manifestations, have recently been added to the classification, with a special consideration of their complexity and their heritable linkage. Details of the newest classification are discussed elsewhere in this issue by Abramovits. The diseases are characterized by spontaneous activation of cells of innate immunity in the absence of ligands. Autoantibodies are usually not found.
Autoimmune versus autoinflammatory
Differentiated by the absence or presence of specific antibodies, the activation of different immune systems, and their genetic features, the disorders share common characteristics in that both result from the immune system targeting and aggressively injuring self-tissues, with a resulting increased inflammation as an expression of the tissue damage mechanisms. These common grounds could create confusion in diagnosis. This conceptualization was defined by The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the US Department of Health and Human Services, National Institutes of Health (NIH), in March 2010 (discussed later). Their publication established several different types of AID.
The mechanism for which the local or systemic damage is produced in autoinflammatory syndromes is complex, involving cellular and cytokine networks, and probably involves a systemic disruption of the molecular basis of mediating and controlling inflammation. These disorders were defined, until recently, by phenotypic features, including recurrent attacks of fever, abdominal pain, arthritis, or cutaneous signs, which occasionally overlap inducing doubts and consequently an inaccurate diagnosis. To date, the improved knowledge of the pathophysiology, the mechanisms of the disease, and the molecular effects of the mediators has allowed an expansion of their classification.
Autoimmune disorders are a consequence of an inappropriate immune response of the body against substances and tissues whose presence is recognized as normal in the body. The immunologic hallmark is the formation of specific antibodies against the target organ or tissue; the immune system mistakes some part of the body as a pathogen and attacks its own cells. This response may be restricted to certain organs (eg, in autoimmune thyroiditis) or involve a particular tissue in different places (eg, Goodpasture disease, which may affect the basement membrane in both the lung and the kidney).
It is important not to confuse autoinflammatory syndromes with autoimmune diseases, which are caused by the body’s adaptive immune system developing antibodies to antigens that then attack healthy body tissues. Autoimmunity and autoinflammation share some common characteristics: both lead to self-directed inflammation, but with different mechanisms. Although autoimmunity involves adaptive immune activation, autoinflammation involves innate immune activation. Autoinflammation is genetically related to perturbations of innate immune function, including proinflammatory cytokine signaling abnormalities, or bacterial sensing, or local tissue abnormalities. The clinical and pathophysiologic expressions of autoinflammation are determined by cells of the innate immune system, including neutrophils and macrophages or nonimmune cells.
Recent discoveries on the contribution of the innate immunity mechanisms in inflammatory disorders have led to a new examination of the current nosology of this large group of diseases. Some investigators suggest a classification with 2 poles. The first is defined by the predominance of autoinflammation, whereas, in the second, 1 autoimmunity predominates.
Mechanisms of self-immunity
The challenge of the immune system is to produce a response to invasive foreign antigens without breaking down the natural immunologic tolerance, reacting to self-components of the recognized structures of the human body. The cellular structures that identify the exposed epitopes and warrant the proper response and mechanisms to inactivate or eliminate self-reactive cells and nonself structures are the preexistent genetically encoded receptors. The discriminating actions and the capability of producing an immune response with the included mechanisms of self-tolerance is the responsibility of the cellular receptors located at the B and T cells. A well-known array of factors, genetically and environmentally associated, could induce altered autoimmunity by breaking down the self-tolerance, preventing the response to self-epitopes.
However, to provide some benefits, a grade of immune tolerance is needed. The concept is exemplified by the following examples: the recognition of neoplastic cells by CD8+ T cells (a contribution that reduces the possibility of cancerous developments at a tissue level), the rapid immune response in the early stages of an infection when the availability of foreign antigens limits the response, or during the inflammatory process involved in the production of healing and repairs following tissue injuries. Stefanova and colleagues (2002) showed that self–major histocompatibility complex (MHC) recognition maintains the responsiveness of CD4+ T cells when foreign antigens are absent.
To explain the origin and mechanisms of immunologic tolerance, several theories have been proposed. The most important hypotheses considered to explain these concepts are represented in Fig. 1 .
Loss of Tolerance
A challenge to this process was reported by investigators around the world, with evidence that shows that the antibody responses are produced by B lymphocytes during spontaneous human autoimmunity. Loss of tolerance by T cells has been hard to show, and where there is evidence for an abnormal T-cell response it is usually not of the antigen recognized by autoantibodies. Some instances supporting this statement are that (1) there are autoantibodies to immunoglobulin (Ig) G heavy chain constant region of the immunoglobulin molecule domains (Fc) but apparently no corresponding T-cell response in rheumatoid arthritis (RA); (2) there are autoantibodies to DNA that cannot evoke a T-cell response, and limited evidence for T-cell responses implicates nucleoprotein antigens in systemic lupus erythematous (SLE); (3) there are autoantibodies to tissue transglutaminase but the T-cell response is to the foreign protein gliadin in celiac disease. The discrepancy created the presumption of human autoimmune disease, in most cases (with probable exceptions including type I diabetes) based on a loss of B-cell tolerance, which makes use of normal T-cell responses to foreign antigens in a variety of aberrant ways. The failure of these mechanisms probably leads to autoimmunity.
Role of Th1/Th2 Balance in Self-immunity
Several investigators consider the balance between Th1/Th2 an important player; it may induce particular responses to determined self-antigens producing the expression of cytokines and inflammatory mediators with clinical manifestations of specific diseases.
Another factor to consider is the possible inactivation or destruction of lymphocytes bearing B-cell or T-cell receptors that recognize and bind self-epitopes; in these circumstances, the loss of self-tolerance can be mediated by different phenomena, such as molecular mimicry, epitope spreading, loss of suppression, sequestered antigens, neoantigens, and induction of scavenger receptors.
Involved Genetic Factors
Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is associated with multiple genes in conjunction with other risk factors. Genetically predisposed individuals do not always develop autoimmune disease; an environmental condition is needed to induce the expression of the genetically preestablished condition.
Three main sets of genes are suspected in many autoimmune diseases. These genes are related to: immunoglobulin, T-cell receptors, and the MHCs. The first two, which are involved in the recognition of antigens, are inherently variable and susceptible to recombination. These variations enable the immune system to respond to a wide variety of invaders, but may also give rise to lymphocytes capable of self-reactivity.
There is also strong evidence to suggest that certain MHC class II allotypes correlated with human leukocyte antigen (HLA) DR2 are strongly positively correlated with SLE. HLA DR3 is strongly correlated with Sjögren syndrome, myasthenia gravis, SLE, and diabetes mellitus (DM) type 1; HLA DR4 is correlated with the genesis of RA, type 1 DM, and pemphigus vulgaris.
A few publications establish the correlation between the MHC class I molecules and the generation of autoimmunity, the association between HLA B27 and ankylosing spondylitis being the most consistent finding reported. The polymorphisms within class II MHC promoters and autoimmune disease may have some type of correlation.
Most recent data associate protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) with multiple autoimmune diseases including type I DM, RA, SLE, Hashimoto thyroiditis, Graves disease, Addison disease, myasthenia gravis, vitiligo, systemic sclerosis, juvenile idiopathic arthritis, and psoriatic arthritis (PsA).
Pathogenesis of Autoimmune Disease
Several operative mechanisms have been reported to be involved in the pathogenesis of autoimmune diseases, besides the previously mentioned genetic predisposition and environmental modulation. A summary of some of the important mechanisms is presented in Fig. 2 .
Autoinflammatory features of psoriasis
Psoriasis
Psoriasis is a papulosquamous skin disease with variable morphology, distribution, severity, and clinical course. It was first described by Robert Willan, a British dermatologist who helped establish psoriasis as a separate entity from leprosy. Widely referred to as psoriasis vulgaris, after the most common clinical type, the condition affects an estimated 2% of the general population and predominantly is a disease of white people. A bimodal age of onset has been reported for psoriasis, with the mean age of onset for the first presentation ranging from 15 to 20 years of age, with a second peak occurring at 55 to 60 years.
Cause
The cause of psoriasis is complex, with evidence that both multiple genes and environmental factors are involved. Population studies report that the incidence of psoriasis is greater in first-degree and second-degree relatives of patients than in the general population. About 30% of patients have an affected first-degree relative, whereas the risk of having the disease is 2 to 3 times greater in monozygotic than in dizygotic twins. Early onset (before age 40 years) psoriasis has been reported to have a stronger genetic basis, because a greater proportion of patients had a family history of psoriasis, more severe disease, and stronger HLA associations (HLA-Cw6, HLA-DR7, HLA-B13, and HLA-Bw57). Major susceptibility loci for psoriasis have been established at chromosome 6p21.3 (PSOR1), whereas other associations have been reported on chromosomes 17q (PSORS2), 4q (PSORS3), 1cenq21 (PSORS4), 3q21 (PSORS5), 19p (PSORS6), 1p (PSORS7), and 4q31 (PSOR9).
Environmental factors also play an important role in the pathogenesis of psoriasis, including infection, skin trauma, drugs, and stress. Beta-hemolytic streptococcus infection of the pharynx and tonsils often precedes the first manifestation of the disease. Infections may also trigger a rare generalized pustular form, called von Zumbusch psoriasis. Mechanical trauma to the skin can trigger the development of psoriatic lesions at the site of the trauma in individuals predisposed to developing the disease, an isomorphic reaction known as the Koebner phenomenon. A positive Koebner predicts subsequent disease activity. The use of medications, such as beta-blockers, cloroquine, tetracyclines, interferons, nonsteroidal antiinflammatory drugs (NSAIDs), and lithium, has also been associated with the onset of psoriasis. Furthermore, lifestyle factors, including alcoholism, smoking, stress, and obesity, have been reported to negatively affect the disease. Fig. 3 shows an integrated perspective of these factors.
Clinical features
Psoriasis generally manifests as chronic inflammation of the skin characterized by disfiguring, scaling, and erythematous plaques accompanied by pain and pruritus. The disease waxes and wanes during a patient’s lifetime, and is often modified by treatment, with few spontaneous remissions. Plaque psoriasis (also called psoriasis vulgaris) is the most common form, affecting 80% to 90% of patients. Plaque psoriasis typically presents as raised areas of inflamed skin covered with a silvery white scale. The scale can easily be removed from a psoriatic plaque, and may reveal focal bleeding points (the Auspitz sign). Lesions often begin as small papules that expand and coalesce to form extensive psoriatic plaques. Lesions are typically distributed symmetrically on the scalp, elbows, knees, and lumbosacral area. Skin involvement may range from only a few plaques to numerous lesions covering almost the entire body surface. Other classifications of psoriasis include inverse psoriasis, erythrodermic psoriasis, pustular psoriasis, and guttate psoriasis ( Table 1 ). The clinical findings in individual patients frequently overlap in more than one type of psoriasis.
| Type | Description | Skin Areas Involved |
|---|---|---|
| Plaque psoriasis | Well-defined, sharply demarcated, erythematous plaques that vary in size from 1 cm to several centimeters | Scalp, trunk, buttocks, and limbs, extensor surfaces such as the elbows and knees |
| Inverse psoriasis (flexural) | Erythematous plaques with minimal scaling because of the moist nature of involved areas Can be confused with candida, intertrigo, and dermatophyte infections | Skin fold areas, including the axillary, genital, perineal, intergluteal, and inframammary areas |
| Erythrodermic psoriasis | Generalized erythema with varying degrees of scaling Can be a life-threatening condition because of hypothermia, hypoalbuminemia, and high-output cardiac failure | Affects almost the entire body surface area |
| Pustular psoriasis | Raised bumps that are filled with noninfectious pus (pustules) Rare Represents active, unstable disease | May be generalized (von Zumbusch disease) or localized to the palms and soles (palmoplantar pustulosis) |
| Guttate psoriasis (eruptive) | Droplike (1–10 mm) salmon pink papules, usually with a fine scale Occurs in less than 2% of patients with psoriasis Often preceded by history of upper respiratory infection with group A beta-hemolytic streptococci Usually self-limiting | Primarily on the trunk and the proximal extremities |
Approximately half of patients with psoriasis have distinctive nail changes related to the disease. These changes include pitting, onycholysis (nail plate separation), oil spots (orange-yellow subungual discoloration), and dystrophy. Fingernails are more commonly affected than toenails. Psoriatic nail disease occurs more frequently in patients with PsA.
Impact of psoriasis
Although psoriasis is rarely life-threatening, the disease negatively affects quality of life and represents a psychosocial and financial burden for patients and the health care system. Psoriasis decreases the quality of life at least as much as diabetes, ischemic heart disease, or chronic obstructive pulmonary disease. Patients also suffer from disfigurement and from social stigmatization, leading to higher rates of depression, anxiety, sexual dysfunction, poor self-esteem, and suicidal thoughts than are found in the general population, even in less severe disease. Moreover, patients with a diagnosis of psoriasis usually require lifelong care with the associated expenses caused by the chronicity of the disease. In the United States, the annual per capita health care and out-of-pocket (OOP) costs for individuals with psoriasis have been reported to be significantly greater than those for individuals without the condition. United States national annual estimates of health care, OOP, and total direct medical expenses for psoriasis were $3.67 billion, $1.49 billion, and $5.17 billion, respectively.
Diagnosis
The diagnosis is made clinically, based on the characteristic appearance of the lesions. A skin biopsy may be necessary to exclude other conditions. Disease severity is loosely based on the amount of body surface area (BSA) involved, with mild being less than 3% BSA involved; moderate, 3% to 10% BSA involved; and severe, greater than 10% BSA involved, although any percentage of involvement on critical areas such as the face or hands may convey a severe rating. The Psoriasis Area and Severity Index (PASI), a measure of overall disease severity and coverage that assesses BSA, erythema, induration, and scaling, is often used in clinical trials but rarely in the clinic.
Histopathologic features: immunopathogenesis
In psoriasis, keratinocyte migration from the basal layer of the epidermis to the skin surface takes only 3 days, in contrast with normal skin development, which takes approximately 4 weeks. Keratinocyte hyperproliferation and abnormal apoptosis result in parakeratosis, characterized by the accumulation of partially differentiated keratinocytes that retain their nuclei and that form the basis of the scaly plaque formation in psoriasis. As such, the illness was initially considered to be a condition primarily of abnormal keratinocyte proliferation and maturation with secondary inflammation. With the identification of cytokines like tumor necrosis factor alpha (TNF-α) and various interleukins in psoriatic plaques, researchers switched focus to identifying and localizing many different types of cytokines within normal and diseased skin.
In 1991, the initial version of the cytokine network theory of psoriasis was proposed to explain its immunopathogenesis. Cytokines are small, biologically active proteins that regulate the growth, function, and differentiation of cells and coordinate the immune response and inflammation. The theory suggested that the dendritic cells (DCs) secreting TNF-α in the dermis played a central role in the initiation and maintenance of the disease. Available data at that time showed that TNF-α could induce relevant adhesion molecules, growth factors, and chemokines.
Clinical research provided further evidence that highly specific reagents targeting TNF-α were observed to improve skin and, in some circumstances, joint disease activity. However, TNF-α has pleiotropic biological effects and redundancy with other cytokines. Thus, a single cytokine such as TNF-α cannot fully account for the inflammatory process in psoriasis considering the diversity and complexity of the cytokine network.
Current evidence suggests that psoriasis is a complex immune-mediated inflammatory disease driven primarily by T cells, particularly Th1 and Th17 cells. This shift in paradigm toward T cells was in part caused by the therapeutic success observed in psoriasis with medications that inhibit T-cell functions, such as cyclosporine A, a substance that diminishes T-cell proliferation and cytokine production.
T-cell activation (Th1 and Th17)
T cells are generally accepted to be the key players in initiating and maintaining pathologic changes in psoriasis. For reasons not yet completely understood, DCs in the skin become activated to recognize and capture a cutaneous antigen, then migrate to the lymph nodes where they stimulate T cells by presenting them with the antigen. This process triggers the proliferation of antigen-recognizing T cells and memory effector cells. However, the antigen responsible for T-cell activation in the skin has to still be conclusively identified. After antigen stimulation, T cells enter the circulatory system and interact with adhesion molecules in endothelial cells of blood vessels. Adhesion molecules, particularly P-selectin and E-selectin, are expressed in higher concentrations in psoriasis. This interaction with adhesion molecules allows the migration of T cells, as well as macrophages, DCs, natural killer (NK) cells, and neutrophils through the blood vessel wall into the skin and around dermal blood vessels. The lymphocytic infiltrate and resident T cells play important roles in preceding and driving the epidermal changes.
Psoriasis has traditionally been classified as a T-cell helper 1 (Th1) disease because of a predominance of Th1 pathway cytokines, such as TNF-α, interferon gamma (IFN-γ), IL-2, and IL-12 in psoriatic plaques. Increased levels of Th1 cytokines in serum have also been reported, and the circulating levels of TNF-α, IFN-γ, IL-2, and IL-18 seem to be correlated with the severity of psoriasis.
IFN-γ is secreted by Th1 cells, DCs, and NK cells, and seems to play a key role in the early stages of the clinical presentation. IFN-γ accelerates the migration of immune cells into the skin and activates monocytes, macrophages, DCs, and endothelial cells. It also stimulates epidermal cell proliferation and inhibits the apoptosis of keratinocytes, causing the hyperproliferation of keratinocytes observed in psoriatic plaques. IL-12 secreted by DC plays a major role in the development of Th1 cell-mediated immune responses. Together with IL-2 from T cells, these cytokines regulate the transcription of IFN-γ and TNF-α. IL-2 is likewise responsible for the differentiation, proliferation, and maturation of T cells into memory effector cells. IL-18, a cytokine important in cellular adhesion, also contributes to secretion of IFN-γ.
TNF-α is an important cytokine of the Th1 pathway. It has pronounced proinflammatory effects and is produced by DCs, T cells, macrophages, and keratinocytes in psoriasis. TNF-α stimulates the proliferation of T cells, other cytokines, and adhesion molecules. In particular, TNF-α induces the expression of IL-6 and C-reactive protein (CRP) in psoriasis. IL-6 induces T-cell activation, stimulates the proliferation of keratinocytes, and mediates the acute-phase response. TNF-α also increases expression of IL-18, a cytokine that provides a strong chemotactic signal for the recruitment of neutrophils. In conjunction with IFN-γ, TNF-α promotes inflammatory cell infiltration of the skin by increasing the expression of intercellular adhesion molecule 1 (ICAM-1). Improvement of cutaneous symptoms with biologic therapies that specifically neutralize TNF-α in patients with psoriasis provide additional evidence of the central role of TNF-α in the immunopathology of the disease.
More recently, studies reported the critical contribution of Th17 pathway–associated cytokines, particularly IL-23 and IL-17, in the pathogenesis of psoriasis. In this new paradigm, the activated DCs in the dermis produce IL-23 and IL-12, which stimulate resident Th17, Th22, and Th1 cells. IL-23 secreted by DCs activates Th17 cells to produce IL-17A and IL-17F, which drive keratinocyte responses. The stimulated epidermis can produce abundant cytokines and inflammatory mediators, including IL-8, chemokine CXC ligand (CXCL), monocyte chemotactic protein (MCP)-1, chemokine CC ligand (CCL) 2, CXCL1, CXCL2, CXCL3, and CCL20. The chemokines attract neutrophils, DCs, and chemokine CC receptor (CCR) and Th17 cells. Also produced are CXCL9, CXCL10, and CXCL11, which further recruit circulating CXCR3 and Th1 cells into the dermis and epidermis. Such chemokine induction and leukocyte recruitment can occur within hours of tissue injury in the skin. Details of this new perspective are presented in Fig. 4 .
