Review ArticleCytokine profiles in localized scleroderma and relationship to clinical features☆
Highlights
► We reviewed the literature for cytokine profiles in localized scleroderma (LS). ► Though limited in LS, most findings reflect cytokine profiles in systemic sclerosis. ► Both Th1 and Th2 cytokines are found to be elevated in the sera of LS patients. ► Elevated cytokines correlate to clinical data such as LS subtype and disease burden. ► Assessment of disease activity and cytokine profile in the tissue should be considered.
Introduction
Localized scleroderma (LS) is a disfiguring fibrotic autoimmune disease of the skin and underlying tissue that is more common in children than adults, with a prevalence of 50 per 100,000 children [1]. It manifests clinically as discolored fibrotic patches or bands of skin and is divided into clinical subtypes: plaque morphea, generalized morphea, deep morphea, and linear scleroderma (of extremities and/or head) [2]. Plaque morphea (Fig. 1a), or circumscribed morphea, is characterized by well defined oval-shaped lesions, and typically does not extend beyond the dermis. Generalized morphea (Fig. 1b) is termed when there are several plaques, which are often confluent and cover a large total surface area of the patient’s skin. Deep morphea (Fig. 1c) is defined as lesions that affect deeper layer of the dermis, extending into the subcutaneous tissue and often muscle. Linear scleroderma (Fig. 1d and e), the most common subtype in children, is characterized by one or more linear streaks down the extremities or head, and causes the most significant deformities and morbidity, including joint contractures, leg length discrepancy, optic neuritis, vasculitic strokes and seizures. Of the subtypes of LS, linear scleroderma and generalized morphea are felt to be more severe, while plaque morphea is considered more benign.
The lesions of LS initially undergo an ‘active phase’ which is clinically recognized by erythema or violaceous color, warmth, expansion of lesions, and/or appearance of new lesions. Histologically, a dense dermal and subcutaneous lymphocytic infiltrate is identified during this stage. This is followed by a ‘damage’ phase characterized by closely packed homogenous dense collagen deposition with minimal inflammation corresponding to physical examination findings of fibrotic patches or linear bands of skin that are thick, hard and discolored on the face, trunk, and extremities [3], [4]. The fibrosis and resultant atrophy of the skin and underlying connective tissue, including subcutaneous fat, muscle, tendons and bone, can cause significant deformity and severe functional impairment in actively growing children and psychological disability that often continues into adulthood [5]. Many therapies have been used to treat this condition but have had variable effects and are associated with morbidity themselves. A better understanding of the pathophysiology of LS would lead toward more directed and efficacious therapies.
Although the pathogenesis of localized scleroderma (LS) remains unknown, several lines of evidence support CD4+ T-helper (Th) cells and the cytokines they produce as playing an important role, as demonstrated in systemic sclerosis (SSc). Despite the different clinical features of LS and SSc regarding organ involvement and skin lesion distribution, the histopathologic features of the skin lesions are indistinguishable and both demonstrate a predominant CD4+ T-helper (Th) lymphocytic infiltrate [6], [7]. In addition to findings in the tissue, Th cells and their associated cytokines have also been identified in the circulating sera and stimulated PBMCs of LS and SSc patients.
T-helper cells consist of three main effector lineages, Th1, Th2 and Th17, each identified by the cytokines they produce. The process of Th cell differentiation is dynamic, incorporating epigenetic factors with antagonistic and self-perpetuating signals from mature T cell effectors to create a transient cell lineage. The plasticity of Th effector cells has caused some debate concerning proper cytokine lineage identification. Classically, Th1 cells have been known to secrete IL-2, IFN-γ, and TNF-α, and are stimulated by IL-2 and IL-12. Th2 cells have been shown to be activated by IL-4 and produce IL-4, IL-5, IL-10 and IL-13. Th17 cells, a more recently identified Th cell subset that has altered the classic Th1/Th2 paradigm, produce IL-17 A/F, IL-21, and IL-22. IL-1, IL-6, IL-23, and TGF-β are now known to play important roles in the differentiation and propagation of the Th17 cell lineage.
Many autoimmune diseases, including scleroderma, are thought to be propagated by an imbalance of Th cell effector lineages and their associated cytokines. Evaluation of the literature reveals a Th2 predominant cytokine profile in the biological specimens (sera, PBMCs, and tissue) of those with SSc [8], [9], [10]. However, the literature available from studies in LS show that Th1, Th2, and Th17 cytokines may contribute equally to the pathogenesis of the disease. The data in LS consists mostly of cytokine analysis of serologic specimens and are outlined below. These studies examined sera IL-2, IL-4, IL-6, IL-8, IL-13, TNF-α, and TGF-β as well as the soluble IL-2 and IL-6 receptors in LS cohorts. Studies with substantial clinical data to compare cytokine presence or level in LS patients with disease characteristics are included in Table 1. A review of the literature for each cytokine or receptor as well as its associated clinical findings in LS is described.
Section snippets
Th1 associated cytokines
Effectors of the Th1 lineage are involved in the cellular immune response and are central to the host inflammatory response. Th1 cells function to eliminate intracellular pathogens via macrophage activation. A large body of evidence also supports the involvement of Th1-released cytokines in autoimmune inflammation. IL-2 and IL-12 work through specific signal transduction pathways to promote the differentiation of naive T-cell precursors into this lineage. IL-2 and IL-12, in turn, are secreted
Th2 associated cytokines
Th2 cells are known to produce IL-4, IL-5, IL-10, and IL-13, and function to eliminate extracellular pathogens through the upregulation of antibody synthesis by B-cells. Cytokines of Th2 lineage have been characterized as pro-fibrotic and anti-inflammatory due to their respective actions as initiators of extracellular matrix production and inhibitors of Th1 cell function. Development of the Th2 cell lineage is induced by IL-4 and propagated by a positive feedback loop involving this effector
Th17 associated cytokines
Th17 cells and effectors are part of a recently defined subset that plays an integral role in the pathogenesis of many inflammatory and autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis [28], [29], [30]. Th17 effectors include IL-17A/F, IL-21, and IL-22. Interplay among IL-1, IL-6, IL-23, and TGF-β is required for the development and propagation of the Th17 lineage. Th17 differentiation is inhibited by
Interleukin-8
IL-8 has been described as chemotactic pro-inflammatory cytokine produced by several cell types including monocytes, endothelial cells, and fibroblasts [48], [49]. Similar to IL-2, IL-4, and IL-6, IL-8 has been detected in the serum of SSc patients, yet is absent from that of healthy controls [50]. As seen with IL-6, IL-8 production by dermal fibroblasts in SSc patients is increased while production by normal, unstimulated fibroblasts is undetectable, suggesting that the molecule also plays a
Soluble interleukin receptors
In addition to an increased cytokine presence in serum and tissue of LS and SSc patients, an increase in levels of serum soluble interleukin-2 receptor (sIL-2r) and interleukin-6 receptor (sIL-6r) has been identified in the sera of SSc and LS patients, suggesting that the receptors may play a role in the pathogenesis of both diseases. Cytokine receptor expression indicates an activation of T-lymphocytes, further supporting the involvement and imbalance of Th1/Th2 cells in SSc and LS.
Autoantibody association
Many of described studies analyzing serum cytokines in LS compare cytokine presence and level to more well established serologic autoimmune markers of disease, such as anti-nuclear antibody (ANA), anti-histone antibody (AHA) and single-stranded DNA antibody (ss-DNA Ab). ANA is a classic marker of autoimmune disease in general and higher titers have been associated with early onset LS [66] as well as increased risk for extracutaneous manifestations of LS [67]. The presence of ss-DNA Ab in LS is
Conclusion
In conclusion, the literature suggests that cytokines of Th1, Th2, and Th17 cell lineages contribute to the pathogenesis of both forms of scleroderma, systemic sclerosis (SSc) and localized scleroderma (LS). Prior studies support the theory of Th1/Th2 imbalance in SSc propagating disease in a Th2 manner, leading to skin fibrosis and damage. Although there are discrepancies within results of various published studies, there is an overall notion that pro-inflammatory Th1 and Th17 associated
Acknowledgement
This work was supported by a grant from the Nancy Taylor Foundation for Chronic Diseases, Inc.
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Source of support: The Nancy Taylor Foundation for Chronic Diseases. No financial support or other benefits from commercial sources were used for the work reported on in the manuscript. The authors have no financial interests which could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work.