Current directions in autoimmunity最新文献

Vitiligo is characterized by progressive skin depigmentation resulting from an autoimmune response targeting epidermal melanocytes. Melanocytes are particularly immunogenic by virtue of the contents of their melanosomes, generating the complex radical scavenging molecule melanin in a process that involves melanogenic enzymes and structural components, including tyrosinase, MART-1, gp100, TRP-2 and TRP-1. These molecules are also prime targets of the immune response in both vitiligo and melanoma. The immunogenicity of melanosomal proteins can partly be explained by the dual role of melanosomes, involved both in melanin synthesis and processing of exogenous antigens. Melanocytes are capable of presenting antigens in the context of MHC class II, providing HLA-DR+ melanocytes in perilesional vitiligo skin the option of presenting melanosomal antigens in response to trauma and local inflammation. Type I cytokine-mediated immunity to melanocytes in vitiligo involves T cells reactive with melanosomal antigens, similar to T cells observed in melanoma. In vitiligo, however, T cell tuning allows T cells with higher affinity for melanocyte differentiation antigens to enter the circulation after escaping clonal deletion in primary lymphoid organs. The resulting efficacious and progressive autoimmune response to melanocytes provides a roadmap for melanoma therapy.

Our increased understanding of the mechanisms of immune-mediated skin disease has led to the growth of therapeutic options for these diseases. Treatment options impact the various levels of the immune response, including the activation and effector function of immune cells. In this review, we give a broad outline of the steps in the immune process that can be altered by immunomodulatory therapy as well as a working model for the potential areas of intervention for new treatments.

Allergic contact dermatitis is a classic example of a cell mediated hypersensitivity reaction in the skin. This occurs as a result of xenobiotic chemicals penetrating into the skin, chemically reacting with self proteins, eventually resulting in a hapten-specific immune response. It is precisely because of this localized immune response that allergic signs and symptoms occur (redness, edema, warmth and pruritus). It has been known for years that conventional T-cells (CD4+ or CD8+ T-cells that express a T-cell receptor alpha/Beta) are critical effectors for this reaction. There is emerging evidence that innate immune lymphocytes such as invariant Natural killer T-cells and even Natural killer cells may play important role. Other T-cell types such as Tregulatory cells and the IL-10 secreting Tregulatory cells type I are likely to be important in the control (resolution) of allergic contact dermatitis. Other cell types that may contribute include B-cells and hapten-specific IgM. Additionally, epidermal Langerhans cells have been ascribed an indispensable role as an antigen presenting cell to educate T-cells of the skin immune system. Studies of mice that lack this cell type suggest that Langerhans cells may be dispensible, and may even play a regulatory role in allergic contact dermatitis. The identity of the antigen presenting cells that complement Langerhans cells has yet to be identified. Lastly, Keratinocytes play a role in all phases of allergic contact dermatitis, from the early initiation phase with the elaboration of inflammatory cytokines, that plays a role in Langerhans cell migration, and T-cell trafficking, through the height of the inflammatory phase with direct interactions with epidermotrophic T-cells, through the resolution phase of allergic contact dermatitis with the production of anti-inflammatory cytokines and tolerogenic antigen presentation to effector T-cells. As the understanding of allergic contact dermatitis continues to improve, this will provide novel therapeutic targets for immune modulating therapy.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease with welldefined skin lesions, including acute CLE, subacute CLE, chronic CLE and intermittent CLE. In the first part of the review, we discuss the variable relationships that exist between the different clinical forms of CLE and the risk of systemic disease activity. Furthermore, we focus on the annular and papulosquamous forms of subacute CLE and emphasize dermal scarring as a characteristic feature of chronic discoid skin disease in contrast to other subtypes of CLE. Various environmental factors influence the clinical expression of CLE and a striking relationship has emerged between sunlight exposure and the various subtypes of this disease. In the second part, we review the evidence for the abnormal long-lasting photoreactivity in CLE, with an overview of the molecular and cellular factors that may underlie this abnormality. In particular, we discuss the role of UV-mediated induction of apoptosis, mediators of inflammation, such as cytokines and chemokines, nitric oxide, T cell-mediated injury, and the influence of regulatory CD4+CD25+ T cells. However, a complete understanding of the diverse pathophysiologic mechanisms and interactions in CLE does not exist and, as there is yet no convincing animal model of CLE, many studies remain descriptive in nature.

Pemphigus is an autoimmune disease of the skin and mucous membranes and is mediated by IgG autoantibodies against desmoglein (Dsg), a cadherin-type cell-cell adhesion molecule in desmosomes. Recently, an active disease mouse model of pemphigus vulgaris (PV) was generated with a unique approach using autoantigen knockout mice, in which selftolerance of the defective gene product is not acquired. This approach included the adoptive transfer of Dsg3-/- lymphocytes to Rag2-/- immunodeficient mice that express Dsg3- induced stable production of pathogenic anti-Dsg3 IgG for over 6 months and the phenotype of PV including oral erosion with the typical histology in recipient mice. Subsequently, AK and NAK series of anti-Dsg3 IgG monoclonal antibodies were developed from the PV model mice. These monoclonal antibodies showed pathogenic heterogeneity in blister formation, which is, at least in part, explained by their epitopes, and synergistic pathogenic effects by combining several monoclonal antibodies reacting in different parts of the molecule. Although this model does not reflect the actual triggers of autoimmune diseases, it does provide a means to investigate the roles of T and B lymphocytes in perpetuating autoantibody production and to clarify unsolved immunological mechanisms in the autoimmune diseases.

Epidermolysis bullosa acquisita (EBA) is an acquired, mechanobullous disease characterized by autoimmunity to type VII collagen. Type VII collagen makes anchoring fibrils, structures that connect the epidermis and its underlying basement membrane zone to the papillary dermis. EBA patients exhibit skin fragility, blisters, scars and milia formation reminiscent of genetic dystrophic epidermolysis bullosa (DEB). DEB patients have diminutive or absent anchoring fibrils due to a genetic defect in the gene encoding type VII collagen. EBA patients have a decrease in normally functioning anchoring fibrils secondary to an abnormality in their immune system in which they produce 'pathogenic' IgG anti-type VII collagen antibodies. The pathogenicity of these autoantibodies has been demonstrated by passive transfer animal models, in which anti-type VII collagen antibodies injected into a mouse produced an EBA-like blistering disease in the animal. EBA has several distinct clinical presentations. It can present with features similar to DEB, bullous pemphigoid, cicatricial pemphigoid, Brunsting-Perry pemphigoid or IgA bullous dermatosis. Treatment for EBA is unsatisfactory, however, some therapeutic success has been reported with colchicine, dapsone, photophoresis, infliximab and intravenous immunoglobulin.

Generalized vitiligo is an acquired disorder in which patches of depigmented skin, overlying hair and oral mucosa result from progressive autoimmune loss of melanocytes from the involved areas. Perhaps the most common pigmentary disorder, vitiligo results from a complex interaction of environmental, genetic and immunologic factors that ultimately contribute to melanocyte destruction, resulting in the characteristic depigmented lesions. In the past few years, studies of the genetic epidemiology of generalized vitiligo have led to the recognition that vitiligo is part of a broader, genetically determined, autoimmune and autoinflammatory diathesis. Attempts to identify genes involved in vitiligo susceptibility have involved gene expression studies, allelic association studies of candidate genes and genome-wide linkage analyses to discover new genes, and these studies have begun to shed light on the mechanisms of vitiligo pathogenesis. It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel therapeutic and prophylactic targets for future approaches to the treatment and prevention of vitiligo and its associated autoimmune diseases.

Atopic dermatitis (also termed atopic eczema and infantile eczema), a chronic, itchy, inflammatory skin disease that sets on at infancy or early childhood, is observed with increasing prevalence around the world, particularly in developed nations. Although sufficient evidences are not yet available to define it as a classical autoimmune disease, autoantigens have been identified. Investigations of atopic dermatitis in human patients and animal models suggest that this disease is initiated, maintained and perpetuated by the actions of cytokines, chemokines, T cells, antigen-presenting cells and other inflammatory cells; there is also evidence of skin barrier defect and angiogenesis. Recent identification of mutations of the epidermal barrier protein filaggrin (encoded by FLG), present in about 9% of people of European origin, with 70% of individuals homozygous or compound heterozygous for FLG null alleles developing atopic dermatitis, provides a strong link between a defect of the epidermal barrier that allows easy penetration of pathogen/allergen through the skin and a systemic hyperactive immune response to the penetrated pathogen/allergen. The newly introduced concept of 'intrinsic' and 'extrinsic' atopic dermatitis has fueled the debate among academic dermatologists as to how 'atopic' atopic dermatitis should be defined. Some recent advancements on the management options for atopic dermatitis are also discussed.

The pathogenesis of organ specific, cell mediated autoimmune alopecia areata (AA) has substantially progressed in the last decade. These advances are partly based upon advances in immunology and genetics, improved technological methodology in RNA, DNA, proteomics, and computer analyses, as well as the development of the C3H/HeJ mouse model of AA. The discovery that full thickness skin grafts transfer AA from C3H/HeJ mice that spontaneously develop AA to multiple non-affected C3H/HeJ mice greatly shortened the time of AA onset and provided many more affected mice in this highly reproducible model of AA. These methodological and genetic advances combine to form practical bases for identifying subtypes of human and mouse AA, characterizing disease mechanisms, improving currently available treatments, and developing new, more effective therapies. In the next decade even more exciting new insights into the pathogenesis of subtypes of human AA, their genetic bases, and therapy development will become available based on in-depth data on specific gene mutations and signaling pathways involved. Other organ specific autoimmune diseases will surely benefit from the rapid progress in understanding AA.

While relatively rare, the clinical presentation of toxic epidermal necrolysis (TENS) is often very dramatic and unfortunately it frequently results in the loss of life due to extensive epidermal necrosis and subsequent complications. The etiology of TENS is fairly well known and linked to ingestion of various medications. However, the pathophysiology and treatment of TENS is less well understood, but abnormal immunological mechanisms have been implicated by some investigators. The purpose of this chapter is to review the clinical features of TENS, followed by dermatopathological and immunopathological aspects of the skin lesions. A review of basic skin biology as regards regulation of keratinocytes' life and death is provided with emphasis on premature cell death. After a review of the immunopathogenic theories for TENS, a discussion of possible therapeutic interventions concludes the chapter. Clearly, many new insights are required at multiple levels of understanding to better manage and perhaps even prevent TENS.