Antigen Processing, Presentation, and Tolerance: Role in Autoimmune Skin Diseases.

Autoreactive T cells pose a constant risk for the emergence of autoimmune skin diseases in genetically predisposed individuals carrying certain HLA risk alleles. Immune tolerance mechanisms are opposed by broad HLA-presented self-immunopeptidomes, a predefined repertoire of polyspecific TCRs, the continuous generation of new antibody specificities by somatic recombination of Ig genes in B cells, and heightened proinflammatory reactivity. Increased autoantigen presentation by HLA molecules, cross-activation of pathogen-induced T cells against autologous structures, altered metabolism of self-proteins, and excessive production of proinflammatory signals may all contribute to the breakdown of immune tolerance and the development of autoimmune skin diseases.

Immunogenic self-peptides - the great unknowns in autoimmunity: Identifying T-cell epitopes driving the autoimmune response in autoimmune diseases.

HLA-associated autoimmune diseases likely arise from T-cell-mediated autoimmune responses against certain self-peptides from the broad HLA-presented immunopeptidomes. The limited knowledge of the autoimmune target peptides has so far compromised the basic understanding of autoimmune pathogenesis. This is due to the complexity of antigen processing and presentation as well as the polyspecificity of T-cell receptors (TCRs), which pose high methodological challenges on the discovery of immunogenic self-peptides. HLA-class I molecules present peptides to CD8+ T cells primarily derived from cytoplasmic proteins. Therefore, HLA-class I-restricted autoimmune responses should be directed against target cells expressing the corresponding parental protein. In HLA-class II-associated diseases, the origin of immunogenic peptides is not pre-specified, because peptides presented by HLA-class II molecules to CD4+ T cells may originate from both extracellular and cellular self-proteins. The different origins of HLA-class I and class II presented peptides determine the respective strategy for the discovery of immunogenic self-peptides in approaches based on the TCRs isolated from clonally expanded pathogenic T cells. Both involve identifying the respective restricting HLA allele as well as determining the recognition motif of the TCR under investigation by peptide library screening, which is required to search for homologous immunogenic self-peptides. In HLA-class I-associated autoimmune diseases, identification of the target cells allows for defining the restricting HLA allotype from the 6 different HLA-class I alleles of the individual HLA haplotype. It furthermore limits the search for immunogenic self-peptides to the transcriptome or immunopeptidome of the target cells, although neoepitopes generated by peptide splicing or translational errors may complicate identification. In HLA class II-associated autoimmune diseases, the lack of a defined target cell and differential antigen processing in different antigen-presenting cells complicate identification of the HLA restriction of autoreactive TCRs from CD4+ T cells. To avoid that all corresponding HLA-class II allotypes have to be included in the peptide discovery, autoantigens defined by autoantibodies can guide the search for immunogenic self-peptides presented by the respective HLA-class II risk allele. The objective of this article is to highlight important aspects to be considered in the discovery of immunogenic self-peptides in autoimmune diseases.

Intracellular Streptococcal Uptake and Persistence: A Potential Cause of Erysipelas Recurrence.

Erysipelas is a severe streptococcal infection of the skin primarily spreading through the lymphatic vessels. Penicillin is the treatment of choice. The most common complication consists in relapses which occur in up to 40% or more of patients despite appropriate antibiotic treatment. They cause lymphatic damage resulting in irreversible lymphedema and ultimately elephantiasis nostras and lead to major health restrictions and high socio-medical costs. Prevention of relapses is an unmet need, because even long-term prophylactic penicillin application does eventually not reduce the risk of recurrence. In this article we assess risk factors and causes of erysipelas recurrence. A systematic literature search for clinical studies addressing potential causes and measures for prevention of erysipelas recurrence was combined with a review of experimental and clinical data assessing the ability and clinical relevance of streptococci for intracellular uptake and persistence. The literature review found that venous insufficiency, lymphedema, and intertrigo from fungal infections are considered to be major risk factors for recurrence of erysipelas but cannot adequately explain the high recurrence rate. As hitherto unrecognized likely cause of erysipelas relapses we identify the ability of streptococci for intracellular uptake into and persistence within epithelial and endothelial cells and macrophages. This creates intracellular streptococcal reservoirs out of reach of penicillins which do not reach sufficient bactericidal intracellular concentrations. Incomplete streptococcal elimination due to intracellular streptococcal persistence has been observed in various deep tissue infections and is considered as cause of relapsing streptococcal pharyngitis despite proper antibiotic treatment. It may also serves as endogenous infectious source of erysipelas relapses. We conclude that the current antibiotic treatment strategies and elimination of conventional risk factors employed in erysipelas management are insufficient to prevent erysipelas recurrence. The reactivation of streptococcal infection from intracellular reservoirs represents a plausible explanation for the frequent occurrence erysipelas relapses. Prevention of erysipelas relapses therefore demands for novel antibiotic strategies capable of eradicating intracellular streptococcal persistence.

Human Leukocyte Antigen-Class I Alleles and the Autoreactive T Cell Response in Psoriasis Pathogenesis.

Psoriasis is a complex immune-mediated inflammatory skin disease characterized by T-cell-driven epidermal hyperplasia. It occurs on a strong genetic predisposition. The human leukocyte antigen (HLA)-class I allele HLA-C*06:02 on psoriasis susceptibility locus 1 (PSORS1 on 6p21.3) is the main psoriasis risk gene. Other HLA-class I alleles encoding HLA molecules presenting overlapping peptide repertoires show associations with psoriasis as well. Outside the major histocompatibility complex region, genome-wide association studies identified more than 60 psoriasis-associated common gene variants exerting only modest individual effects. They mainly refer to innate immune activation and the interleukin-23/Th/c17 pathway. Given their strong risk association, explaining the role of the HLA-risk alleles is essential for elucidating psoriasis pathogenesis. Psoriasis lesions develop upon epidermal infiltration, activation, and expansion of CD8+ T cells. The unbiased analysis of a paradigmatic Vα3S1/Vß13S1-T-cell receptor from a pathogenic epidermal CD8+ T-cell clone of an HLA-C*06:02+ psoriasis patient had revealed that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation, and it identified a peptide form ADAMTS-like protein 5 as an HLA-C*06:02-presented melanocyte autoantigen. These data demonstrate that psoriasis is an autoimmune disease, where the predisposing HLA-class I alleles promote organ-specific inflammation through facilitating a T-cell response against a particular skin-specific cell population. This review discusses the role of HLA-class I alleles in the pathogenic psoriatic T-cell immune response. It concludes that as a principle of T-cell driven HLA-associated inflammatory diseases proinflammatory traits promote autoimmunity in the context of certain HLA molecules that present particular autoantigens.

Melanocytes: Target Cells of an HLA-C*06:02-Restricted Autoimmune Response in Psoriasis.

HLA-C*06:02 is the main psoriasis risk allele. By the unbiased analysis of a Vα3S1/Vß13S1 T-cell receptor from pathogenic psoriatic CD8+ T cells, we had recently proven that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation in psoriasis and identified ADAMTSL5 as a melanocyte autoantigen. We concluded that psoriasis is based on a melanocyte-specific immune response and that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway. Understanding this pathway, however, requires more detailed explanation. It is based on the fact that an HLA class I-restricted autoreactive CD8+ T-cell response must be directed against a particular target cell type, because HLA class I molecules present peptide antigens generated from cytoplasmic (i.e., intracellular) proteins. This review summarizes the findings on the melanocyte-specific autoimmune response in the context of the immune mechanisms related to HLA function and T-cell receptor-antigen recognition. Identifying melanocytes as target cells of the psoriatic immune response now explains psoriasis as a primary autoimmune skin disease.

Autoimmune aspects of psoriasis: Heritability and autoantigens.

Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.

Disseminated eruptive giant mollusca contagiosa in an adult psoriasis patient during efalizumab therapy.

Molluscum contagiosum is a common viral skin infection in children with atopic diathesis and not rare in HIV patients. We report a 45-year-old psoriasis patient who developed eruptive mollusca contagiosa during an antipsoriatic treatment with efalizumab.

Sequential use of infliximab and etanercept in generalized pustular psoriasis.

Generalized pustular psoriasis is a dramatic potentially life-threatening psoriasis variant and represents a major therapeutic challenge. Tumor necrosis factor alpha (TNF-alpha) inhibitors have been shown to be highly effective in psoriasis vulgaris and psoriasis arthritis. Currently, TNF-alpha can be targeted therapeutically by 2 different approaches. TNF-alpha antibodies show a fast onset of action and a long-lasting activity. Soluble TNF-alpha receptors have a slower onset and a shorter duration of activity, which allows a rapid cessation of the drug's activity in the case of adverse events. Here we report that a remission of generalized pustular psoriasis achieved by the TNF-alpha antibody infliximab was maintained by long-term application of the soluble TNF-alpha receptor etanercept. Sequential therapy with TNF-alpha antibodies and TNF-alpha receptors may represent a novel concept that combines a rapid onset of action in the initiation therapy with a lower risk for severe adverse events in the maintenance treatment of pustular psoriasis.

Disease mimicry--a pathogenetic concept for T cell-mediated autoimmune disorders triggered by molecular mimicry?

Molecular mimicry is considered as a mechanism by which infectious pathogens may break immunological tolerance and cause autoimmune disease. It implicates that peptides shared between pathogen and host may induce cross-reactive immune reactions. According to this hypothesis, the resulting autoimmune response actually represents a secondary immune response. It is mediated by cross-reactive T cells that have been educated in a primary immune response against a particular pathogen. Using psoriasis vulgaris as a model, this article discusses the potential functional consequences molecular mimicry should have for the resulting autoimmune disease. It proposes that due to the functional memory of T cells, which is an integral feature of adaptive immunity, the phenotype of an autoimmune disease induced by molecular mimicry should reflect the immune mechanisms raised in the primary immune response. This process might be called 'disease mimicry'.

Topical treatment with imiquimod may induce regression of facial keratoacanthoma.

Keratoacanthoma (KA) is a rapidly growing tumour histologically resembling squamous cell carcinoma. Although it may regress spontaneously, KA is routinely treated by excision or radiation therapy. Here we report on the successful therapeutic use of imiquimod for the treatment of KA. Four patients with a one to six week history of facial KA were treated with imiquimod cream 5 % every second day for four to 12 weeks. In each patient, KA fully regressed under topical treatment with imiquimod. In three of the patients, KA had disappeared within four to six weeks. In two patients, disappearance was confirmed histologically. No recurrence occurred during a four- to six-month follow-up-period. Our observations indicate that topical immunostimulation with imiquimod may induce or promote immune defence mechanisms leading to KA regression. Imiquimod might therefore prove to be an effective non-invasive treatment modality for KA that warrants more extensive evaluation by clinical studies.