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Psoriasis is a chronic inflammatory disorder of the skin, with genetic factors reportedly involved in the disease pathogenesis. Numerous studies reported psoriasis candidate genes. However, these tend to involve mostly in the European and Asian populations. Here, we report the first genome-wide association study (GWAS) in an Egyptian population, identifying susceptibility variants for psoriasis using a two-stage case-control design. In the first discovery stage, we carried out a genome-wide association analysis using the Infinium® Global Screening Array-24 v1.0, on 253 cases and 449 control samples of Egyptian descent. In the second replication stage, 26 single-nucleotide polymorphisms (SNPs) were selected for replication in additional 321 cases and 253 controls. In concordance with the findings from previous studies on other populations, we found a genome-wide significant association between the MHC locus and the disease at rs12199223 (Pcomb = 6.57 × 10-18 ) and rs1265181 (Pcomb = 1.03 × 10-10 ). Additionally, we identified a novel significant association with the disease at locus, 4q32.1 (rs12650590, Pcomb = 4.49 × 10-08 ) in the vicinity of gene GUCY1A3, and multiple suggestive associations, for example rs10832027 (Pcomb = 7.28 × 10-06 ) and rs3770019 (Pcomb = 1.02 × 10-05 ). This proposes the existence of important interethnic genetic differences in psoriasis susceptibility. Further studies are necessary to elucidate the downstream pathways of the new candidate loci.
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Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Estudos de Casos e Controles , Egito/epidemiologia , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Inflamação , Complexo Principal de Histocompatibilidade , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , RiscoRESUMO
BACKGROUND: Mucous membrane pemphigoid (MMP) is an autoimmune subepithelial blistering disease with predominant involvement of mucosal surfaces. It is usually diagnosed by direct immunofluorescence microscopy of frozen biopsies, demonstrating linear deposits of complement, IgG or IgA along the basement membrane. The aim of this study was to investigate the utility of immunohistochemistry on formalin-fixed, paraffin-embedded tissue biopsies for the diagnosis of MMP and to compare its sensitivity to that of direct immunofluorescence microscopy. METHODS: We examined 50 biopsies from 34 patients with immunologically confirmed MMP by immunohistochemistry for C3d, C4d, IgG and IgA. RESULTS: Linear deposits of C3d were detected in 46% of biopsies, and 53% of patients had at least one biopsy positive for C3d. Linear deposits of C4d were detected in 52% of biopsies and 59% of patients had at least one biopsy positive for C4d. Overall, 56% of biopsies and 68% of patients were positive by either C3d or C4d or both stainings. The sensitivity of either staining in mucosal biopsies was lower than in skin samples. Basement membrane deposits of IgG or IgA could not be detected in any biopsy. CONCLUSIONS: Our findings demonstrate that immunohistochemistry for C3d or C4d is a helpful screening procedure for cases of suspected MMP where frozen tissue is not readily available. Negative findings, however, do not exclude a possible diagnosis of MMP and should prompt an additional biopsy for direct immunofluorescence studies. Immunohistochemical detection of IgG or IgA cannot yet be used for the diagnosis of MMP.
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Imuno-Histoquímica/métodos , Penfigoide Mucomembranoso Benigno/diagnóstico , Penfigoide Mucomembranoso Benigno/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Membrana Basal/patologia , Biópsia , Complemento C3d/análise , Complemento C4b/análise , Feminino , Técnica Direta de Fluorescência para Anticorpo , Humanos , Imunoglobulina A/análise , Imunoglobulina G/análise , Masculino , Pessoa de Meia-Idade , Mucosa/patologia , Fragmentos de Peptídeos/análise , Sensibilidade e Especificidade , Adulto JovemRESUMO
Animal models have enhanced our understanding of the pathogenesis of autoimmune diseases. For these models, genetically identical, inbred mice have commonly been used. Different inbred mouse strains, however, show a high variability in disease manifestation. Identifying the factors that influence this disease variability could provide unrecognized insights into pathogenesis. We established a novel Ab transfer-induced model of epidermolysis bullosa acquisita (EBA), an autoimmune disease characterized by (muco)-cutaneous blistering caused by anti-type VII collagen (COL7) autoantibodies. Blistering after anti-COL7 IgG (directed against the von Willebrand factor A-like domain 2) transfer showed clear variability among inbred mouse strains, that is, severe cutaneous blistering and inflammation in C57BL/6J and absence of skin lesions in MRL/MpJ mice. The transfer of anti-COL7 IgG into irradiated, EBA-resistant MRL/MpJ mice, rescued by transplantation with bone marrow from EBA-susceptible B6.AK-H2k mice, induced blistering. To the contrary, irradiated EBA-susceptible B6.AK-H2k mice that were rescued using MRL/MpJ bone marrow were devoid of blistering. In vitro, immune complex activation of neutrophils from C57BL/6J or MRL/MpJ mice showed an impaired reactive oxygen species release from the latter, whereas no differences were observed after PMA activation. This finding was paralleled by divergent expression profiles of immune complex-activated neutrophils from either C57BL/6J or MRL/MpJ mice. Collectively, we demonstrate that radiosensitive cells determine the varying extent of skin inflammation and blistering in the end-stage effector phase of EBA.
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Células da Medula Óssea/imunologia , Transplante de Medula Óssea/métodos , Dermatite/imunologia , Epidermólise Bolhosa Adquirida/imunologia , Animais , Autoanticorpos/imunologia , Vesícula/imunologia , Células da Medula Óssea/efeitos da radiação , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Redes Reguladoras de Genes/imunologia , Humanos , Imunoglobulina G/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Neutrófilos/imunologia , Neutrófilos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Coelhos , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Especificidade da Espécie , Transcriptoma/imunologiaRESUMO
BACKGROUND: MicroRNAs (miRNAs) are small endogenous non-coding RNAs that control genes at post-transcriptional level. They are essential for development and tissue differentiation, and such altered miRNA expression patterns are linked to the pathogenesis of inflammation and cancer. There is evidence that miRNA expression is genetically controlled similar to the transcription of protein-coding genes and previous studies identified quantitative trait loci (QTL) for miRNA expression in the liver. So far, little attention has been paid to miRNA expression in the skin. Moreover, epistatic control of miRNA expression remains unknown. In this study, we characterize genetic regulation of cutaneous miRNA and their correlation with skin inflammation using a previously established murine autoimmune-prone advanced intercross line. RESULTS: We identified in silico 42 eQTL controlling the expression of 38 cutaneous miRNAs and furthermore found two chromosomal hot-spots on chromosomes 2 and 8 that control the expression of multiple miRNAs. Moreover, for 8 miRNAs an interacting effect from pairs of SNPs was observed. Combining the constraints on genes from the statistical interaction of their loci and further using curated protein interaction networks, the number of candidate genes for association of miRNAs was reduced to a set of several genes. A cluster analysis identified miR-379 and miR-223 to be associated with EBA severity/onset, where miR-379 was observed to be associated to loci on chromosome 6. CONCLUSION: The murine advanced intercross line allowed us to identify the genetic loci regulating multiple miRNA in skin. The recurrence of trans-eQTL and epistasis suggest that cutaneous miRNAs are regulated by yet an unexplored complex gene networks. Further, using co-expression analysis of miRNA expression levels we showed that multiple miRNA contribute to multiple pathways that might be involved in pathogenesis of autoimmune skin blistering disease. Specifically, we provide evidence that miRNA such as miR-223 and miR-379 may play critical role in disease progression and severity.
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Doenças Autoimunes/genética , Vesícula/genética , Estudos de Associação Genética , Predisposição Genética para Doença , MicroRNAs/genética , Pele/metabolismo , Animais , Doenças Autoimunes/imunologia , Vesícula/imunologia , Modelos Animais de Doenças , Epistasia Genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Camundongos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Pele/patologia , TranscriptomaRESUMO
UNLABELLED: Non-coding RNAs (ncRNAs) are known to play important functional roles in the cell. However, their identification and recognition in genomic sequences remains challenging. In silico methods, such as classification tools, offer a fast and reliable way for such screening and multiple classifiers have already been developed to predict well-defined subfamilies of RNA. So far, however, out of all the ncRNAs, only tRNA, miRNA and snoRNA can be predicted with a satisfying sensitivity and specificity. We here present ptRNApred, a tool to detect and classify subclasses of non-coding RNA that are involved in the regulation of post-transcriptional modifications or DNA replication, which we here call post-transcriptional RNA (ptRNA). It (i) detects RNA sequences coding for post-transcriptional RNA from the genomic sequence with an overall sensitivity of 91% and a specificity of 94% and (ii) predicts ptRNA-subclasses that exist in eukaryotes: snRNA, snoRNA, RNase P, RNase MRP, Y RNA or telomerase RNA. AVAILABILITY: The ptRNApred software is open for public use on http://www.ptrnapred.org/.
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RNA não Traduzido/classificação , Análise de Sequência de RNA/métodos , Software , Biologia Computacional/métodos , Regulação da Expressão Gênica , RNA não Traduzido/química , Máquina de Vetores de SuporteRESUMO
BACKGROUND: Disseminated intravascular coagulation (DIC) can frequently be observed in patients with severe inflammatory response. It is still correlated with a poor prognosis. Activation of coagulation activity leads to occlusions of small vessels resulting in various organ failure symptoms. In addition, secondary fibrinolysis leads to an increased risk of bleedings and means a therapeutic dilemma. Here, we present a case of a 61-year-old Caucasian man with a severe case of DIC and its clinical complications. METHODS: We report the case of a man with a severe case of DIC. Data collection was performed retrospectively. RESULTS: We report the case of a 61-year-old Caucasian man with contact to pigeon droppings in his medical history. This was followed by a rhinopharyngitis, an exanthema, and a recurring priapism. Thrombotic occlusions were predominant on admission, and necrosis of the lower legs, the hands, and the genital resulted in amputation. Hypoperfusion of the rectum and the bladder lead to the creation of a descendostoma and an uretrostoma. Anticoagulation was managed by continuous infusion of unfractionated heparin and activated protein C supplementation. Long-term anticoagulation is managed with rivaroxaban. CONCLUSIONS: Cryptococcus soil inhalation may cause severe DIC resulting in extremity amputations; however, effective anticoagulation and activated protein C supplementation might extenuate the progress. As multiple complications might occur, an interdisciplinary cooperation is essential.
Assuntos
Columbidae , Criptococose/microbiologia , Cryptococcus/patogenicidade , Fezes/microbiologia , Isquemia/microbiologia , Trombose/microbiologia , Amputação Cirúrgica , Animais , Anticoagulantes/administração & dosagem , Antifúngicos/uso terapêutico , Criptococose/sangue , Criptococose/diagnóstico , Criptococose/terapia , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/terapia , Esquema de Medicação , Humanos , Exposição por Inalação/efeitos adversos , Isquemia/sangue , Isquemia/diagnóstico , Isquemia/terapia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Trombose/sangue , Trombose/diagnóstico , Trombose/terapia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoAssuntos
Mucosa Nasal , Doenças Nasais , Humanos , Mucosa Nasal/patologia , Doenças Nasais/diagnósticoRESUMO
Primary Cutaneous Gamma-Delta (γδ) T-Cell Lymphoma (PCGDTCL) is a rare primary cutaneous lymphoma of aggressive nature. Only a few cases with an initially indolent course over years have been published. PCGDTCL can mimic diseases with benign behavior in their clinical and histopathological presentation, such as lupus erythematosus profundus, but also other lymphomas, for example subcutaneous panniculitis-like T-cell lymphoma. In our patient, the results of histopathological, immunofluorescence microscopy, and clinical examinations of early lesions first led to the diagnosis of lupus erythematosus profundus. Two years after this diagnosis and 6 years after the first clinical symptoms appeared, the disease progressed with erosive and ulcerating plaques and a PCGDTCL with hemophagocytic syndrome with an aggressive course was diagnosed. A distinct correlation of clinical, histopathological, immunohistochemical, and molecular-pathological examinations is needed to differentiate between the potentially malignant and benign diseases. Re-biopsies of different skin lesions in uncertain cases are strongly indicated. This case demonstrates that an indolent clinical phenotype can precede an aggressive clinical course in PCGDTCL.
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Background: Facial dermatitis is a common dermatologic condition. It is usually treated with either topical corticosteroids or calcineurin inhibitors. However, the use of these drugs is limited by side effects, including skin atrophy, local immunosuppression and possible oncogenicity. Objective: The aim of the study was to evaluate the use of wet dressings with black tea for treating facial dermatitis. Methods: We performed a prospective, open, uncontrolled before-after study enrolling 22 patients with atopic or contact facial dermatitis who were treated with black tea dressings and an emollient cream over 6 days. Disease severity was assessed using the (1) Facial Eczema Area and Severity Index, (2) Visual analog scale for pruritus, (3) Investigator`s Global Assessment score, and (4) Patient's Self-Assessment score. The study was registered at www.ClinicalTrials.gov as NCT02941432. Results: A dramatic and highly significant reduction of all four disease activity scores occurred within the first 3 days of treatment and the patients continued to improve between days 3 and 6. No side effects were observed. Conclusion: Black tea dressings represent an effective treatment option for facial dermatitis. Its advantages include lack of side effects, low cost, and easy availability.
Assuntos
Dermatite Atópica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Chá/química , Adulto , Idoso , Bandagens , Dermatite Atópica/patologia , Face/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/química , Estudos Prospectivos , Prurido/patologia , Índice de Gravidade de Doença , Chá/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
Autoimmune blistering diseases (AIBDs) of the skin are characterized by autoantibodies against different intra-/extracellular structures within the epidermis and at the basement membrane zone (BMZ). Binding of the antibodies to their target antigen leads to inflammation at the respective binding site and degradation of these structures, resulting in the separation of the affected skin layers. Clinically, blistering, erythema and lesions of the skin and/or mucous membranes can be observed. Based on the localization of the autoantigen, AIBDs can be divided into pemphigus (intra-epidermal blistering diseases) and pemphigoid diseases (sub-epidermal blistering diseases), respectively. Although autoantigens have been extensively characterized, the underlying causes that trigger the diseases are still poorly understood. Besides the environment, genetic factors seem to play an important role in a predisposition to AIBDs. Here, we review currently known genetic and immunological mechanisms that contribute to the pathogenesis of AIBDs. Among the most commonly encountered genetic predispositions for AIBDs are the HLA gene region, and deleterious mutations of key genes for the immune system. Particularly, HLA class II genes such as the HLA-DR and HLA-DQ alleles have been shown to be prevalent in patients. This has prompted further epidemiological studies as well as unbiased Omics approaches on the transcriptome, microbiome, and proteome level to elucidate common and individual genetic risk factors as well as the molecular pathways that lead to the pathogenesis of AIBDs.
Assuntos
Autoantígenos , Doenças Autoimunes , Predisposição Genética para Doença , Genômica , Dermatopatias Vesiculobolhosas , Alelos , Autoantígenos/genética , Autoantígenos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Humanos , Fatores de Risco , Dermatopatias Vesiculobolhosas/genética , Dermatopatias Vesiculobolhosas/imunologia , Dermatopatias Vesiculobolhosas/patologiaRESUMO
Bullous pemphigoid (BP) is a rare autoimmune skin blistering disease, characterized by the presence of autoantibodies against hemidesmosomal autoantigens. Cytokine expression is altered in BP patients, and several of these differently expressed cytokines, including IL-1α, IL-1ß, IL-8, and TNF-α, contribute to disease pathogenesis. Since genetic polymorphisms in the genes of these cytokines might be implicated in susceptibility to BP disease, we aimed at testing this implication in susceptibility to BP in an Iranian cohort. Blood samples were collected from the subjects and genomic DNA was extracted. To detect the single nucleotide polymorphisms (SNPs), IL-1α (rs1800587), IL-1ß (rs1143627, rs16944, rs1143634), IL-8 (rs4073), and TNF-α (rs1799964, rs1800630, rs1799724, and rs361525) genes were genotyped in BP patients and healthy controls as well as IL-8 (rs4073) in pemphigus vulgaris (PV) patients. Quantitative gene expression was evaluated by RT-PCR analysis. A significant difference was observed in the distribution of genotypes or alleles of IL-8 SNP between the BP patients and controls. The A-allele of IL-8 SNP is significantly more prevalent in the control individuals compared to the BP patient. To further validate this observation, we included PV patients as an additional control. Again, the A-allele of IL-8 SNP is significantly more prevalent in the PV compared to the BP patients. While we observed a trend toward significant differences regarding alleles of TNF-α rs1799724 as well as alleles of TNF-α rs1799964, this difference was, however, not evident after correction for multiple analysis. There was no significant difference in all other studied SNPs. In contrast to IL-1α, IL-1ß, and TNF-α, IL-8 gene expression levels were significantly higher in the patients than that of controls. The minor allele in IL-8 SNP might play a protective role in susceptibility to BP in Iranian patients. Although higher expression levels of IL-8 gene was found in the patients compared with healthy controls, these levels, however, suggest no association with the examined polymorphism. Moreover, further investigation revealed an elevation in gene expression between wild and polymorphic genotypes of IL-1α rs1800587 and TNF-α rs361525 in the patient group and these SNPs are therefore associated with altering the levels of gene expression.
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Citocinas , Regulação da Expressão Gênica/imunologia , Penfigoide Bolhoso , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Citocinas/genética , Citocinas/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/genética , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. Most intriguingly, BP is distinct from other autoimmune diseases because it predominantly affects elderly individuals above the age of 75 years, raising the question why autoantibodies and the clinical lesions of BP emerges mostly in this later stage of life, even in individuals harboring known putative BP-associated germline gene variants. The mitochondrial genome (mtDNA) is a potential candidate to provide additional insights into the BP etiology; however, the mtDNA has not been extensively explored to date. Therefore, we sequenced the whole mtDNA of German BP patients (n = 180) and age- and sex-matched healthy controls (n = 188) using next generation sequencing (NGS) technology, followed by the replication study using Sanger sequencing of an additional independent BP (n = 89) and control cohort (n = 104). While the BP and control groups showed comparable mitochondrial haplogroup distributions, the haplogroup T exhibited a tendency of higher frequency in BP patients suffering from neurodegenerative diseases (ND) compared to BP patients without ND (50%; 3 in 6 BP with haplogroup T). A total of four single nucleotide polymorphisms (SNPs) in the mtDNA, namely, m.16263T>C, m.16051A>G, and m.16162A>G in the D-loop region of the mtDNA, and m.11914G>A in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 gene (MT-ND4), were found to be significantly associated with BP based on the meta-analysis of our NGS data and the Sanger sequencing data (p = 0.0017, p = 0.0129, p = 0.0076, and p = 0.0132, respectively, Peto's test). More specifically, the three SNPs in the D-loop region were negatively, and the SNP in the MT-ND4 gene was positively associated with BP. Our study is the first to interrogate the whole mtDNA in BP patients and controls and to implicate multiple novel mtDNA variants in disease susceptibility. Studies using larger cohorts and more diverse populations are warranted to explore the functional consequences of the mtDNA variants identified in this study on immune and skin cells to understand their contributions to BP pathology.
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DNA Mitocondrial , Genoma Mitocondrial/imunologia , NADH Desidrogenase , Penfigoide Bolhoso , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Autoantígenos/genética , Autoantígenos/imunologia , DNA Mitocondrial/genética , DNA Mitocondrial/imunologia , Distonina/genética , Distonina/imunologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , NADH Desidrogenase/genética , NADH Desidrogenase/imunologia , Colágenos não Fibrilares/genética , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/genética , Penfigoide Bolhoso/imunologia , Colágeno Tipo XVIIRESUMO
Autoimmune skin blistering diseases (AIBD) are characterized by autoantibodies that are directed against structural proteins in the skin and adjacent mucous membranes. Some clinical signs are typical for a specific AIBD, however, correct diagnosis requires the detection of tissue-bound or circulating autoantibodies. The gold standard for diagnosis of AIBD is the detection of autoantibodies or complement component 3 by direct immunofluorescence (DIF) microscopy of a perilesional biopsy. Circulating antibodies can be detected via indirect immunofluorescence (IIF) microscopy of different tissue substrates including human skin, monkey esophagus, and more recently, recombinant forms of the different target antigens. Latter are also employed in various commercial ELISA systems and by immunoblotting in in-house assays available in specialized laboratories. ELISA systems are also particularly valuable for monitoring of the disease activity during the disease course which can be helpful for treatment decisions. Exact diagnosis is essential for both treatment and prognosis, since some AIBD are associated with malign tumors such as paraneoplastic pemphigus and anti-laminin 332 mucous membrane pemphigoid. This review presents clinical and immunopathological features of AIBD for the state-of the art diagnosis of these disorders.
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A link between hypovitaminosis D and development of autoimmune bullous disorders has been suggested recently, but this association has not been elaborated experimentally. Here, the role of vitamin D was investigated in epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-induced blistering skin disease. Oral administration of the hormonally active vitamin D metabolite calcitriol ameliorated clinical disease severity and dermal neutrophil infiltration in both an antibody transfer- and immunization-induced EBA mouse model. Mechanistically, calcitriol hindered immune effector cell activation as evidenced by increased L-selectin expression on Gr-1+ cells in calcitriol-treated mice with antibody transfer-induced EBA, as well as suppressed in vitro immune complex-induced reactive oxygen species production in calcitriol-treated murine neutrophils. Additionally, calcitriol administration was associated with an increase of regulatory T (CD4+FoxP3+) and B (CD19+IL10+) cells as well as reduction of pro-inflammatory T helper 17 (CD4+IL-17+) cells in mice with immunization-induced EBA. In line, levels of circulating anti-type VII collagen autoantibodies were lower in mice that received calcitriol compared to solvent-treated animals. Together with the observed state of hypovitaminosis D in most cases of an analyzed EBA patient cohort, the results of this study support the use of vitamin D derivatives or analogs for patients with EBA and related diseases.
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Autoanticorpos/sangue , Doenças Autoimunes/tratamento farmacológico , Calcitriol/uso terapêutico , Epidermólise Bolhosa Adquirida/tratamento farmacológico , Vitaminas/uso terapêutico , Administração Oral , Adulto , Idoso , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Calcitriol/farmacologia , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Epidermólise Bolhosa Adquirida/sangue , Epidermólise Bolhosa Adquirida/diagnóstico , Epidermólise Bolhosa Adquirida/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Resultado do Tratamento , Vitaminas/farmacologiaRESUMO
Cell stress-inducible Hsp90 has been recognized as key player in mediating inflammatory responses. Although its systemic blockade was successfully used to treat autoimmune diseases in preclinical models, efficacy of a topical route of Hsp90 inhibitor administration has so far not been evaluated in chronic inflammatory and autoimmune-mediated dermatoses. Here, effects of the Hsp90 blocker 17-allylamino-demethoxygeldanamycin (17AAG) applied topically to the skin were determined in experimental inflammatory epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-induced blistering skin disease. Topical 17AAG ameliorated clinical disease severity when given before or during the occurrence of skin lesions without causing cutaneous or systemic toxicity in mice with antibody transfer- and immunization-induced EBA. In both EBA models and in the setting of locally induced inflammation, topical 17AAG treatment was associated with (i) reduced neutrophilic infiltrates, (ii) decreased NF-κB activation, (iii) lowered expression of matrix metalloproteinases and Flii, and (iv) induction of anti-inflammatory Hsp70 in the skin. Our results suggest that topical delivery of Hsp90 antagonists, offering the benefit of a reduced risk of systemic adverse effects of Hsp90 inhibition, may be useful for the control of EBA and possibly other related inflammatory skin disorders.
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Autoanticorpos/imunologia , Benzoquinonas/administração & dosagem , Epidermólise Bolhosa Adquirida/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/administração & dosagem , Administração Tópica , Animais , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Epidermólise Bolhosa Adquirida/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/fisiologia , Pele/patologiaRESUMO
Regulatory T cells (Tregs) are well known for their modulatory functions in adaptive immunity. Through regulation of T cell functions, Tregs have also been demonstrated to indirectly curb myeloid cell-driven inflammation. However, direct effects of Tregs on myeloid cell functions are insufficiently characterized, especially in the context of myeloid cell-mediated diseases, such as pemphigoid diseases (PDs). PDs are caused by autoantibodies targeting structural proteins of the skin. Autoantibody binding triggers myeloid cell activation through specific activation of Fc gamma receptors, leading to skin inflammation and subepidermal blistering. Here, we used mouse models to address the potential contribution of Tregs to PD pathogenesis in vivo. Depletion of Tregs induced excessive inflammation and blistering both clinically and histologically in two different PD mouse models. Of note, in the skin of Treg-depleted mice with PD, we detected increased expression of different cytokines, including Th2-specific IL-4, IL-10, and IL-13 as well as pro-inflammatory Th1 cytokine IFN-γ and the T cell chemoattractant CXCL-9. We next aimed to determine whether Tregs alter the migratory behavior of myeloid cells, dampen immune complex (IC)-induced myeloid cell activation, or both. In vitro experiments demonstrated that co-incubation of IC-activated myeloid cells with Tregs had no impact on the release of reactive oxygen species (ROS) but downregulated ß2 integrin expression. Hence, Tregs mitigate PD by altering the migratory capabilities of myeloid cells rather than their release of ROS. Modulating cytokine expression by administering an excess of IL-10 or blocking IFN-γ may be used in clinical translation of these findings.
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INTRODUCTION: Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune bullous dermatosis (AIBD). Treatment of EBA is challenging and mostly relies on systemic immunosuppression. During the last decade, intensive research led to the identification of new potential therapeutic targets that interfere in different phases of disease progression. Therapeutic interventions acting upon these candidate drug targets in animal models of EBA, such as cytokine-modulating biologics and small molecules, have validated them as potential new therapeutic strategies for EBA patients. AREAS COVERED: In this paper, we review the current treatments for EBA, describe the pathogenesis of the disease, and finally specify new drug candidates for the development of a more specific therapy with minimized side-effects for EBA and potentially other autoimmune diseases. EXPERT OPINION: We currently understand EBA as a disease that evolves from the interplay of many different signaling pathways. These signaling pathways, which are described in this review, provide new targets for EBA treatment. The ultimate goal of this research field is the development of specific, pathogenesis-based therapeutic strategies. Through identification of up- or downregulated pathways that dominate disease progression in individual patients, we expect therapy in EBA to become more and more precise and move towards a patient-based therapy.