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1.
Cell Mol Life Sci ; 78(6): 2709-2727, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33386888

RESUMO

Psoriasis is a chronic inflammatory disease of the skin that affects about 2-3% of the population and greatly impairs the quality of life of affected individuals. Psoriatic skin is characterized by excessive proliferation and aberrant differentiation of keratinocytes, as well as redness caused by increased dilation of the dermal blood vessels and infiltration of immune cells. Although the pathogenesis of psoriasis has not yet been completely elucidated, it is generally believed to arise from a complex interplay between hyperproliferating keratinocytes and infiltrating, activated immune cells. So far, the exact triggers that elicit this disease are still enigmatic, yet, it is clear that genetic predisposition significantly contributes to the development of psoriasis. In this review, we summarize current knowledge of important cellular and molecular mechanisms driving the initiation and amplification stages of psoriasis development, with a particular focus on cytokines and emerging evidence illustrating keratinocyte-intrinsic defects as key drivers of inflammation. We also discuss mouse models that have contributed to a better understanding of psoriasis pathogenesis and the preclinical development of novel therapeutics, including monoclonal antibodies against specific cytokines or cytokine receptors that have revolutionized the treatment of psoriasis. Future perspectives that may have the potential to push basic research and open up new avenues for therapeutic intervention are provided.


Assuntos
Psoríase/patologia , Anticorpos Monoclonais/uso terapêutico , Citocinas/genética , Citocinas/metabolismo , Estudo de Associação Genômica Ampla , Antígenos HLA-C/genética , Humanos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Psoríase/tratamento farmacológico , Psoríase/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Necrose Tumoral/imunologia , Fatores de Necrose Tumoral/metabolismo
2.
Science ; 371(6527)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33479125

RESUMO

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.


Assuntos
Dermatite Atópica/embriologia , Dermatite Atópica/patologia , Psoríase/embriologia , Psoríase/patologia , Pele/embriologia , Animais , Atlas como Assunto , Movimento Celular , Conjuntos de Dados como Assunto , Células Dendríticas/imunologia , Dermatite Atópica/imunologia , Fármacos Dermatológicos/farmacologia , Humanos , Imunidade Inata/genética , Metotrexato/farmacologia , Camundongos , Fagócitos/imunologia , Psoríase/imunologia , Análise de Célula Única , Pele/citologia , Pele/imunologia , Linfócitos T/imunologia , Transcriptoma
4.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348540

RESUMO

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet's disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8+ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the "mis-immunopeptidome" that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8+ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.


Assuntos
Aminopeptidases/genética , Síndrome de Behçet/imunologia , Coriorretinopatia de Birdshot/imunologia , Genes MHC Classe I , Antígenos de Histocompatibilidade Classe I/genética , Imunidade/genética , Antígenos de Histocompatibilidade Menor/genética , Psoríase/imunologia , Espondilite Anquilosante/imunologia , Alelos , Linfócitos T CD8-Positivos/imunologia , Humanos , Polimorfismo de Nucleotídeo Único
5.
Am J Hum Genet ; 107(4): 612-621, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32888428

RESUMO

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.


Assuntos
Artrite Reumatoide/genética , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Psoríase/genética , Adulto , Alelos , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Cromossomos Humanos Par 6/química , Hipersensibilidade a Drogas/complicações , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Registros Eletrônicos de Saúde , Europa (Continente) , Feminino , Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Antígenos HLA-B/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Penicilinas/efeitos adversos , Proteína Tirosina Fosfatase não Receptora Tipo 22/imunologia , Psoríase/complicações , Psoríase/imunologia , Autorrelato , Linfócitos T/imunologia , Linfócitos T/patologia , Estados Unidos
6.
J Am Acad Dermatol ; 83(6): 1704-1716, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32891785

RESUMO

OBJECTIVE: To provide guidance about management of psoriatic disease during the coronavirus disease 2019 (COVID-19) pandemic. STUDY DESIGN: A task force (TF) of 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care was convened. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by questions received by the NPF. A Delphi process was conducted. RESULTS: The TF approved 22 guidance statements. The average of the votes was within the category of agreement for all statements. All guidance statements proposed were recommended, 9 with high consensus and 13 with moderate consensus. LIMITATIONS: The evidence behind many guidance statements is limited in quality. CONCLUSION: These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk and outcome, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 2 and what they should do if they develop COVID-19. The guidance is intended to be a living document that will be updated by the TF as data emerge.


Assuntos
Infecções por Coronavirus/epidemiologia , Imunossupressores/efeitos adversos , Organizações sem Fins Lucrativos/normas , Pneumonia Viral/epidemiologia , Psoríase/tratamento farmacológico , Comitês Consultivos/normas , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Consenso , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Cuidados Críticos/normas , Técnica Delfos , Dermatologia/normas , Epidemiologia/normas , Humanos , Infectologia/normas , Organizações sem Fins Lucrativos/organização & administração , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Psoríase/complicações , Psoríase/imunologia , Reumatologia/normas , Estados Unidos/epidemiologia
7.
Mol Immunol ; 126: 95-100, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32795664

RESUMO

Although T cells are considered as the central component in immune-mediated diseases, supportive evidence has demonstrated that B cells also contribute to the progression of these diseases. B cells are divided into various subsets according to their secreted cytokines. Different B cell subsets play diverse roles in immune-mediated dermatoses. Regulatory B cells (Bregs) are defined functionally by their ability to secrete IL-10, which has been revealed to contribute to immunological tolerance. Drugs that deplete B cells, such as rituximab, are now used for the treatment of several immune-mediated dermatoses. In this review, we present and discuss the current knowledge on the roles of B cells in several immune-mediate dermatoses including psoriasis, pemphigus, bullous pemphigoid, and dermatomyositis, atopic dermatitis.


Assuntos
Linfócitos B Reguladores/imunologia , Dermatite Atópica/imunologia , Dermatomiosite/imunologia , Penfigoide Bolhoso/imunologia , Pênfigo/imunologia , Psoríase/imunologia , Animais , Linfócitos B Reguladores/efeitos dos fármacos , Linfócitos B Reguladores/metabolismo , Dermatite Atópica/sangue , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Dermatomiosite/sangue , Dermatomiosite/tratamento farmacológico , Dermatomiosite/patologia , Desmogleína 3/metabolismo , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interleucina-10/metabolismo , Depleção Linfocítica/métodos , Penfigoide Bolhoso/sangue , Penfigoide Bolhoso/tratamento farmacológico , Penfigoide Bolhoso/patologia , Pênfigo/sangue , Pênfigo/tratamento farmacológico , Pênfigo/patologia , Psoríase/sangue , Psoríase/tratamento farmacológico , Psoríase/patologia , Pele/imunologia , Pele/patologia
8.
Scand J Immunol ; 92(5): e12953, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32757303

RESUMO

Psoriasis is an inflammatory disease that arises in genetically predisposed individuals. Chronic skin lesions that contain activated immune cells can persist for years. Systemic inhibition of TNF, IL-17 and IL-23 cytokines has revolutionized psoriasis care during the recent decades. Unfortunately, local relapse of disease is common at previously inflamed sites after cessation of treatment. This highlights that fundamental pathologic alterations of the affected tissues are not completely resolved during clinical remission. Here, we present arguments for a local disease memory located in both dermis and epidermis in psoriasis skin. We decipher different cellular components and intercellular crosstalk that sustain local disease memory and amplify disease relapse in human psoriasis. Decrypting the mechanisms underlying the establishment and persistence of pathogenic memory cells in resolved psoriasis may provide new therapeutic perspectives aimed at long-term remission of psoriasis.


Assuntos
Cicatriz/imunologia , Citocinas/imunologia , Interleucina-17/imunologia , Queratinócitos/imunologia , Psoríase/imunologia , Pele/imunologia , Cicatriz/metabolismo , Citocinas/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Humanos , Memória Imunológica/imunologia , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Psoríase/metabolismo , Recidiva , Pele/metabolismo , Pele/patologia
9.
Scand J Immunol ; 92(4): e12945, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32697368

RESUMO

In the past decades, clinical and experimental evidence has demonstrated that psoriasis is an immune-mediated inflammatory disease of the skin that occurs in genetically susceptible individuals. Psoriasis also shows clear autoimmune pathomechanisms, but specific cellular targets for the onset and maintenance of psoriatic lesions were not established until 2014. Since then, four psoriasis autoantigens were discovered, namely cathelicidin LL-37, melanocytic ADAMTSL5, lipid antigen PLA2G4D and keratin 17. Autoreactive T cells against these autoantigens were found in a number of patients with moderate-to-severe plaque psoriasis. Moreover, the discovery of autoantibodies against LL-37 and ADAMTSL5 and their strong association with psoriatic arthritis (PsA) suggest a potential role of these autoantibodies in the pathogenesis of PsA. This review discusses the current studies on psoriatic autoantigens and the associated circulating autoantibodies and their mechanisms involved in the development and maintenance of psoriatic plaques. Recent autoimmune evidence fuelled the discussion on psoriasis as an autoimmune skin disorder and has the potential to develop new treatment strategies with protective and therapeutic antigen-targeted methods.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Psoríase/imunologia , Proteínas ADAMTS/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/imunologia , Autoimunidade/imunologia , Fosfolipases A2 do Grupo IV/imunologia , Humanos , Queratina-17/imunologia
10.
Proc Natl Acad Sci U S A ; 117(28): 16465-16474, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601220

RESUMO

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.


Assuntos
Arthrodermataceae/fisiologia , Microbiota , Psoríase/imunologia , Pele/microbiologia , Animais , Arthrodermataceae/classificação , Arthrodermataceae/genética , Arthrodermataceae/isolamento & purificação , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/microbiologia , Feminino , Humanos , Imunidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/microbiologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Simbiose , Células Th17/imunologia
11.
J Am Acad Dermatol ; 83(5): 1523-1526, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32622891
13.
Expert Opin Biol Ther ; 20(8): 829-830, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32510244

RESUMO

INTRODUCTION: In light of the current Covid-19 pandemic and the ongoing, extensive debate about the use of biological agents in psoriatic patients, we felt compelled to relate our experience in the use of secukinumab in the same cohort before and during the lockdown in Italy. Areas covered: Secukinumab was not discontinued, and there were no cases of confirmed infection with SARS-CoV-2 in this cohort. Expert opinion: In our practice, there is no evidence favoring the discontinuation of secukinumab in these patients. We also present a brief commentary on the use of biological agents in patients with moderate-to-severe plaque psoriasis.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Fatores Biológicos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Fatores Biológicos/farmacologia , Terapia Biológica/métodos , Estudos de Coortes , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Feminino , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Itália , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Psoríase/complicações , Psoríase/imunologia , Resultado do Tratamento
15.
J Pharmacol Sci ; 144(1): 52-56, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32565006

RESUMO

The use of biological drugs in psoriasis is replacing traditional therapies due to their specific mechanism and limited side effects. However, the use of Interleukin 17 inhibitors and the modification of its cytokine pathway could favor the risk of fungal infections. All-trans retinoic acid is an active metabolite of vitamin A with anti-inflammatory and immunoregulatory properties through its capacity to stimulate both innate and adaptive immunity and to its effects on proliferation, differentiation and apoptosis in a variety of immune cells. Furthermore, it has been recently discovered that All-trans retinoic acid has a direct fungistatic effect against Candida and Aspergillus Fumigatus. On the basis of these new insights, in the current review, we suggest that the evaluation of serum level of All-trans retinoic acid or vitamin A should be considered as a predictive marker for the development of fungal infections among psoriatic patients treated with Interleukin 17 inhibitors. In clinical practice, vitamin A test could be added in the routine hospital diagnostic management for a better selection of psoriatic patients eligible to Interleukin 17 inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Candidíase/diagnóstico , Candidíase/etiologia , Dermatomicoses/diagnóstico , Dermatomicoses/etiologia , Interleucina-17/antagonistas & inibidores , Micoses/diagnóstico , Micoses/etiologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Vitamina A/sangue , Biomarcadores/sangue , Candidíase/prevenção & controle , Citocinas/metabolismo , Dermatomicoses/prevenção & controle , Humanos , Interleucina-17/metabolismo , Micoses/prevenção & controle , Seleção de Pacientes , Valor Preditivo dos Testes , Risco , Transdução de Sinais/efeitos dos fármacos , Tretinoína/sangue
16.
J Dtsch Dermatol Ges ; 18(7): 675-681, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32447845

RESUMO

Various immune cells and their messenger substances influence the development of psoriasis. Cytokines of the IL-17 family are of particular importance. In addition to IL-17A, which plays a central role in the pathogenesis of psoriasis, other subtypes of the IL-17 family also have a proinflammatory effect. This review provides an up-to-date overview of the immunopathogenesis of psoriasis with regard to the six IL-17 subtypes, in particular their physiological and pathogenic properties, as well as their significance for psoriasis therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-17/fisiologia , Psoríase/imunologia , Humanos , Interleucina-17/química , Psoríase/tratamento farmacológico , Receptores de Interleucina-17/fisiologia
20.
Sci Rep ; 10(1): 5851, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245990

RESUMO

LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.


Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/imunologia , Anticorpos Anti-Proteína Citrulinada/imunologia , Anticorpos Antinucleares/imunologia , Formação de Anticorpos/imunologia , DNA/imunologia , Células Dendríticas/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/etiologia , Masculino , Psoríase/etiologia , Psoríase/imunologia , Células Th17/imunologia
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