RESUMO
The concept that psoriasis is an autoimmune disease needs to be questioned. The autoimmune label has been based on molecular mimicry between streptococcal and keratin proteins and the existence of homologous peptides between these proteins. However, it is only peripheral blood CD8, and not CD4, T lymphocytes that respond to the homologous peptides. This ignores the fact that it is CD4 T cells which are necessary to initiate psoriasis. Recent studies on skin bacterial microbiota have found a variety of bacteria in both normal skin and psoriatic lesions. In biopsy specimens, the most common phylum was Firmicutes and the most common genus streptococcus in both psoriasis and normal skin. The innate immune system is activated in psoriasis, and recent genetic findings have shown the majority of susceptibility loci are associated with innate immunity. There is a known clinical relationship between both Crohn's disease (CD) and periodontitis, and psoriasis, and patients with psoriasis share mutations in some innate immunity genes with individuals with CD. It is now accepted that CD is due to a breakdown of immune tolerance (dysbiosis) to bacteria in the intestine. These findings suggest that psoriasis is initiated by an abnormal response to bacteria in the skin due to genetic factors.
Assuntos
Doenças Autoimunes/imunologia , Psoríase/imunologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/microbiologia , Doença de Crohn/etiologia , Doença de Crohn/imunologia , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Microbiota , Modelos Biológicos , Mimetismo Molecular/imunologia , Psoríase/etiologia , Pele/microbiologiaRESUMO
A susceptibility locus for psoriasis, PSORS4, has been mapped to chromosome 1q21 in the region of the epidermal differentiation complex. The region has been refined to a 115 kb interval around the loricrin (LOR) gene. However, no evidence of association between polymorphisms in the LOR gene and psoriasis has been found. Therefore, we have analysed association to three candidate gene clusters of the region, the S100, small proline-rich protein (SPRR) and PGLYRP (peptidoglycan recognition protein) genes, which all contain functionally interesting psoriasis candidate genes. In previous studies, the SPRR and S100 genes have shown altered expression in psoriasis. Also polymorphisms in the PGLYRP genes have shown to be associated with psoriasis. We genotyped altogether 29 single nucleotide polymorphisms (SNPs) in 255 Finnish psoriasis families and analysed association with psoriasis using transmission disequilibrium test. A five-SNP haplotype of PGLYRP SNPs associated significantly with psoriasis. There was also suggestive evidence of association to SPRR gene locus in Finnish families. To confirm the putative associations, selected SNPs were genotyped also in a family collection of Swedish and Irish patients. The families supported association to the two gene regions, but there was also evidence of allelic heterogeneity.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 1/genética , Heterogeneidade Genética , Psoríase/etnologia , Psoríase/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Proteínas Ricas em Prolina do Estrato Córneo/genética , Feminino , Finlândia , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Lactente , Irlanda , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Suécia , Adulto JovemRESUMO
The clinical association of streptococcal infections and psoriasis is well established. The recent finding that the T cells in psoriasis skin respond to streptococcal peptidoglycan now suggests a pathway for an adaptive immune response to the streptococcal organism. These observations may allow for possible vaccines to be developed for psoriasis.
Assuntos
Psoríase/terapia , Infecções Estreptocócicas , Vacinação , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Psoríase/genética , Psoríase/imunologia , Psoríase/patologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/imunologiaRESUMO
Psoriasis can be provoked or exacerbated by a variety of different environmental factors, particularly infections and drugs. Strong evidence exists for the induction of guttate psoriasis by a preceding tonsillar Streptococcus pyogenes infection, whereas disease exacerbation has been linked with skin and/or gut colonization by Staphylococcus aureus, Malassezia, and Candida albicans. The role, if any, of viruses (papillomaviruses, HIV, and endogenous retroviruses) present in lesional skin is at present unknown. The use of various drugs, such as lithium, beta-blockers, antimalarial agents, nonsteroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors, has also been associated with induction or worsening of disease in psoriatic patients.
Assuntos
Infecções Bacterianas/complicações , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Micoses/complicações , Psoríase/etiologia , Viroses/complicações , Humanos , Ativação Linfocitária , Psoríase/induzido quimicamente , Psoríase/microbiologia , Psoríase/virologiaRESUMO
Evidence, largely from Irish pedigrees, indicates that a susceptibility locus for psoriasis maps to chromosome 4q. The gene encoding interferon regulatory factor-2 (IRF-2) maps to this region, and, as mice lacking IRF-2 exhibit a dermatologic phenotype resembling many aspects of human psoriasis, IRF-2 represents an attractive positional candidate. We set out to establish whether variation in IRF-2 sequence or expression was related to the development of psoriasis. First, the promoter, coding, and adjacent untranslated regions of IRF-2 were screened in individuals from 4q-linked families. Neither variant identified (IVS1A+29A/G; IVS3+729T/C), however, had functional credentials or statistical evidence supporting a susceptibility role. Second, in 62 Irish parent-offspring trios ascertained for psoriasis, we conducted a linkage-disequilibrium screen of the IRF2 region using a dense microsatellite map (covering 1.5 Mb from D4S1554 to D4S1540). Though there was nominal association for D4S1554/D4S2348 haplotypes (p=0.03) with one haplotype showing particularly skewed transmission to psoriatic offspring (p=0.0002, uncorrected), these markers lie some distance (500 kb) from IRF-2. Finally, we found no abnormalities of IRF-2 protein expression or distribution in skin biopsies from psoriatic individuals. These diverse lines of inquiry allow us to exclude variation in IRF2 as responsible for the 4q-linkage signal previously identified in Irish pedigrees.
Assuntos
Cromossomos Humanos Par 4 , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Desequilíbrio de Ligação , Psoríase/genética , Proteínas Repressoras , Fatores de Transcrição , Mapeamento Cromossômico , Proteínas de Ligação a DNA/análise , Humanos , Imuno-Histoquímica , Fator Regulador 2 de Interferon , MutaçãoRESUMO
Dermatitis herpetiformis (DH) is an IgA mediated blistering skin disease characterized by the presence of granular deposits of IgA in papillary dermis. The major significant advances in our understanding of DH have been the demonstration that DH patients also have coeliac diseases (CD) and that the rash is also gluten dependent. As a result, it is now possible to cure patients by gluten withdrawal from the diet. The other major significant finding has been the presence of IgA in the uninvolved, now used as the diagnostic criterion for the disease. Despite the fact that it has been known for over fifty years that gluten causes the enteropathy of CD, and for over thirty years the rash of DH, it is still not known how gluten produces these effects. Future immunological studies may look at ways of inducing tolerance to gluten peptides once the toxic ones have been identified. Vaccination against gluten peptides may also be possible in those affected with gluten sensitive disorders.
Assuntos
Autoanticorpos/análise , Dermatite Herpetiforme/epidemiologia , Dermatite Herpetiforme/imunologia , Imunoglobulina A/imunologia , Adolescente , Adulto , Distribuição por Idade , Idade de Início , Biópsia por Agulha , Terapia Combinada , Dermatite Herpetiforme/patologia , Dermatite Herpetiforme/terapia , Fármacos Dermatológicos/uso terapêutico , Dieta , Feminino , Glutens/metabolismo , Humanos , Imunoglobulina A/análise , Imuno-Histoquímica , Incidência , Masculino , Prognóstico , Medição de Risco , Distribuição por SexoRESUMO
Microorganisms have been implicated in the pathogenesis of psoriasis. Previous studies of psoriasis and normal skin have used swabs from the surface rather than skin biopsies. In this study, biopsies were taken from 10 patients with psoriasis and 12 control subjects from unmatched sites. Samples were analysed with massive parallel pyrosequencing on the 454 platform targeting the 16S rRNA gene and the variable regions V3-V4. The samples grouped into 19 phyla, 265 taxon and 652 operational units (OTUs) at 97% identity. A cut-off abundance level was set at 1%. The three most common phyla in both normal and psoriasis skin were Firmicutes (39% psoriasis, 43% normal skin), Proteobacteria (38% psoriasis, 27% normal skin) and Actinobacteria (5% psoriasis, 16% normal skin, p = 0.034). In trunk skin, Proteobacteria were present at significantly higher levels in psoriasis compared to controls (52 vs. 32%, p = 0.0113). The commonest genera were Streptococci in both psoriasis (32%) and normal skin (26%). Staphylococci were less common in psoriasis (5%) than in controls (16%), as were Propionibacteria (psoriasis 0.0001669%, controls 0.0254%). Both Staphylococci and Propionibacteria were significantly lower in psoriasis versus control limb skin (p = 0.051, 0.046, respectively). This study has shown some differences in microbiota between psoriasis and normal skin. Whether these are of primary aetiological significance, or secondary to the altered skin of psoriasis remains to be determined.
Assuntos
Bactérias/classificação , Infecções Bacterianas/microbiologia , Metagenoma , Psoríase/microbiologia , Pele/microbiologia , Adulto , Bactérias/genética , Bactérias/isolamento & purificação , Infecções Bacterianas/complicações , Infecções Bacterianas/genética , Infecções Bacterianas/patologia , Biópsia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Psoríase/complicações , Psoríase/genética , Psoríase/patologia , RNA Ribossômico 16S/análise , Pele/patologia , Adulto JovemRESUMO
BACKGROUND: Cutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica. This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3ζ, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs. CONCLUSION: Our results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions.
Assuntos
Arginase/metabolismo , Leishmaniose Cutânea/patologia , Pele/enzimologia , Pele/patologia , Adolescente , Adulto , Biópsia , Complexo CD3/análise , Antígenos CD4/análise , Antígenos CD8/análise , Criança , Etiópia , Feminino , Humanos , Leucócitos Mononucleares/química , Leucócitos Mononucleares/enzimologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Evidence exists that microorganisms, particularly in the throat and skin, play a role in the pathogenesis of psoriasis. The aim of this study was to investigate whether evidence for the presence of bacteria, including Streptococcus pyogenes, can be demonstrated in the peripheral blood of patients with guttate and/or chronic plaque psoriasis. Peripheral blood samples from 20 patients with psoriasis, seven guttate, six chronic plaque and seven chronic plaque with associated guttate flare and from 16 control subjects were studied for the presence of bacteria by PCR using universal 16S ribosomal DNA primers and specific primers for S. pyogenes. Sequence analysis of amplified 16S rRNA sequences was used to determine taxonomic identity. Ribosomal bacterial DNA was detected in the blood of all 20 patients with psoriasis, but in none of the controls. Streptococci were detected in six of seven patients with guttate psoriasis, but none had staphylococci. In contrast, staphylococci were identified in 9 of 13 patients with chronic plaque psoriasis, whilst only 2 demonstrated streptococci. In three psoriasis patients, species other than streptococci and staphylococci were identified. These findings suggest that psoriasis is associated with bacteraemia, with distinct taxonomic groups present in guttate and chronic plaque psoriatic subtypes. The causes of the bacteraemia and its implications in psoriasis have yet to be determined.
Assuntos
DNA Bacteriano/sangue , Psoríase/microbiologia , Pele/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus/genética , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/genética , Bacteriemia , Doença Crônica , Progressão da Doença , Humanos , Reação em Cadeia da Polimerase , Psoríase/complicações , Psoríase/fisiopatologia , Pele/microbiologia , Pele/patologia , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/fisiopatologia , Staphylococcus/patogenicidade , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/fisiopatologia , Streptococcus pyogenes/patogenicidadeRESUMO
In two-thirds of patients with guttate psoriasis (GP), there is good evidence that the eruption is triggered by a streptococcal throat infection. We attempted to determine if a specific epitope of the bacterial pathogen was associated with the humoral immune response in GP patients. Antibody titres against beta-haemolytic streptococci (BHS) extracts in sera from 14 patients with GP, 10 healthy controls and 10 chronic plaque psoriasis (CPP) patients were determined by ELISA. Antibody BHS reactivity was investigated using immunoblotting, followed by epitope mapping using peptide-phage display. The highest GP antibody titres (10,000-25,000) were found in sera that had a matching streptococcal isolate, three sera had high (5,000-12,500) and seven had raised titres (500-5,000). In the healthy control group, three had relatively high and seven lower titres. All the CPP sera had very low titres (<500). In the immunoblots, three major bands were recognised by all the GP sera, and, to a lesser extent, by four healthy controls. No GP-specific protein was identified. Epitope mapping identified 10 phage clones that specifically bound 2 or 3 GP sera, displaying five different peptide sequences that were not streptococcal in origin. These findings suggest that the antigen specificity of the humoral response to BHS in GP does not differ from that of non-psoriatic individuals.
Assuntos
Anticorpos Antibacterianos/sangue , Psoríase/imunologia , Streptococcus pyogenes/imunologia , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Ensaio de Imunoadsorção Enzimática , Mapeamento de Epitopos , Feminino , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , Dados de Sequência MolecularRESUMO
Peptidoglycan (PG), a major cell-wall component of Gram-positive bacteria, has been detected within antigen-presenting cells in various inflammatory conditions, including psoriasis. The additional presence of T-helper 1 cells specific for streptococcal or staphylococcal PG in psoriasis skin lesions implicates PG as an important T-cell stimulator for the disease. PG is a major target for the innate immune system, and associations between genetic polymorphisms of recognition receptors for PG and various auto-inflammatory diseases have been identified. The location of these genes within four linkage sites for psoriasis raises the possibility that an altered innate recognition of PG might contribute to the enhanced T-cell response to the bacterial antigen. These observations suggest that PG is a major aetiological factor for psoriasis and emphasize the importance of PG in bacterial-infection-induced inflammatory disease.
Assuntos
Imunidade Inata , Modelos Imunológicos , Peptidoglicano/imunologia , Psoríase/etiologia , Streptococcus/patogenicidade , Parede Celular/metabolismo , Humanos , Tonsila Palatina/microbiologia , Psoríase/imunologia , Psoríase/microbiologia , Dermatopatias/etiologia , Streptococcus/imunologia , Linfócitos T/imunologia , Linfócitos T/microbiologiaRESUMO
We have recently described a group A streptococcal (GAS)-reactive Th-1 subset specifically present in skin lesions of chronic plaque psoriasis. To investigate MHC presentation of GAS cell wall proteins, dermal T cell lines (TCL) cultured from the lesional skin of 39 HLA-typed psoriasis patients were stimulated with a cell wall extract, stained for intracellular IFN-gamma expression, and analyzed by flow cytometry. TCL from a further seven psoriasis patients were also tested with S. mutans extract. Eight TCL were tested in the presence of anti-Class II antibodies or allogeneic antigen-presenting cells. The dermal T cell IFN-gamma responses to the cell wall extract, which ranged from < 1 to 28%, were significantly higher than that to S. mutans extract (p = 0.0052) and were self-HLA-DR allele restricted. A significantly decreased response was observed in TCL from DR15+ (n = 13) versus DR15- (n = 26) patients (p = 0.0377). In addition, DR15+ patients had a later age of onset of disease and a decreased history of sore throats. In contrast, TCL from HLA-DR7+ (n = 23) patients responded similarly to those from individuals lacking the DR7 allele. However, DR7+ patients who coexpressed the MHC Class I antigen, Cw6 (n = 14) had a significantly higher IFN-gamma response than Cw6-, DR7+ patients (n = 7; p = 0.0288) whose responses were also significantly lower than those of patients expressing non-DR7 alleles (n = 16; p = 0.0302). This study has shown that HLA-DR15 expression is associated with a reduced dermal Th-1 response to GAS cell wall proteins in patients with psoriasis. It is proposed that HLA-DR allelic variation may contribute to disease phenotype via effects on the immune response to group A streptococci.
Assuntos
Apresentação de Antígeno , Parede Celular/imunologia , Antígenos HLA-DR/imunologia , Interferon gama/imunologia , Psoríase/imunologia , Pele/imunologia , Streptococcus/imunologia , Células Th1/imunologia , Adulto , Idade de Início , Idoso , Proteínas de Bactérias/imunologia , Extratos Celulares/imunologia , Parede Celular/química , Células Cultivadas , Feminino , Genes MHC da Classe II/genética , Antígenos HLA-C/imunologia , Subtipos Sorológicos de HLA-DR , Humanos , Masculino , Pessoa de Meia-Idade , Faringite/genética , Faringite/imunologiaRESUMO
A girl aged 7 from St. Vincent in the West Indies developed a papular eruption and papillomata 3 months after her arrival in England. Dark-ground examination of serum obtained from one of the papillomata revealed treponemes, and serological tests for treponemal disease were positive. The lesions responded rapidly to treatment with parenteral penicillin (AU)