Psoriasis is not an autoimmune disease?

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.

Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families.

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.

Evaluation of a charity-led secondary breast cancer support day: a model of survivorship care.

It has been estimated that there are 36,000 women living with secondary breast cancer in the UK. Many feel isolated and unsupported, their information needs unmet and unaware of available support services such as palliative care or support groups that could help to improve their quality of life. To try to address these needs, a monthly support day was established in 2014 by the national UK breast cancer charity Breast Cancer Haven (BCH) at their Yorkshire centre. The support day provides an opportunity for personal introductions and discussion with other people with secondary breast cancer, to obtain information about breast cancer-related topics of their choice, to eat a healthy lunch and to experience a visualisation/relaxation session. To evaluate how helpful this support day was to its participants, they were asked to complete a feedback form at the end of the day. A total of 171 forms were completed from 26 support days during the period February 2014-July 2018. Participants stated that they found the support day helpful, relaxing, informative, supportive and enjoyable. All except two felt it met their needs and expectations and the majority found the length of the day just right. The personal introduction and discussion session were most frequently cited as the most useful part of the day, with the majority of participants (N = 144, 96.7%) rating it as very or moderately helpful. These findings show that the BCH support day, developed to address the needs of people with secondary breast cancer, is a model of survivorship care that can have a positive impact on their lives.

Psoriasis--a possible candidate for vaccination.

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.

Triggering psoriasis: the role of infections and medications.

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.

Variation at the IRF2 gene and susceptibility to psoriasis in chromosome 4q-linked families.

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.

Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin.

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.

A randomised controlled pilot feasibility study of the physical and psychological effects of an integrated support programme in breast cancer.

A pilot study was conducted to assess recruitment and effectiveness of an integrated support programme in women with breast cancer. Twelve participants were randomised to receive medical care with or without the support programme. Psychosocial questionnaires and immune/hormonal assays were completed at baseline, three and six months. Recruitment was problematic. In the intervention group, mental fatigue was significantly improved (p = 0.016) compared to controls; increased NK cell activity suggested an improvement in immune function. Total stress (p = 0.009), anxiety (p = 0.032) and endocrine-specific (p = 0.032) symptoms were significantly improved in the controls. A large-scale randomisation trial appears warranted, dependent upon effective recruitment.

Evidence for the presence of bacteria in the blood of psoriasis patients.

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.

The role of microorganisms in atopic dermatitis.

Atopic dermatitis (AD) is a common, fluctuating skin disease that is often associated with atopic conditions such as asthma and IgE-mediated food allergy and whose skin lesions are characterized by a Th-2 cell-mediated response to environmental antigens. The increasing prevalence and severity of atopic diseases including AD over the last three decades has been attributed to decreased exposure to microorganisms during early life, which may result in an altered Th-1/Th-2-balance and/or reduced T cell regulation of the immune response. Patients with AD exhibit defects in innate and acquired immune responses resulting in a heightened susceptibility to bacterial, fungal and viral infections, most notably colonization by S. aureus. Toxins produced by S. aureus exacerbate disease activity by both the induction of toxin-specific IgE and the activation of various cell types including Th-2 cells, eosinophils and keratinocytes. Allergens expressed by the yeast Malazessia furfur, a component of normal skin flora, have also been implicated in disease pathogenesis in a subset of AD patients. Microorganisms play an influential role in AD pathogenesis, interacting with disease susceptibility genes to cause initiation and/or exacerbation of disease activity.

Peptidoglycan: a major aetiological factor for psoriasis?

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.

Reduced IFN-gamma responses associated with HLA-DR15 presentation of streptococcal cell wall proteins to dermal Th-1 cells in psoriasis.

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.