| 1. |
- Verma, Deepti, 1969-, et al.
(författare)
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Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 141:3, s. 586-595.e5
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is linked to systemic inflammation and cardiovascular comorbidities, but studies of the underlying cellular mechanisms are lacking. The NLRP3 inflammasome is genetically associated with psoriasis, and its activation is increasingly linked with cardiovascular disease. In this study, we show that patients with psoriasis exhibited higher plasma levels of inflammasome-generated IL-1ß and IL-18, without any correlation to skin lesion severity. Increased constitutive expression of the inflammasome sensors NLRP3, NLRP1, and AIM2 was found in peripheral blood cells of the patients and also of those with mild disease, and this was accompanied by an increased caspase-1 reactivity in the myeloid blood subsets. TNF-a was found to activate selectively the NLRP3 inflammasome without the requirement for a priming signal. TNF-a was found to signal through the TNFR?caspase-8?caspase-1 alternative inflammasome pathway, which proceeds independently of pyroptosis. Patients who received anti-TNF therapy had normalized plasma IL-1ß and IL-18 levels as well as normalized caspase-1 reactivity. This was in contrast to the patients treated with methotrexate who exhibited persistent, increased caspase-1 reactivity. Thus, we show that the TNF-a-mediated activation of NLRP3 inflammasomes in patients with psoriasis may contribute to systemic inflammation. Anti-TNF therapy normalized inflammasome function, suggesting a mechanism for the cardiovascular risk?reducing effect.
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| 2. |
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| 3. |
- Arkblad, Eva L, et al.
(författare)
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Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene.
- 2010
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Ingår i: Clinical biochemistry. - : Elsevier BV. - 1873-2933 .- 0009-9120. ; 43:3, s. 331-4
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrimidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. We here report a frequency analysis of one of the major splice-site mutations in the DPDY gene, and further two new DPYD gene variants. DESIGN AND METHODS: Restriction fragment length polymorphism (RFLP) and DNA sequence analysis were performed on genomic DNA and mRNA. RESULTS: In 400 patients that were diagnosed with cancer and were eligible for 5-FU treatment, 14 patients were found to be heterozygous for the splice-site mutation DPYD IVS14+1G>A, which corresponds to a population frequency of 3.5%. Two novel variants in the DPYD gene were identified. The first case was heterozygous for DPYD c.1796T>C (p.M599T). In the second case, we observed heterozygosity for the splice-site mutation DPYD IVS14+17A>G. CONCLUSIONS: We report two new DPYD gene variants, of which DPYD c.1796T>C is potentially pathogenic, whereas DPYD IVS14+17A>G is suggested as a variant without clinical significance.
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| 4. |
- Carén, Helena, 1979, et al.
(författare)
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High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors; Four cases of homozygous deletions of the CDKN2A gene.
- 2008
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Neuroblastoma is a very heterogeneous pediatric tumor of the sympathetic nervous system showing clinically significant patterns of genetic alterations. Favorable tumors usually have near-triploid karyotypes with few structural rearrangements. Aggressive stage 4 tumors often have near-diploid or near-tetraploid karyotypes and structural rearrangements. Whole genome approaches for analysis of genome-wide copy number have been used to analyze chromosomal abnormalities in tumor samples. We have used array-based copy number analysis using oligonucleotide single nucleotide polymorphisms (SNP) arrays to analyze the chromosomal structure of a large number of neuroblastoma tumors of different clinical and biological subsets. Results Ninety-two neuroblastoma tumors were analyzed with 50 K and/or 250 K SNP arrays from Affymetrix, using CNAG3.0 software. Thirty percent of the tumors harbored 1p deletion, 22% deletion of 11q, 26% had MYCN amplification and 45% 17q gain. Most of the tumors with 1p deletion were found among those with MYCN amplification. Loss of 11q was most commonly seen in tumors without MYCN amplification. In the case of MYCN amplification, two types were identified. One type displayed simple continuous amplicons; the other type harbored more complex rearrangements. MYCN was the only common gene in all cases with amplification. Complex amplification on chromosome 12 was detected in two tumors and three different overlapping regions of amplification were identified. Two regions with homozygous deletions, four cases with CDKN2A deletions in 9p and one case with deletion on 3p (the gene RBMS3) were also detected in the tumors. Conclusion SNP arrays provide useful tools for high-resolution characterization of significant chromosomal rearrangements in neuroblastoma tumors. The mapping arrays from Affymetrix provide both copy number and allele-specific information at a resolution of 10–12 kb. Chromosome 9p, especially the gene CDKN2A, is subject to homozygous (four cases) and heterozygous deletions (five cases) in neuroblastoma tumors.
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| 5. |
- Carlsson, Hanna, 1979, et al.
(författare)
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Cluster analysis of S100 gene expression and genes correlating to psoriasin (S100A7) expression at different stages of breast cancer development
- 2005
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Ingår i: Int J Oncol. ; 27:6, s. 1473-81
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression patterns in ductal carcinoma in situ (DCIS) and invasive and metastatic breast tumors have been determined using serial analysis of gene expression (SAGE). The purpose of this approach was to identify biologically and clinically meaningful subgroups of DCIS with a high risk of progression to invasive disease. The analyses have led to the identification of several differentially expressed genes, such as HIN-1, dermcidin and S100A7 (psoriasin). The aim of the present study was further to delineate the expression profile of S100 genes using information from 22 breast epithelial SAGE libraries. We demonstrated the down-regulation of S100A6 and S100A10 in breast cancer, irrespective of pathological stage. S100P and S100Z were both up-regulated in cancer; whereas S100A7, S100A8 and S100A9 were strongly up-regulated only in DCIS. The hierarchical clustering of S100 gene expression in these 22 libraries revealed two major groups with distinguishable S100 gene expression profiles. One of them was characterized by the high concomitant expression of S100A7, S100A8 and S100A9. Using SAGE informatics, we found 21 genes with a high positive correlation to S100A7 expression in libraries representing different categories of tissues archived at SAGE Genie, suggesting a function of psoriasin that is not tissue specific. Like S100A7, several of these genes displayed cation-binding properties. We also report the strong correlation in the breast epithelial SAGE libraries between the expression of S100A7 and genes reported as being up-regulated in DCIS, as well as in the inflammatory skin disorder, psoriasis; including RGS5, UPK1A, TMPRSS3, S100A9, p53, SCCA1, SCCA2 and KRT17.
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| 6. |
- Carlsson, Hanna, 1979, et al.
(författare)
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Psoriasin (S100A7) and calgranulin-B (S100A9) induction is dependent on reactive oxygen species and is downregulated by Bcl-2 and antioxidants
- 2005
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Ingår i: Cancer Biol Ther. ; 4:9, s. 998-1005
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Tidskriftsartikel (refereegranskat)abstract
- S-100 proteins are calcium-binding proteins with important growth regulatory functions. Of these proteins, psoriasin and calgranulin-B have been shown to be highly upregulated in ductal carcinoma in situ (DCIS) of the breast and in psoriasis. The purpose of this study was to further elucidate the functional relevance of the overexpression of these two S-100 proteins in psoriasis and DCIS. We report the induction of both proteins by reactive oxygen species, phorbol ester TPA, and the induction of psoriasin in response to the PI3K inhibitor wortmannin. We also demonstrate that Bcl-2 overexpression represses the induction of psoriasin and calgranulin-B under these different conditions. The same effect was obtained with the antioxidant NAC, which indicates that the suppression of psoriasin and calgranulin-B induction is mediated by the antioxidant function of Bcl-2. Furthermore, we demonstrate that overexpression of a dominant negative IKKbeta also inhibits the induction of psoriasin suggesting that the NFkappaB pathway is involved in the induction of this protein. Also, we found NFkappaB responsive DNA elements in the upstream promoter region of psoriasin. MCF10A cells with a stable retroviral overexpression of psoriasin were significantly more resistant to H2O2-induced cell death than control cells further supporting the hypothesis that these S-100 proteins may play a role in oxidative stress response.
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| 7. |
- Ekman, Anna-Karin, et al.
(författare)
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Overexpression of Psoriasin (S100A7) Contributes to Dysregulated Differentiation in Psoriasis.
- 2017
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Ingår i: Acta Dermato-Venereologica. - : Society for the Publication of Acta Dermato - Venereologica. - 0001-5555 .- 1651-2057. ; 97:4, s. 441-448
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasin, which is highly expressed in psoriasis, is encoded by a gene located within the epidermal differentiation complex. The aim of this study was to investigate the effect of endogenous psoriasin on disturbed keratinocyte differentiation in psoriasis. Immunohistochemical staining revealed a gradient of psoriasin expression in the psoriatic epidermis with highest expression in the suprabasal, differentiated layers. Induction of keratinocyte differentiation caused concurrent expression of psoriasin and the differentiation marker involucrin. The differentiation-induced psoriasin expression was found to be mediated by the protein kinase C pathway. The downregulation of psoriasin expression by small interfering RNA revealed that psoriasin mediates the expression of involucrin, desmoglein 1, transglutaminase 1 and CD24 in normal differentiation. The lentivirus-mediated overexpression of psoriasin, mimicking the psoriatic milieu, gave rise to an altered regulation of differentiation genes and an expression pattern reminiscent of that in psoriatic epidermis. These findings suggest that psoriasin contributes to the dysregulated differentiation process in the psoriasis epidermis.
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| 8. |
- Enerbäck, Charlotta, 1965, et al.
(författare)
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Cytogenetic analysis of 477 psoriatics revealed an increased frequency of aberrations involving chromosome region 11q
- 1999
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Ingår i: Eur J Hum Genet. ; 7:3, s. 339-44
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is an inflammatory skin disorder affecting approximately 3% of the population. Genetic studies published so far have shown a complex genetic inheritance with heterogeneity and a putative major susceptibility locus in the HLA region on chromosome 6. We have collected a large amount of material consisting mostly of small nuclear families in order to perform a genome-wide scan for psoriasis-associated genes. In order to focus the scan properly on possible candidate regions, we performed a cytogenetic analysis of 477 unrelated psoriatics. We divided our findings into sporadic, affecting a minor fraction of the cells, and constitutional, i.e. they were present in all cells examined. We found three cases of balanced translocation, all of which involved chromosome 11q. Two of these had a breakpoint in q12-13, whilst one involved the telomeric part of chromosome 11q. In order to characterise further the breakpoint on 11q12-13, we used bacterial artificial chromosomes (BACs) analysed by fluorescent in situ hybridisation (FISH). We were able to show that the persons had a close, but not identical breakpoints; they were separated by at least 5 cM. The major atopy locus is located in this region, as well as a locus for insulin-dependent diabetes mellitus, both being conditions with a pathogenetic mechanism involving antigen presentation.
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| 9. |
- Enerbäck, Charlotta, 1965, et al.
(författare)
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Evidence that HLA-Cw6 determines early onset of psoriasis, obtained using sequence-specific primers (PCR-SSP)
- 1997
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Ingår i: Acta Derm Venereol. ; 77:4, s. 273-6
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis vulgaris has previously been shown to associate with certain HLA alleles. HLA-Cw6 is considered to be the primary association, based on calculations of relative risk after serological typing. This association is reportedly more pronounced in early- than in late-onset psoriasis. We performed a PCR-based typing with sequence-specific primers, which has been shown to give a more complete result than serology. Two hundred and one unrelated patients with psoriasis, with a mean age of 40 years, and 77 healthy controls were typed. Two thirds (67%) of the patients were positive for one or two copies of the allele, while the corresponding figure for the control group was 12%. A significant peak for age at onset of 21 or younger was seen for the Cw6 carriers. For patients older than 21 at onset, the frequency of Cw6 was significantly lower; e.g. for patients with an age at onset between 30 and 35 the frequency was comparable to the level of the control group. The high frequency of Cw6 among patients with an age at onset of 21 or younger is in agreement with data of other groups. In comparison with this age-at-onset group the frequency of Cw6 is sharply reduced among patients with an age at onset of 22 years or older, which contrasts with earlier studies. This may reflect differences between population groups but may also be due to the higher sensitivity of the PCR-based HLA-Cw6 typing method. In view of these findings, we suggest that psoriasis is a genetically determined disease, in which the additional presence of HLA-Cw6 is associated with the characteristic of early onset.
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| 10. |
- Enerbäck, Charlotta, 1965, et al.
(författare)
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S gene (Corneodesmosin) diversity and its relationship to psoriasis; high content of cSNP in the HLA-linked S gene
- 2000
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Ingår i: J Invest Dermatol. - 0022-202X .- 0022-202X. ; 114:6, s. 1158-63
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a heterogeneous disease in which several reports suggest the presence of a susceptibility gene in or in the proximity of the human leukocyte antigen complex in chromosome 6p. There is an association between HLA-Cw6 and young onset of the disease. The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes. We have studied this gene in a large Swedish psoriasis population and we report a strikingly high degree of polymorphism in the coding parts of the gene, 1 every 100 base pairs. We used a stratified approach to compare the polymorphic variants in patients and controls. A single nucleotide polymorphism in the coding region leading to an amino acid exchange (Ser-->Phe) that differed significantly between patients and controls was identified (position 619). Owing to a high allele frequency in a larger control group, however, and an insignificant influence of the variant on the age at onset distribution curve based on a large psoriasis population, we could not confirm that this coding single nucleotide polymorphism was involved in disease etiology. We also examined the single nucleotide polymorphism in position 1243, recently proposed to have an influence on the pathogenesis of the disease. This polymorphism showed less association to the disease as compared with the single nucleotide polymorphism at positions 619 and 722. Such a high degree of variation present also in an HLA gene which is not involved in immune response indicates the difficulty involved in assessing the role of a specific allele in the pathogenesis of a complex disease in this region. A strong association effect due to linkage disequilibrium in an extended region in the HLA complex is also a complicating factor.
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