Psoriasis Patients with Specific HLA-Cw Alleles and Lower Plasma IL-17 Level Show Improved Response to Topical Lindioil Treatment.

Purpose: Lindioil, a medicine refined from indigo naturalis (a herb used in Chinese medicine), is effective in treating severe psoriasis; however, responses vary across individual patients. We aim to investigate genetic predispositions associated with treatment response to topical Lindioil among patients with psoriasis and correlations with plasma cytokine patterns. Patients and Methods: We enrolled 72 psoriasis patients treated with Lindioil ointment and analyzed the human leukocyte antigen class C (HLA-Cw) genotypes and plasma cytokine expression patterns. We developed regression models of treatment response, defined as Psoriasis Area and Severity Index (PASI) 75, to examine correlations among HLA-Cw alleles, cytokine levels, and treatment response to Lindioil. Results: Patients harboring HLA-Cw*06:02 were significantly more likely to respond to Lindioil (P = 0.02, odds ratio [OR]: 6.88), whereas Lindoil was ineffective in those harboring HLA-Cw*01:02 (P = 0.01, OR: 0.28). Patients who were HLA-Cw*06:02-positive or HLA-Cw*01:02-negative had better PASI scores and body surface area (BSA) improvement (73.3% vs 44.4%, P<0.001) following an 8-week treatment period. Psoriasis patients achieving PASI 75 after 8 weeks presented with lower baseline plasma interleukin-17 (IL-17) levels than those who did not achieve PASI 75 (PASI 75: 11.28 pg/mL vs PASI <75: 15.82 pg/mL, P = 0.05). Conclusion: Our findings suggest that the presence of the HLA-Cw*06:02 or HLA-Cw*01:02 alleles and plasma IL-17 levels are predictive markers of treatment response to Lindioil ointment in patients with psoriasis.

Correlation between HLA-Cw*0602 and LCE3B_LCE3C-del allele interaction and psoriasis vulgaris in a population of Mongolian nationality in Inner Mongolia / 中国基层医药

Objective:To investigate the effect of HLA-Cw*0602 and LCE3B_LCE3C-del allele interaction on the risk of psoriasis vulgaris in a population of Mongolian nationality in Inner Mongolia. Methods:A total of 365 Mongolian patients with psoriasis vulgaris who received treatment in The Affiliated Hospital of Inner Mongolia Medical University from January 2006 to December 2015 (case group) and 284 healthy subjects who concurrently received physical examination in the same hospital (control group) were included in this study. After sex and age matching, and quality control, the correlations between HLA-Cw*0602 and LCE3B_LCE3C-del allele and psoriasis vulgaris in a population of Mongolian nationality were analyzed using SPSS 20.0 software. The interaction between HLA-Cw*0602 and LCE3B_LCE3C-del alleles (adjusting for potential confounders including age and sex) was analyzed using logistic regression. Results:Logistic regression interaction item Int of dominant inheritance mode HLA-Cw*0602 allele and recessive inheritance mode LCE3C_LCE3B-del allele revealed OR = 2.38, P = 0.033, and interaction index S = 1.21, indicating that there was a synergistic effect between the two alleles. Conclusion:The co-existence of HLA-Cw*0602 and LCE3B_LCE3C-del may increase the risk of psoriasis vulgaris in a population of Mongolian nationality in Inner Mongolia.

Genomic DNA methylation in HLA-Cw*0602 carriers and non-carriers of psoriasis.

BACKGROUND: HLA-Cw*0602 has long been established as one of the most important genetic biomarkers in psoriasis. However, the epigenetic and gene expression differences between HLA-Cw*0602 carriers and non-carriers has not yet been investigated. OBJECTIVE: We aim to explore the whole-genome methylation and gene expression differences between HLA-Cw*0602 carriers and non-carriers. METHODS: HLA imputation was performed to get landscape of variants in this region. Genome-wide DNA methylation was compared between positive and negative HLA-Cw*0602 groups. Eleven methylation loci were selected for further validation in additional 43 cases. For differentially methylated genes, GO and KEGG were used to annotate gene functions. RESULTS: We imputed 29,948 variants based on the constructed HLA reference panels, and obtained 42 HLA-Cw*0602 carriers and 72 non-carriers. Significant methylation differences were detected at 4321 sites (811 hypo- and 3510 hypermethylated). The cg02607779 (KLF7, P = 0.001), cg06936779 (PIP5K1A, P = 0.002), cg03860400 (BTBD10, P = 0.017) and cg26112390 (GOLGA2P5, P = 0.019) were identified and validated to be the significant CpGs contributed to different HLA-C*0602 groups. Among the hypo- and hypermethylated sites, the top CpGs were in gene body and CpG island. CONCLUSION: We performed the first whole-genome study on methylation differences between psoriatic individuals with or without HLA-Cw*0602, and found the key methylation sites which may contribute to the carrying status of HLA-Cw*0602. Methylation loci located in gene body and CpG island are more likely to affect the methylation levels in HLA-Cw*0602 carriers. This integrated analysis shed light on novel insights into the pathogenic mechanisms of genomic methylation in different HLA genotypes of psoriasis.

HLA-Cw6 homozygosity in plaque psoriasis is associated with streptococcal throat infections and pronounced improvement after tonsillectomy: A prospective case series.

BACKGROUND: Carriage of the HLA-Cw*0602 allele is associated with a particular set of clinical features and treatment responses in psoriasis. Tonsillectomy can improve psoriasis. OBJECTIVES: We sought to evaluate whether HLA-Cw*0602 predicts a favorable outcome after tonsillectomy of patients with psoriasis. METHODS: This prospective case series followed up 28 tonsillectomized patients with plaque psoriasis for 24 months. The Psoriasis Area and Severity Index, Psoriasis Disability Index, and Psoriasis Life Stress Inventory were used for assessment. Tonsils were swabbed for bacteria and patients genotyped for HLA-Cw*0602. RESULTS: After tonsillectomy, HLA-Cw*0602 homozygotes showed significantly more improvement, compared with heterozygous and HLA-Cw*0602-negative patients. Thus, Psoriasis Area and Severity Index score was reduced by 82% in the homozygous patients compared with 42% and 31%, respectively (P < .001), Psoriasis Disability Index score improved by 87% compared with 38% and 41%, respectively (P < .001), and Psoriasis Life Stress Inventory score was 82% reduced compared with 60% and 54%, respectively (P < .001). The homozygotes more often had psoriasis onset associated with a throat infection (P = .007) and an increased frequency of streptococcal throat infections per lifetime (P = .038). LIMITATIONS: Few patients were included and some data were retrospective. CONCLUSIONS: Homozygous HLA-Cw*0602 carriage in plaque psoriasis may predict a favorable outcome after tonsillectomy.

Streptococcus pyogenes-induced cutaneous lymphocyte antigen-positive T cell-dependent epidermal cell activation triggers TH17 responses in patients with guttate psoriasis.

BACKGROUND: Guttate psoriasis (GP) is characterized by acute onset of small, rounded psoriatic lesions. Although this particular phenotype of psoriasis is usually associated with streptococcal throat infections and mainly occurs in HLA-Cw6(+) patients, the specific immunologic response to this innate stimulus that causes these skin lesions is poorly understood. OBJECTIVE: This study aims to elucidate how key cellular elements of patients with GP respond to Streptococcus pyogenes and whether this initial immune response is favored by the genetic and environmental background of these patients. METHODS: Circulating memory T cells and autologous epidermal cells from samples from either patients with GP (n = 14) or healthy control subjects (n = 6) were cocultured ex vivo in the presence of an S pyogenes extract. Levels of the psoriasis-associated cytokines IL-17A, IL-17F, IFN-γ, TNF-α, IL-6, and IL-8 were determined. The expression of several genes with increased (DEFB4, S100A7, LCN2, IL36G, IL8, CXCL9, CXCL10, and CXCL11) or decreased (FLG and LOR) transcripts in psoriatic lesions was examined in keratinocytes treated with coculture supernatants. RESULTS: When skin-homing effector memory cutaneous lymphocyte antigen-positive T cells were used in cocultures, a TH17-dominant response was observed, as reflected by the higher amounts of IL-17A and IL-17F than IFN-γ. Moreover, a higher TH17 response was observed in cells isolated from patients with flares associated with a streptococcal tonsillitis and with the HLA-Cw6 allele (cohort 1). In addition, in normal keratinocytes the supernatants from these cocultures induced an increase in IL-17-associated genes, such as DEFB4, S100A7, LCN2, IL36G, and IL8 but a decrease in FLG and LOR, thereby confirming the role of activated TH17 cells. CONCLUSION: This study reveals a dominant TH17 response of cutaneous lymphocyte antigen-positive T cells activated by epidermal cells and S pyogenes in patients with GP.

NKG2C, HLA-E and their association with psoriasis.

Natural killer (NK) cell activation is regulated by the integration of signals from inhibitory and activating cell surface receptors. Both NKG2A and NKG2C pair with CD94 to form inhibitory and activating receptors specific for the HLA-E-canonical peptide complex. HLA-E is a non-classical MHC class Ib molecule with limited polymorphism. It preferentially binds to and presents leader sequence peptides derived from classical MHC class I molecules. Wilson et al. have identified an association between NKG2C deficiency and psoriasis. They have also discovered an HLA-C-dependent association between HLA-E and psoriasis. Their research highlights the importance of NK cells in the pathophysiology of psoriasis. Herein, we propose two different models to explain the association between NKG2C, HLA-E and psoriasis. In the first model, we hypothesize that NKG2C deficiency and/or HLA-E O1:01 can inhibit the ability of NK cells to regulate autoreactive T cells, predisposing to psoriasis. The second model proposes that HLA-E 01:03 can disrupt the presentation of the psoriasis-inducing self-determinant by HLA-C, thereby protecting against psoriasis.

Construction of psoriasis susceptibility gene / 中国药理学通报

Aim To prepare for psoriasis transgenic animals, psoriasis susceptible gene was constructed. Methods Extract gDNA from blood preparations of psoriasis patients, screen positive gDNA owns HLA-Cw*0602 gene, then copy the whole sequence and link it to pMD-19T Simple Vector. Results The identification showed the construction of psoriasis susceptible gene was sucessful. Conclusion The successful construction of HLA-Cw*0602 gene will lay the foundation for development of transgenic animal models of psoriasis.

Correlations Between HLA-Cw*0602 and Clinical Picture in Korean Psoriatic Patients / 대한피부과학회지

BACKGROUND: HLA-Cw6 has the strongest individual association with psoriasis in many racial groups, and associations with the positive family history and early age at onset have been noted in many studies. OBJECTIVE: The aim of this study was to investigate whether Cw6 correlate with the clinical parameters of Korean psoriatic patients. METHODS: One hundred and twelve unrelated patients with psoriasis, and 166 healthy controls were examined with regard to Cw*0602, using a PCR-SSP method. We divided the patients into two groups according to Cw*0602 positivity, and compared two groups with reference to several clinical parameters. RESULTS: The results are summarized as follows: 1. Cw*0602 was found in 69.6% of the 112 patients, but only in 9.0% of the 166 healthy controls(p<0.05, RR=23.1). 2. The presence of Cw*0602 correlated with early age at onset(26.1 vs. 32.5 years, p<0.05), and Cw*0602 was present in 75.0% of the patients with early onset(p<0.05, RR=30.2). 3. The presence of Cw*0602 did not correlate with a positive family history of psoriasis among the first-degree relatives, but correlated with an overall positive family history (p<0.05). 4. There were no positive correlations with arthritis, the history of inpatient treatment, the clinical type of psoriasis, and onset or exacerbation after upper respiratory infection. CONCLUSION: The presence of Cw*0602 correlated with a positive family history for psoriasis and early age at onset, but did not correlate with arthritis, the history of inpatient treatment, the clinical type of psoriasis, and onset or exacerbation after upper respiratory infection.