The role of polymorphism of interleukin-2, -10, -13 and TNF-α genes in cutaneous T-cell lymphoma pathogenesis.

INTRODUCTION: As the pathogenesis of cutaneous T-cell lymphomas (CTCL) is not fully understood, inherited gene polymorphisms are considered to play a role in the development of lymphomas. AIM: To investigate whether certain gene polymorphisms might be involved in the development of CTCL. MATERIAL AND METHODS: In the case-control study we compared the frequency of nine selected single nucleotide polymorphisms (SNP) of seven genes (rs1800587/-889 C/T of interleukin (IL)-1α, rs2069762/-330G/T) and rs2069763/+166G/T of IL-2, rs1800925/-1112 C/T of IL-13, rs1800896/-1082 A/G of IL-10, rs4073/-251 A/T of IL-8, rs5370/K198N, rs180054/-1370T/G of endothelin-1 and rs1800629/-308 G/A of TNF-α) in 43 CTCL and Polish cases using the amplification refractory mutation system polymerase chain reaction method. RESULTS: We have found that two genotypes, -330GG of IL-2 and -1112TT of IL-13 both promoter variants associated with "hypertranscription phenotype", were over-represented in CTCL patients compared to healthy controls, and they increase the risk of malignancy development (OR = 5.82, p = 0.001 for IL-2 -330 GG, and OR = 5.67, p = 0.0024 for IL-13 -1112 TT). On the other hand, high transcription -308A allele of the TNF-α gene and -1082GG of IL-10 genotype is less frequent in lymphoma patients and has protective effects on the development of CTCL (OR = 0.45, p = 0.0466 for -308A of TNF-α, and OR = 0.35, p = 0.0329 for -1082GG of IL-10 genes). CONCLUSIONS: Our results indicate that hypertranscription promoter variants of IL-2 and IL-13 genes could be estimated as the risk factor for development of CTCL, while TNF-α and IL-10 variants have a protective effect.

Frequency of streptococcal upper respiratory tract infections and HLA-Cw*06 allele in 70 patients with guttate psoriasis from northern Poland.

INTRODUCTION: The association of guttate psoriasis with a streptococcal throat infection and HLA-Cw*06 allele is well established in different populations. Nevertheless, only few studies on this form of disease have been performed in the Polish population. AIM: To analyze the frequencies of streptococcal-induced guttate psoriasis and HLA-Cw*06 allele in 70 patients with guttate psoriasis originating from northern Poland. MATERIAL AND METHODS: Seventy patients with guttate psoriasis and 24 healthy volunteers were enrolled into the study. Both groups were sex- and age-matched. The evidence of streptococcal infection was based on the positive throat swabs and/or elevated ASO titers. The modified method, including PCR-SSP and PCR-RFLP, was applied to HLA-Cw*06 genotyping. RESULTS: HLA-Cw*06 allele was confirmed in 49 (70%) out of 70 patients, which is significantly higher than in the control population (30%) (p = 0.001). Evidence for streptococcal infection was found in 34 (48.5%) subjects with psoriasis. Twenty-seven of them (79%) carried HLA-Cw*06 allele. In 36 individuals in whom no evidence of streptococcal infection was found, 14 (39%) did not carry HLA-Cw*06 allele. CONCLUSIONS: Our data confirm that HLA-Cw*06 is a major, but not imperative, genetic determinant for guttate psoriasis.

Chemokines and cytokines network in the pathogenesis of the inflammatory skin diseases: atopic dermatitis, psoriasis and skin mastocytosis.

Chemokines are signaling peptides which regulate cell trafficking and provide control of the tissue-specific cell homing. In the skin, chemokines are secreted both by the resident cells such as keratinocytes, melanocytes, fibroblasts, dendritic cells and mast cells, as well as by infiltrated cells - lymphocytes, eosinophils, and monocytes. Chemokines, together with cytokines, participate in induction and maintenance of inflammation in the skin and regulate the composition of the cellular infiltrates. Inflammation within the skin is a feature shared by atopic dermatitis and psoriasis, two of the most common dermatoses. Accumulation of activated mast cells in the affected skin is seen both in atopic dermatitis and in psoriasis. This paper presents a concise overview of the current knowledge on the role chemokines have in pathogenesis of atopic dermatitis, psoriasis, and mastocytosis, a disease caused directly by the accumulation and activation of mast cells in the skin.

Safety profile of antimicrobial peptides: camel, citropin, protegrin, temporin a and lipopeptide on HaCaT keratinocytes.

Antimicrobial peptides (AMPs) are an essential part of the innate immunity of the skin and mucosal surfaces. They have a broad spectrum of antimicrobial activity: antibacterial, antifungal, antiviral as well as antiprotozoal. Numerous studies using AMPs as potential agents against different microbes has been performed during the last two decades. Here we investigated antistaphylococcal activity and safety of following AMPs: camel, citropin, protegrin, temporin A and lipopeptide Palm-KK-NH2. The susceptibility of the strains of Staphylococcus aureus isolated from the patients with erythrodermia to conventional antibiotics and AMPs was determined by the broth dilution method. The cytotoxicity assay was performed on HaCaT keratinocytes. Tested peptides turned out to be very effective against all clinical isolates, including strains resistant to conventional antibiotics. The majority of the examined peptides as well as conventional antimicrobials do not exert any toxic effect on HaCaT cells in minimal inhibitory concentration. Peptides are very promising agents for the topical treatment of staphylococcal skin infections. The most promising seem to be citropin 1.1 and temporin A, as they were toxic only in two highest concentration (50 and 100 microg/mL), with relatively low MIC values.

Childhood nail alterations in Polish population.

The epidemiology and nature of childhood nail apparatus pathology is not well known. The aim of our study was to investigate the frequency and nature of nail alterations in Polish pediatric patients. Among 1588 patients diagnosed and treated at our clinic due to nail alterations, 82 (5.16%) patients under age 16 were selected. The most frequent (36.59%) diagnosis were variants of normal nails, which were observed in 30 patients. The most common pathology were viral warts (19.51%). Differences in the distribution of onychomycosis and viral warts in children and adults were statistically significant. Onychomycosis was more common in adults (60.39% vs. 9.76%), whereas viral warts were more common in children (19.51% vs. 5.86%; P<0.0001). Melanonychia was diagnosed in one (1.22%) case. Benign and malignant tumors were not observed. In conclusion, distribution of nail apparatus pathology in children is different comparing with adults. In the group of children under 6 years of age, there were mainly variants of normal nails, whereas in older children viral infection and acquired structural disorders were recorded. The risk of nail apparatus malignancy in childhood seems to be extremely low.

Interleukin-13 promoter gene polymorphism -1112 C/T is associated with atopic dermatitis in Polish patients.

Interleukin 13 (IL-13) is one of the major cytokines involved in the IgE synthesis in patients with atopic dermatitis (AD). IL-13 gene has been mapped on chromosome 5q31-33 region associated with atopic conditions, where several polymorphisms are described. The aims of the study were to establish the frequency of the IL-13 gene polymorphism and its relation to serum IgE and IL-13 levels and SCORAD. In 180 AD patients and 167 healthy volunteers, the -1112 C/T IL-13 gene polymorphism was genotyped using allele-specific PCR method. Serum total IgE (tIgE) level was measured by Uni-CAP 100 and IL-13 level using ELISA standard kit. The -1112T allele frequency was significantly higher in AD patients compared to controls (P=0.00001). The TT and CT genotypes were correlated with increased serum tIgE concentration (P=0.0004). The TT genotype was associated with severe, CT genotype with moderate and CC genotype with mild course of AD (P=0.0008). Both CT and TT genotypes predominated in cases of AD with concomitant asthma, while CC genotype was not found in any case in this group (P=0.03). The mean levels of serum IL-13 and tIgE were significantly higher in AD with concomitant asthma than in cases without asthma (IL-13 P=0.03 and tIgE P=0.0001). There was positive correlation between serum concentration of IL-13 (P=0.0005) and tIgE (P=0.0000001) and severity of AD as assessed by SCORAD index. Our results confirmed the significant role of -1112 C/T IL-13 gene polymorphism in the pathogenesis of AD.

Dermatitis artefacta--a long way from the first clinical symptoms to diagnosis.

Dermatitis artefacta is a disease that occurs as a result of a self-inflicted injury to the skin. The problem quite often is undiagnosed for a long time until the clinical look of bizarre skin lesions combined with non-specific histology and normal blood tests lead to the final identification. This report presents the case of a 62-year-old man who was diagnosed after 10 years of duration of disease. We discuss the reasons for such behavior and the possibilities of dermatological and general interventions.

A retrospective study of 12 cases of pyoderma gangrenosum: why we should avoid surgical intervention and what therapy to apply.

Lesions of skin are ubiquitous in the medical field. The varying etiopathologies with similar presentation can pose a misleading picture, especially when faced with less common skin diseases. Furthermore, the misdiagnosis can cause detrimental effects on the patient's morbidity and mortality, which was seen in the case series study we performed on pyoderma gangrenosum. The history of 12 patients were analyzed in reference to the course of the disease, accompanying diseases, clinical picture, histopathological examination, surgical intervention before diagnosis, and treatment. Within this group of 12 patients, five were exposed to surgical interventions before diagnosis of pyoderma gangrenosum. The 5 patients were all exposed to prolonged aggravation of the disease process, followed by remission after proper diagnosis and treatment therapy. This study was done to improve the knowledge of surgeons about pyoderma gangrenosum considering the frequency of skin lesion cases in the surgical practice. Knowledge of the disease is essential to diagnose pyoderma gangrenosum in early stages to avoid interventions that may prolong or worsen the outcome. Surgical interventions in these patients should be avoided before proper diagnosis. The key to a better prognosis of pyoderma gangrenosum patients is often in the hands of surgeons.

Activity of Antimicrobial Peptides and Conventional Antibiotics against Superantigen Positive Staphylococcus aureus Isolated from the Patients with Neoplastic and Inflammatory Erythrodermia.

Superantigens are proteins comprising a group of molecules produced by various microorganisms. They are involved in pathogenesis of several human diseases. The aim of the study was the comparison of susceptibility to antibiotics and antimicrobial peptides (AMPs) of Staphylococcus aureus (SA) strains producing staphylococcal enterotoxins SEA, SEB, SEC, SED, and TSST-1 and nonproducing ones. In the group of the total 28 of the patients with erythrodermia the presence of SA was confirmed in 24 cases. The total of 14 strains of SA excreted enterotoxins SEA, SEC, SED, and TSST-1. We did not observe that strains producing mentioned superantigens were less susceptible to AMPs (aurein 1.2, citropin 1.1, lipopeptide, protegrin 1, tachyplesin 3, temporin A, and uperin 3.6). The opposite situation was observed in conventional antibiotics. SA strains excreting tested superantigens had higher MICs and MBCs than nonproducing ones. The interesting finding considering the high efficacy of AMPs, against all examined strains of SA, makes them attractive candidates for therapeutic implication.

2-Chlorodeoxyadenosine treatment for cutaneous T-cell lymphoma.

The primary cutaneous lymphomas are often indolent but difficult to treat. In the early stages psoralen and ultraviolet-A therapy is the standard treatment whereas at the tumor stage chemotherapy (e.g. pegylated doxorubicin) is often used for debulking. The purine analog 2-chlorodeoxyadenosine (2CdA) acts in non-Hodgkin's lymphoma and has been used in our center for the treatment of advanced primary cutaneous T-cell lyphomas (CTCL). Here, we report on the efficacy and side effects of 2CdA in six patients with CTCL. One patient died owing to myelosuppression. Partial responses were seen in four cases but full remission was observed in only one case. We concluded that 2CdA has a limited usefulness in the management of advanced CTCL.

[Are there any clinical evaluations confirming higher incidence of skin cancers as a result of pimecrolimus therapy?]. / Czy istnieja dowody kliniczne potwierdzajace fakt, ze terapia pimekrolimusem zwieksza ryzyko nowotworóW skóry?

Pimecrolimus (SDZ ASM 981), nonsteroid anty-inflammatory ackomycin-derived drug has more and more indications in dermatology. It has been recommended in therapy of atopic and contact dermatitis at the beginning. Nowadays pimecrolimus is used in the treatment of seborrhoic dermatitis, post-steroidal rosacea, bullous diseases etc. News reporting higher incidence of skin cancers after pimecrolimus application has not been proved clinically. The common use of mentioned medication forced us to detailed analysis of references concerning that problem.

Th1 response and cytotoxicity genes are down-regulated in cutaneous T-cell lymphoma.

PURPOSE: Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes. EXPERIMENTAL DESIGN: Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4(+) cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression. RESULTS: We identified a set of Th1-specific genes [e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES)] to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations. CONCLUSIONS: Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.

Primary cutaneous T-cell lymphomas show a deletion or translocation affecting NAV3, the human UNC-53 homologue.

Multicolor fluorescent in situ hybridization (FISH) was used to identify acquired chromosomal aberrations in 12 patients with mycosis fungoides or Sézary syndrome, the most common forms of primary cutaneous T-cell lymphoma (CTCL). The most frequently affected chromosome was 12, which showed clonal deletions or translocations with a break point in 12q21 or 12q22 in five of seven consecutive Sézary syndrome patients and a clonal monosomy in the sixth patient. The break point of a balanced translocation t(12;18)(q21;q21.2), mapped in the minimal common region of two deletions, fine mapped to 12q2. By locus-specific FISH, the translocation disrupted one gene, NAV3 (POMFIL1), a human homologue of unc-53 in Caenorhabditis elegans. A missense mutation in the remaining NAV3 allele was found in one of six cases with a deletion or translocation. With locus-specific FISH, NAV3 deletions were found in the skin lesions of four of eight (50%) patients with early mycosis fungoides (stages IA-IIA) and in the skin or lymph node of 11 of 13 (85%) patients with advanced mycosis fungoides or Sézary syndrome. Preliminary functional studies with lentiviral small interfering RNA-based NAV3 silencing in Jurkat cells and in primary lymphocytes showed enhanced interleukin 2 expression (but not CD25 expression). Thus, NAV3 may contribute to the growth, differentiation, and apoptosis of CTCL cells as well as to the skewing from Th1-type to Th2-type phenotype during disease progression. NAV3, a novel putative haploinsufficient tumor suppressor gene, is disrupted in most cases of the commonest types of CTCL and may thus provide a new diagnostic tool.

Polymorphism of the TAP1 gene in Polish patients with psoriasis vulgaris.

Psoriasis vulgaris is a HLA-associated common and persistent inflammatory skin disease of unknown aetiology. The transporters associated with antigen processing (TAP) genes are polymorphic genes located in the HLA class II region and due to their essential involvement in class I antigen presentation might be additional susceptibility genes to psoriasis. To investigate the possible involvement of the TAP1 gene in the pathogenesis of psoriasis, we analysed its polymorphism in 169 Polish patients with psoriasis vulgaris and compared them with 66 healthy controls. The frequency of TAP1*D was significantly increased in the patients, compared to the control group. The TAP alleles were also analysed with respect to the age of onset of psoriasis in the patients but no significant differences were recorded. In conclusion, our data suggest that the TAP1*D allele could lead to genetic susceptibility to psoriasis vulgaris in Poles.