Major review: Exfoliation syndrome; advances in disease genetics, molecular biology, and epidemiology

The genetics of contact allergy are still only partly understood, despite decades of research; this might be a consequence of inadequately defined phenotypes used in the past. A recommendation is to study an extreme phenotype, namely, polysensitization (sensitization to three or more unrelated allergens). Another approach to unravel the genetics of contact allergy is the study of candidate genes. In this review, we summarize studies on the associations between genetic variation (e.g. single-nucleotide polymorphisms) in certain candidate genes and contact allergy. Polymorphisms and mutations affecting the following proteins were studied: (i) filaggrin; (ii) N-acetyltransferase (NAT) 1 and 2; (iii) glutathione-S-transferase (GST) M and T; (iv) manganese superoxide dismutase; (v) angiotensin-converting enzyme (ACE); (vi) tumour necrosis factor (TNF); and (vii) interleukin-16 (IL-16). The polymorphisms of NAT1, NAT2, GSTM, GSTT, ACE, TNF and IL-16 were shown to be associated with an increased risk of contact allergy. In one of our studies, the increased risk conferred by the TNF and IL-16 polymorphisms was confined to polysensitized individuals. Other relevant candidate genes may be identified by studying diseases related to contact allergy in terms of clinical symptoms, a more general pathology (inflammation), and possibly an overlapping genetic background, such as irritant contact dermatitis.

Genetic factors in contact allergy--review and future goals.

The interleukin (IL)-1 family includes 11 members that are important in inflammatory processes. It includes various agonists and two antagonists, IL-1Ra and IL-36Ra. Our aim was to investigate whether the IL-1 family is involved in allergic contact dermatitis (ACD). The expression of IL-1 family members was evaluated by PCR and immunohistochemistry in the positive patch test reaction site (involved skin) and in the uninvolved skin of ACD patients. We also examined these cytokines in an ex vivo model of ACD. The antagonistic activity of IL-36Ra was evaluated by injecting recombinant IL-36Ra in uninvolved skin biopsies of ACD patients. IL-1Ra and IL-36Ra expression was quantified in mononuclear cells of nickel-sensitized patients challenged in vitro with nickel. IL-33 involvement in ACD was investigated by intra-dermal injection of anti-IL-33 in the uninvolved skin of patients ex vivo. Results showed that IL-1β, IL-1Ra, IL-36α, IL-36β, IL-36γ and IL-33 expression, but not IL-36Ra expression, was enhanced in ACD-involved skin. Immunohistochemical analysis and ex vivo skin cultures confirmed these results. Injection of anti-IL-33 in ACD-uninvolved skin inhibited IL-8 expression, whereas IL-36Ra inhibited IL-36α, IL-36β, IL-36γ and IL-8 expression. Nickel induced IL-1Ra expression in lymphocytes of nickel-sensitized patients. Hence, various IL-1 agonists and antagonists may be involved in ACD pathogenesis.

The balance between pro- and anti-inflammatory cytokines is crucial in human allergic contact dermatitis pathogenesis: the role of IL-1 family members.

The IL-1 family of cytokines comprises 11 proteins with pro- and anti-inflammatory functions that are mediated through an equally large group of receptors and coreceptors Dysregulation of the IL-1 system may lead to diseases such as psoriasis, atopic dermatitis, contact dermatitis and cutaneous lupus erythematosus These inflammatory skin conditions greatly affect quality of life and life expectancy, and their frequencies are increasing However, treatment options for these diseases are unsatisfactory This review briefly summarizes new findings, reported in the past 2 years, implicating IL-1 family members in skin inflammation Furthermore, how the biological activities of the IL-1 family members may be inhibited is discussed

Targeting the IL-1 family members in skin inflammation.

Inflammation plays a major role in the induction and progression of several skin diseases. Overexpression of the major epidermal proinflammatory cytokines interleukin (IL) 1 alpha (IL-1α) and 1 beta (IL-1β) is positively correlated with symptom exacerbation and disease progression in psoriasis, atopic dermatitis, neutrophilic dermatoses, skin phototoxicity, and skin cancer. IL-1β and the interleukin-1 receptor I (IL-1RI) have been used as a therapeutic target for some autoinflammatory skin diseases; yet, their system-wide effects limit their clinical usage. Based on the local effects of extracellular IL-1α and its precursor, pro-IL-1α, we hypothesize that this isoform is a promising drug target for the treatment and prevention of many skin diseases. This review provides an overview on IL-1α and IL-β functions, and their contribution to inflammatory and malignant skin diseases. We also discuss the current treatment regimens, and ongoing clinical trials, demonstrating the potential of targeting IL-1α, and not IL-1β, as a more effective strategy to prevent or treat the onset and progression of various skin diseases.

The Role of Interleukin-1 in Inflammatory and Malignant Human Skin Diseases and the Rationale for Targeting Interleukin-1 Alpha.

Background: It has been shown that the family of interleukin-1 receptor antagonist (IL-1 RA) and tumour necrosis factor-alpha (TNFα) genes are polymorphic and related to some inflammatory diseases. Allergic contact dermatitis is the classic presentation of delayed-type hypersensitivity responses to exogenous agents. A number of genes playing role in inflammatory response may be associated with allergic contact dermatitis.



Objectives: To investigate whether there is an association between IL-1RA and TNFα gene polymorphisms and allergic contact dermatitis in Turkish patients with allergic contact dermatitis.



Methods: This study was performed by the collaboration of Departments of Dermatology and Medical Genetics, Ege University, Faculty of Medicine. A total of 50 patients (31 females and 19 males) with allergic contact dermatitis, and 100 age- and sex-matched controls (58 females and 42 males) were included in the study. IL-1RA Variable Number of Tandem Repeats (VNTR) polymorphism in intron 2 and TNFα-308G-A polymorphism were genotyped by using polymerase chain reaction and agarose gel electrophoresis.



Results: The frequency of IL-1RA 1/2 (48%) genotype was significantly higher (P = 0.002) in patient group than that is found in control group (22%). The frequency of TNFα (TNF G-308A) G/G genotype was significantly higher in patient group (68%) than that is found in control group (31%) (P = 0.008).



Conclusions: Our findings suggest that TNFα (G/G) gene polymorphism may play role in susceptibility to allergic contact dermatitis in Turkish patients.

Interleukin-1 receptor antagonist and tumour necrosis factor-alpha gene polymorphisms in Turkish patients with allergic contact dermatitis.

The purpose of this study is to evaluate whole lysyl oxidase like 1 (LOXL1) gene by sequence analysis in Turkish patients with exfoliation glaucoma (XFG). A total of 48 (35 male, 13 female) patients with XFG were enrolled. Besides routine ophthalmological examination, peripapillary retinal nerve fibre layer (RNFL) analysis with optic coherence tomography was performed. Blood samples of 2 ml with EDTA were obtained and sent to Medical Genetics Department, Molecular Genetics Laboratory for LOXL1 polymorphism (PCR and agarose gel imaging) analysis. The role of the detected changes on disease severity was evaluated. No LOXL1 gene mutations in any of the patients were detected. Three types of single-nucleotide polymorphisms (SNPs) including R141L(rs1048661), A320A(rs41435250), and F184F were detected in 17 (35.3 %) patients. When compared, SNP-positive patients had thinner RNFL than SNP-negative patients (64.5 ± 17.6 and 66.1 ± 20.4 µ, respectively), and SNP-positive patients had higher cupping/disc ratio than SNP-negative patients (0.76 ± 0.2 and 0.70 ± 0.3, respectively). However, both values were not statistically significant (p = 0.966 and p = 0.539, respectively). When compared, R141L-positive patients had significantly thinner cornea thickness (516.11 ± 30.3 µ) than R141L-negative patients (556.69 ± 27.2 µ) (p = 0.004). There was not any statistical significant difference in the means of age, gender, BCVA, MD, PSD, IOP, number of hypotensive agents, and percent of glaucoma surgery (p > 0.05). In this study group of Turkish population, no LOXL1 mutations were found. No associations between the defined SNPs (A320A, R141L and F184F) and the severity of the disease were detected.

LOXL1 gene analysis in Turkish patients with exfoliation glaucoma

Mannose-binding lectin (MBL) is a component of the innate immune system and acts as a complement activator through the lectin pathway. Genetic variations of MBL and low MBL levels cause several infection problems, which may also be related to pregnancy problems. We aimed to investigate the role of MBL gene codon 54 polymorphism and serum MBL levels in pregnancy problems and premature delivery. In this prospective study, MBL gene codon 54 polymorphism and serum MBL levels were studied in 45 mothers who delivered earlier than 35 gestational weeks. The frequency of MBL gene codon 54 variant allele B was much higher (homozygous 4.4% and heterozygous 33.3%) in the study group mothers than the previously reported frequency in the healthy Turkish population (homozygous 2-6%, heterozygous 12-20%). MBL variant allele B frequency was closely related to low MBL levels (<0.1 μg/ml), vaginitis and increased IL-6 levels. The median MBL levels were lower than the critical level of 0.1 μg/ ml in study mothers who had recurrent miscarriage, infertility, preeclampsia, gestational diabetes mellitus, preterm premature rupture of membranes with duration of longer than 72 hours, tocolysis, histological chorioamnionitis, urinary tract infection and vaginitis. MBL gene codon 54 variant allele B is related to low serum MBL levels, increased IL-6 levels, genitourinary infections and may cause pregnancy-related problems such as infertility, recurrent miscarriage and preterm delivery.

Mannose-binding lectin may affect pregnancy outcome

39 ©Copyright 2018 by Ege University Faculty of Medicine, Department of Pediatrics and Ege Children’s Foundation The Journal of Pediatric Research, published by Galenos Publishing House. Ad dress for Cor res pon den ce Ebru Canda MD, Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, İzmir, Turkey Phone: +90 505 525 29 16 E-mail: ebru.canda@gmail.com ORCID ID: orcid.org/0000-0002-9175-1998 Re cei ved: 06.11.2017 Ac cep ted: 25.12.2017 1Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, İzmir, Turkey 2Ege University Faculty of Medicine, Department of Radiology, İzmir, Turkey 3Ege University Faculty of Medicine, Department of Biochemistry, İzmir, Turkey 4Ege University Faculty of Medicine, Department of Genetics, İzmir, Turkey Ebru Canda1, Melis Köse1, Havva Yazıcı1, Esra Er1, Cenk Eraslan2, Sema Kalkan Uçar1, Sara Habif3, Emin Karaca4, Hüseyin Onay4, Ferda Özkınay4, Mahmut Çoker4

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Feriştah Özkinay

Papers

Interleukin-1 receptor antagonist and tumour necrosis factor-alpha gene polymorphisms in Turkish patients with allergic contact dermatitis.

LOXL1 gene analysis in Turkish patients with exfoliation glaucoma

Mannose-binding lectin may affect pregnancy outcome

Clinical, Neuroimaging, and Genetic Features of the Patients with L-2-Hydroxyglutaric Aciduria

The first report of fibular agenesis, tibial campomelia, and oligosyndactyly syndrome with hydrocephaly.