Role of the Th1 and Th17 Pathway in Subacute Sclerosing Panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal disease caused by reactivation of a mutated measles virus in brain tissue. The process of reactivation is yet to be elucidated. In this study, the possible roles of the Th1 (interleukin [IL]-12, interferon [IFN]-γ) and the Th17 axis (IL-23, IL-17, IL-22), particularly of IL-17, in the pathogenesis of SSPE were investigated. Briefly, mononuclear cells from SSPE patients were stimulated using measles virus peptide, and the release of IL-12, IL-23, IL-22, IFN-γ, and IL-17 cytokines was measured using enzyme-linked immunosorbent assay and/or enzyme-linked immunosorbent spot assay (ELISpot). We found that in comparison to the mononuclear cells obtained from healthy donors, cells from SSPE patients exhibited increased levels of IL-12, IL-23, IL-17, IL-22, and IFN-γ cytokines in response to measles virus stimulation. However, the same result was not obtained with cytomegalovirus and phytohemagglutinin. Using flow cytometry, mononuclear cells obtained from SSPE patients and healthy controls were also analyzed for the presence of intracellular IL-17 in response to measles virus stimulation. On stimulation, the number of IL-17-positive cells were found to be higher among mononuclear cells obtained from the patients. In addition, the numbers of IL-17- and IFN-γ-positive cells were significantly increased in SSPE patients. In conclusion, this study demonstrates that both the IL-12/IFN-γ and the IL-23/IL-17/IL-22 pathways are functionally abnormal in SSPE pathogenesis. Targeting these pathways and their specific pro-inflammatory mediator production may provide a new strategy to suppress SSPE development.

Interleukin-12 (-1188) A/C and interferon-γ (+874) A/T gene polymorphisms in subacute sclerosing panencephalitis patients.

The two polymorphisms [IL-12 (-1188) A/C and the IFN-γ (+874) A/T)] are known to have functional consequences and henceforth were analyzed in subacute sclerosing panencephalitis (SSPE) patients to reveal a possible relation with these polymorphisms and this debilitating disease. For the IL-12 (-1188) A/C polymorphism, 78 patients and 90 healthy individuals were analyzed. An increase in the AA genotype was determined (p = 0.02, OR = 2.06). There was also a statistically significant difference between the control group and the patients with respect to the allele frequencies (p = 0.04, OR = 1.65). For the IFN-γ (+874) A/T polymorphism, 69 SSPE patients and 115 controls were studied and there was not a significant difference between the two groups. Our findings suggested that not the IFN-γ (+874) A/T but the IL-12 (-1188) A/C polymorphism is correlated with SSPE and having an AA genotype or A allele decreases the risk of developing SSPE by 2.06- and 1.65-fold, respectively.

In vitro interferon γ improves the oxidative burst activity of neutrophils in patients with chronic granulomatous disease with a subtype of gp91phox deficiency.

AIM OF THIS STUDY: Chronic granulomatous disease (CGD) is a genetically heterogeneous primary immunodeficiency caused by a defect in phagocyte production of oxygen metabolites, and resulting in infections produced by catalase-positive microorganisms and fungi. Interferon γ (IFN-γ) has a multitude of effects on the immune system. Although preliminary studies with CGD patients on treatment with IFN-γ showed that it enhanced phagocytosis and superoxide production, ongoing studies did not reveal a significant increase of this function. Here we investigated the oxidative capacity of phagocytes in different subtypes of CGD patients on treatment with IFN-γ in vitro. MATERIAL AND METHODS: Fifty-seven patients with CGD from 14 immunology centres were enrolled to our multi-centre study. Twenty-one patients were studied as controls. Oxidative burst assay with dihydrorhodamine 123 (DHR) was used and the stimulation index (SI) was calculated with respect to CGD subtypes in both neutrophils and monocytes before, and then one and 24 hours after adding IFN-γ. RESULTS: Upon comparison of the SIs of the patients' neutrophils before in vitro IFN-γ at hour 0, and after adding IFN-γ at hour 1 and 24 were compared, and the differences were determined between hours 0-24 and hours 1-24. This difference was especially apparent between hours 1-24. In CGD subtypes, particularly in gp91phox subtype, it was seen that, following in vitro IFN-γ, SIs of neutrophils began to increase after hour 1, and that increase became more apparent at hour 24. CONCLUSIONS: Our study showed that IFN-γ treatment may increase the oxidative bursting activity by increasing the superoxide production in neutrophils, particularly in gp91phox subtype.

The influence of CTLA-4 single nucleotide polymorphisms on acute kidney allograft rejection in Turkish patients.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a cell surface protein, which down-regulates the immune response at CTLA-4/CD28/B7 pathway. We aimed to investigate the influence of the -318 C/T, +49 A/G, -1661 A/G and CT60A/G, and CTLA-4 gene polymorphisms on acute rejection of kidney allograft in Turkish patients. The study design was a case-control study that consists of three groups: Group 1 (n = 34) represented the kidney transplant (Ktx) recipients who experienced acute rejection, Group 2 (n = 47) was randomly assigned Ktx recipients without acute rejection, and Group 3 (n = 50) consisting of healthy volunteers to evaluate the normal genomic distribution. The polymerase chain reaction-restriction fragment length polymorphism technique was used to determine the polymorphisms. Genotype and allele frequencies among three groups denoted similar distributions for +49 A/G, -1661 A/G, and CT60A/G. Conversely, -318 C/T genotype was three times more frequent in the acute rejection group than in the non-rejection group (OR = 3.45; 95%CI = 1.18-10.1, p = 0.015) and two times more frequent than the healthy control group (OR = 2.45; 95% CI = 0.98 - 6.11, p = 0.047). Additionally, having a T allele at -318 position was significantly associated with acute rejection (0.147 vs. 0.043, OR = 3.45; 95% CI = 1.13-10.56, p = 0.02). 318C/T gene polymorphism and T allelic variant were found to be associated with increased acute rejection risk in Turkish kidney allograft recipients.

Cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis in a child with interleukin-12 receptor beta-1 deficiency.

Defects in the interleukin 12 (IL-12)/interferon gamma (IFN-γ) pathway result in Mendelian susceptibility to mycobacterial disease (MSMD). IL-12 receptor beta 1 (IL-12Rß1) deficiency, the most common form of MSMD, is associated with weakly virulent mycobacteria and salmonella. Infections in patients with this deficiency are extraintestinal, or septicemic, recurrent infections with nontyphoid salmonellae. Here we report a case of an IL-12Rß1 deficiency with cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis.

Interleukin-1ß secretion in hippocampal sclerosis patients with mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common medically intractable epilepsy syndrome. Although pathogenesis of HS still remains highly controversial, genetics may play a role as a predisposing factor. Previous evidence in a Japanese population revealed that the homozygotes for allele T at position -511 of the interleukin (IL)-1ß gene promoter region (IL-1ß-511 T/T) confers susceptibility to the development of HS. However, whether this polymorphism has an effect on IL-1ß levels in MTLEHS patients was not demonstrated. This study aimed to analyze the distribution of this particular polymorphism in a group of Turkish HS patients and correlate the polymorphism with IL-1ß secretion from the lymphocytes, thus revealing a functional role for IL-1ß in the etiopathogenesis of HS. A single base pair polymorphism at position -511 in the promoter region of the IL-1ß gene was analyzed. The spontaneous and 1 ng/mL lipopolysaccharidestimulated production of IL-1ß by peripheral blood mononuclear cells after 4 and 24 h of incubation were measured by ELISA method. The heterozygous type (-511 C/T) was the most common genotype. There was no difference in frequency of allele -511 T between patients and controls. Analysis of IL-1ß levels, genotype and allele distributions showed no significant difference among the groups (P>0.05). Nevertheless, it was seen that patients who carry a T allele at position -511 of the IL-1ß gene had increased IL-1ß levels. T-allele carriage may be important. Only IL-1ß secretion from the lymphocytes has been assessed in this study. Considering the importance of IL-1ß in the etiopathogenesis of HS, further studies are needed to evaluate locally produced IL-1ß levels.

Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A mutation in one of the 4 genes encoding the components p22(phox), p47(phox), p67(phox), and p40(phox) of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A mutation in the CYBB gene encoding gp91(phox) leads to X-linked recessive CGD. OBJECTIVE: The aim of this study is to show the correlation between clinical, functional, and genetic data of patients with CGD from Turkey. METHODS: We report here the results of 89 patients with CGD from 73 Turkish families in a multicenter study. RESULTS: Most of the families (55%) have an AR genotype, and 38% have an X-linked genotype; patients from 5 families with a suspected AR genotype (7%) were not fully characterized. We compared patients with CGD according to the severity of NADPH oxidase deficiency of neutrophils. Patients with A22(0), A67(0) or X91(0) phenotypes with a stimulation index of 1.5 or less have early clinical presentation and younger age at diagnosis (mean, 3.2 years). However, in p47(phox)-deficient cases and in 5 other AR cases with high residual oxidase activity (stimulation index ≥ 3), later and less severe clinical presentation and older age at diagnosis (mean, 7.1 years) were found. Pulmonary involvement was the most common clinical feature, followed by lymphadenitis and abscesses. CONCLUSION: Later and less severe clinical presentation and older age at diagnosis are related to the residual NADPH oxidase activity of neutrophils and not to the mode of inheritance. CGD caused by A22(0) and A67(0) subtypes manifests as severe as the X91(0) subtype.

Escherichia coli brain abscess in a twin pair associated with TLR4 gene mutation.

Brain abscesses are uncommon complications of bacterial meningitis or sepsis in neonates and infants. The causative pathogens of brain abscess in newborns are various. Of those, Escherichia coli is rarely seen as a pathogen in brain abscess at this age. Herein we reported brain abscesses in twin infants caused by E. coli sepsis. Interestingly, genetic analysis identified heterozygous Toll-like receptor 4 (TLR4) gene mutation in the twins. Because TLR plays an important role in the natural response to bacterial products and initiates specific immune response against these pathogens, this may explain the development of brain abscess in the present case.

CTLA-4 (+49A/G) polymorphism and type-1 diabetes in Turkish children.

OBJECTIVE: To evaluate the contribution of cytotoxic T-Iymphocyte antigen-4(CTLA-4)+49A/G polymorphism to the susceptibility to type-1 diabetes (T1D) in Turkish children. METHODS: A case-control study was designed to include 91 Turkish children with T1D and 99 healthy controls. CTLA-4 (+99A/G) gene polymorphism typing was done by PCR amplification followed by restriction fragment length polymorphism method. RESULTS: The genotype and allele frequencies of the CTLA-4 (+99A/G)polymorphism in patients with T1D were not different from those in the controls (p>0.05). The allele frequency of G was 36.2% in patients with T1D,and 31.8% in controls (p>0.05). Additionally, this polymorphism was not associated with the clinical and laboratory characteristics of the patients with T1D (p>0.05). CONCLUSIONS: Our case-control study suggests that the CTLA-4 (+99A/G) gene polymorphism is not associated with T1D in the Turkish population.

Human leukocyte antigens class I and class II in patients with pemphigus in southern Turkey.

BACKGROUND: Genetic factors that predispose individuals to pemphigus are considered to play important roles in the development of the disease. Furthermore, population studies of patients with pemphigus have clearly shown that the most prevalent alleles differ across ethnic groups. OBJECTIVES: This controlled study was designed to detect the distribution of human leukocyte antigen (HLA) class I and II alleles in Turkish patients with pemphigus. METHODS: Sixty patients diagnosed with pemphigus according to clinical findings, histology, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were enrolled in the study. The control group consisted of 60 healthy adult transplant donors. HLA typing was carried out using a polymerase chain reaction (PCR) with sequence-specific primers (SSP) method. RESULTS: The frequencies of HLAs A*11, CW*01, DRB1*04, DRB1*14, DQB1*05, and DPB1*0401 were found to be statistically significantly higher in the disease group than in controls. By contrast, the frequencies of HLAs B*18, B*50, DRB1*11, DQB1*02, DQB1*06, DPB1*0301, and DPB1*1102 were statistically significantly lower in the pemphigus group than in controls. Linkage dysequilibrium analysis showed that DRB1*14/DQB1*05, A*11/DQB1*05, and A*11/DRB1*14 alleles were detected frequently in pemphigus patients, and DRB1*11/DQB1*05, DRB1*14/DQB1*02, B*50/DQB1*02, and B*50/DPB1*0301 alleles appeared frequently in healthy controls. CONCLUSIONS: The results suggest that DRB1*04, DRB1*14, DQB1*05, and DPB1*0401 class II HLAs and A*11 and CW*01 class I HLAs are associated with pemphigus in southern Turkey. Observed differences in LD patterns between patients and controls suggest that the coexistence of the respective alleles is strongly determinant of predisposition towards (DRB1*14/DQB1*05 and A*11/DQB1*05) or protection against (B*50/DQB1*02) the disease.

Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis.

Serum IL-17 levels and IL-17 mRNA expression have been reported to be higher in psoriatic skin than normal skin. There are very limited data in the literature about difference in the levels of this cytokine in various clinical disease subtypes. We aimed to evaluate whether there is a difference in the level of this cytokine according to clinical subtypes of psoriasis. 70 psoriasis patients (30 plaque psoriasis, 20 guttate psoriasis, and 20 pustular psoriasis) and 50 age- and sex-matched healthy volunteers were included in the study. Serum IL-17 levels were determined by ELISA. Skin biopsies obtained from lesions and non-lesional skin area of 12 patients and healthy individuals (n = 5) were analyzed by quantitative PCR (qPCR) to measure the mRNA levels of IL-17. Statistically, the serum IL-17 levels did not exhibit any difference between the patients and control groups. However, analysis of each subgroup revealed that the IL-17 levels were significantly higher in pustular psoriasis group (10.09 ± 12.6 pg/ml) than controls (4.4 ± 4.1 pg/ml) (p = 0.02). In addition, the IL-17 levels of plaque psoriasis patients with PASI score ≥10 (11.30 ± 6.0 pg/ml) were significantly higher than that of patients with PASI score <10 (3.39 ± 2.6 pg/ml) and controls (p < 0.001). The Pearson correlation analysis showed a positive correlation between the serum IL-17 levels and PASI. Lesional skin samples of psoriasis patients showed significantly higher levels of IL-17 mRNA compared with perilesional skin samples (p = 0.017). Also, in the pustular psoriasis, IL-17 mRNA levels were found to be distinctively high in comparison with other clinical subtypes and healthy controls. Our results indicate that IL-17 and Th17 cells have an important role in pustular psoriasis and severe psoriasis.

Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.

BACKGROUND: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. OBJECTIVE: To elucidate mechanisms underlying different forms of HIES. METHODS: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. RESULTS: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. CONCLUSION: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.

Relationship between periodontal findings and specific polymorphisms of interleukin-1alpha and -1beta in Turkish patients with Behçet's disease.

Genetic factors predispose individuals to Behçet's disease (BD) and periodontal disease. IL-1 has been implicated in the pathogenesis of both BD and periodontal disease. The relationship between periodontitis and pathogenesis of BD has not yet been determined. Since IL-1 has been implicated in the pathogenesis of both BD and periodontal disease, we aimed to investigate the possible relation of the periodontal scores and SNPs of IL-1alpha-889C/T, IL-1beta-511C/T, and IL-1beta+3962T/C with BD compared to healthy controls (HC) and recurrent aphtous stomatitis (RAS). A total of 155 Turkish individuals were enrolled in this study. The periodontal status of all subjects was evaluated according to the WHO community periodontal index of treatment needs. For genotyping, CTS-PCR-SSP was employed. IL-1alpha-889C allele was significantly higher in BD patients (p = 0.03) and RAS (p = 0.02) compared to HC. The frequency of IL-1beta+3962T allele was significantly higher in RAS patients compared to HC (p = 0.015). Male gender (p = 0.04), age (p = 0.02) and carrying IL-1beta-511T allele (p = 0.01) were found to be a significant risk factors for higher periodontal scores in Turkish population. We can speculate that susceptibility to the development of periodontal disease could be influenced by IL-1 SNPs. Periodontitis-induced autoinflammatory response also may play a role in the development/severity of BD and RAS via IL-1 gene alteration.

Cutting edge: A common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy.

TLRs constitute an essential family of pattern recognition molecules that, through direct recognition of conserved microbial components, initiate inflammatory responses following infection. In this role, TLR1 enables host responses to a variety of bacteria, including pathogenic species of mycobacteria. In this study, we report that I602S, a common single nucleotide polymorphism within TLR1, is associated with aberrant trafficking of the receptor to the cell surface and diminished responses of blood monocytes to bacterial agonists. When expressed in heterologous systems, the TLR1 602S variant, but not the TLR1 602I variant, exhibits the expected deficiencies in trafficking and responsiveness. Among white Europeans, the 602S allele represents the most common single nucleotide polymorphism affecting TLR function identified to date. Surprisingly, the 602S allele is associated with a decreased incidence of leprosy, suggesting that Mycobacterium leprae subverts the TLR system as a mechanism of immune evasion.

Interferon-gamma gene+874T-A polymorphism is associated with tuberculosis and gamma interferon response.

Interferon-gamma is the most important cytokine in resistance to mycobacterial diseases and common variants of interferon-gamma gene could be related to tuberculosis susceptibility. We tested the hypothesis that the interferon-gamma+874T-A polymorphism is associated with tuberculosis disease, and affects the interferon-gamma response. We determined by pyrosequencing the distribution of the interferon-gamma+874T-A polymorphism in a Turkish population of 319 patients with pulmonary tuberculosis, 42 children with severe forms of tuberculosis and 115 healthy donors. We also analysed whether any correlation exists between this polymorphism and interferon-gamma response to Mycobacterium tuberculosis antigens by ELISPOT in 58 pulmonary tuberculosis cases, and the results were analysed according to the genotypes. We found that the minor allele (T) frequency was significantly lower in patients with pulmonary tuberculosis when compared to controls (P=0.024, OR=0.7), a similarly significant decrease in the frequency of TT genotype was observed in patients with pulmonary tuberculosis, compared to the control group (P=0.02, OR=0.49). IFN-gamma responses to PPD antigen in TT genotype was found to be significantly higher than the AA group (P>0.001). Non-parametric correlation analysis of ELISPOT data showed significant reverse correlation in PPD, CFP10 and ESAT6 values and IFN-gamma +874 genotypes. These results show that the IFN-gamma +874T-A polymorphism is related to the IFN-gamma response and the magnitude of the response decreases during transition from TT- to TA and to AA genotypes. Our data suggest that similar to various Caucasian populations, in a Turkish population the IFN-gamma+874 T-A polymorphism is also associated with tuberculosis disease and affects the magnitude of the IFN-gamma response.

Interleukin-1alpha, interleukin-1beta, and interleukin-1Ra polymorphisms in febrile seizures.

Febrile seizures are the most common form of childhood seizures. The exact mechanism promoting convulsions during a common febrile illness remains unknown, but it is accepted that genetic influences are likely to account for at least some of the cases. Previous studies reported high interleukin-1beta levels in the cerebrospinal fluid of patients with febrile seizures. Recently, an association between a regulatory polymorphism in the genes encoding interleukin-1beta and interleukin-1Ra and febrile seizures was reported. In this study, we attempted to confirm these findings. We analyzed the cytokine gene polymorphisms of interleukin-1beta, interleukin-1alpha, and interleukin-1Ra of 73 children with febrile seizure and 152 healthy controls. The distribution of interleukin-1beta -511, interleukin-1alpha -889, and interleukin-1Ra genotypes and alleles did not differ significantly between cases and controls. Our data suggest that the studied gene polymorphisms of interleukin-1beta, interleukin-1alpha, and interleukin-1Ra do not have a significant role in the pathogenesis of febrile seizures.

The effect of cetirizine on IFN-gamma and IL-10 production in children with allergic rhinitis.

Cetirizine, one of the most commonly used antihistamines for the treatment of allergic diseases, possesses some anti-inflammatory properties. Despite its common use, the effect of cetirizine on the production of cytokines from peripheral blood mononuclear cells (PBMCs) needs further clarification. The aim of this study was to investigate whether cetirizine changes interleukin (IL)-10, (IF)-gamma and IL-4 production from PBMCs in children with allergic rhinitis. Thirteen children with allergic rhinitis sensitized to house dust mite (HDM) were treated with cetirizine for four weeks. Blood samples were drawn just prior to the treatment, on the last day of the treatment and two weeks following the cessation of treatment The cytokine production from PBMCs was tested in the presence or absence of HDM allergen and measured by ELISA assay. An augmentation in IL-10 production was observed in PBMCs at the 4th week of cetirizine treatment (p<0.05). Furthermore, a significant increase in IFN-gamma production was observed following the therapy. IL-4 release did not change at all time points tested. In addition, IFN-gamma/IL-4 ratio increased following cetirizine treatment. Cetirizine induced a shift in the human Th1/Th2 cytokine balance toward a Th1 type response by increasing IFN-gamma production and augmenting suppressor cytokine release (IL-10). We concluded that apart from its known antihistaminic properties, cetirizine may modulate allergic inflammation while the patients are on regular treatment schedules.

TNF-alpha G-308A polymorphism is associated with rheumatic fever and correlates with increased TNF-alpha production.

Previous studies suggested that abnormal regulation of TNF-alpha production may have a role in the pathogenesis of rheumatic fever (RF). Polymorphism at the promoter region of TNF-alpha gene (-308 A) has recently been shown to be associated with rheumatic heart disease (RHD) in Mexican patients. Although this polymorphism has long been shown to affect TNF-alpha gene expression in cell lines, its role in production of the cytokine in RF patients has not been studied. We therefore investigated TNF-alpha G-308A single nucleotide polymorphism and its effect on TNF-alpha production in 71 Turkish RF patients and 89 ethnically matched healthy controls. The TNF-alpha-308A allele frequency was found to be significantly higher in RF patients (RHD+arthritis) than in healthy controls [p<0.0032 Odds ratio (OR)=3.4, 95% confidence interval (CI) (1.5-7.7)]. When RHD patients were analyzed as a separate group, significant difference persisted [p<0.0055, OR=3.3, 95% CI (1.5-7.6)]. More importantly, ELISPOT analysis demonstrated that existence of A allele was associated with higher TNF-alpha production compared with G allele. Our data suggest that carrying a high responder TNF-alpha-308A allele may be a genetic factor in increasing the susceptibility to develop RF disease.

Clinical importance of circulating and cellular expression levels of Fas and Fas ligand in pediatric patients with lymphoproliferative malignancies.

Objectives of this study were to determine the extend of soluble Fas (sFas) and soluble FasL (sFasL) at the time of diagnosis and to evaluate its prognostic relevance under chemotherapy in childhood lymphoproliferative malignancies. The authors measured the circulating sFas and sFasL by ELISA in 25 children with newly diagnosed either ALL or NHL, as well as their expression of Fas and FasL at the time of diagnosis and remission. They did not observe any statistically significant difference between the patient group and age-matched healthy controls for sFas levels, whereas sFasL concentration in study population at the time of diagnosis was significantly higher than that in control subjects (1.05 +/- 1.46 vs. 0.36 +/- 0.18 ng/mL, p = .024). At remission the authors observed a significant decrease in the sFasL levels of all patients whose sFasL concentrations were above the minimal detectable level at the time of diagnosis (p = .008). sFasL and Fas/FasL immunohistochemical staining did not have an effect on survival. sFasL may be a marker in monitoring complete remission in children with LPM.