Correction to: Primary immunodeficiencies in Central and Eastern Europe-the power of networking Report on the activity of the Jeffrey Modell Foundation Centers Network in Central and Eastern Europe.

Due to authors' internal mistake they have misspelled the name of one of the co-authors in this article.

Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes.

Interleukin 27 (IL-27), a member of the IL-12 family, is important for T cell differentiation; however, little is known about its effect on dendritic cells (DCs). IL-27 can activate multiple signaling cascades, including the JAK/STAT pathway, and depending on the setting it can both promote and antagonize inflammatory responses. An anti-inflammatory function of IL-27 has been reported in several autoimmune diseases; however, in type 1 diabetes (T1D), an autoimmune disease where autoreactive cytotoxic T cells attack insulin-producing beta cells, IL-27 has been shown to have a dual role and contradictory effects. Here, we show impaired IL-27 signaling in a large cohort of T1D patients (n = 51) compared to age- and gender-matched healthy donors. Increased expression of the IL-27 receptor subunit IL-27Ralpha mRNA in purified myeloid DCs (mDCs), detected by gene expression microarrays was mirrored by enhanced signal transduction in T1D mDCs in response to IL-27 stimulation. Higher STAT phosphorylation in T1D patients was also accompanied by elevated expression of the inhibitory molecules PD-L1, PD-L2 and PD-1, which may suggest not only immunomodulatory mechanisms of IL-27 in T1D but also a compensatory effort of T1D dendritic cells against the ongoing inflammation.

Primary immunodeficiencies in Central and Eastern Europe-the power of networking Report on the activity of the Jeffrey Modell Foundation Centers Network in Central and Eastern Europe.

Jeffrey Modell Foundation centers' network activities in Central and Eastern Europe (JMF CEE) have contributed to the development of care for patients with primary immunodeficiencies. On the data continuously collected from individual centers in participating countries since 2011, we demonstrate a steady improvement in a number of aspects concerning complex care for patients with primary immunodeficiencies. The presented data show an improvement of awareness about these rare diseases across the whole Central and Eastern European region, an increase in newly diagnosed patients as well as genetically confirmed cases, earlier establishment of diagnosis, and improved access to clinical treatment. We also present an active patient involvement that is reflected in the expansion of patient organization centers and their activities. The cooperation within the JMF CEE network has also contributed to greater international exposure of participating centers and further to the gradual development of research activities in the rapidly evolving field of primary immunodeficiencies. The improvement of all important aspects of the complex field of primary immunodeficiencies within the JMF CEE network documents the strength and advantages of the joint and coordinated networking.

[Anakinra treatment in Schnitzler syndrome -  results of the first retrospective multicenter study in six patients from the Czech Republic]. / Lécba anakinrou u Schnitzler syndromu -  výsledky první retrospektivní multicentrické studie sesti pacientu z Ceské republiky.

BACKGROUND: Schnitzler syndrome is a very rare, acquired, autoinflammatory disease of mostly adult onset with characteristic combination of chronic recurrent urticaria and monoclonal immunoglobulin M or G gammopathy predisposing the patients to malignant lymphoproliferation. In this work, we analyzed the results of bio-logical therapy with anakinra on a national level aiming to supply data for effective pharmaco-economic estimates, lay the grounds of nationwide patient registry, raise awareness among professional public and optimize provided health care. PATIENTS AND METHODS: The retrospective study (10/ 2006- 9/ 2013) included six males with definite Schnitzler syndrome verified by the new Strasbourg criteria. All patients were pretreated with antihistamines, nonsteroidal antiinflammatory drugs and glucocorticoids. Four patients underwent two or more treatment lines including intravenous bisphosphonates, 2- chlorodeoxyadenosine (cladribine), interferonα, PUVA photochemotherapy, cyclosporine A, thalidomide, bortezomib, chlorambucil, cyclophosphamide, colchicine and methotrexate. Anakinra monotherapy was initiated in standard dosing (100 mg subcutaneously daily). RESULTS: Complete and partial remissions were achieved in five (83%) and one patients (17%), respectively. Complete remission was characterized by urticaria and pain regression (within hours), normalization of inflammatory markers (with--in days) and bone metabolism improvement assessed by the markers of osteoblastic osteoformation and osteoclastic osteoresorption in one case (within weeks). With normalized inflammatory markers (including interleukin6 and interleukin18), arthralgia and sporadic exacerbations of urticaria and fevers persist in the patient in partial remission with proven Q703K polymorphism in NLRP3 gene. The median treatment followup was 30.5 months (37.2 ± 31.2 (n = 6)). The dosing interval was prolonged in one case of complete remission to 48 hours. No serious adverse reactions occurred during anakinra application. CONCLUSION: In Schnitzler syndrome, anakinra represents an effective, verified and safe medication with potentionally longterm administration not compromising its original efficacy and subjective tolerance. Anakinra, blocking autonomous inflammatory reaction of the organism via interleukin1 pathway, is a generally accepted first line treatment that should be made available in standard dosing for all Schnitzler patients.

Cluster of patients with Familial Mediterranean fever and heterozygous carriers of mutations in MEFV gene in the Czech Republic.

Familial Mediterranean fever (FMF) is a well-described monogenic autosomal recessive disorder with highest occurrence in the Mediterranean region. In this article, we describe the experience of a center in the Czech Republic that follows four families with members bearing mutations in MEFV gene without provable ancestry from the Mediterranean region. We also discuss the clinical picture of the heterozygous variants that were present in our cohort. The typical clinical presentation in heterozygotes corresponds to data described in the international literature. The possibility of combination of mutations and/or polymorphisms in different genes and epigenetic or environmental influences on the clinical symptoms are taken into account.

A prospective study in children with a severe form of atopic dermatitis: clinical outcome in relation to cytokine gene polymorphisms.

BACKGROUND AND OBJECTIVE: The course of atopic dermatitis (AD) in childhood is characterized by typical changes in phenotype, including a shift from skin involvement to respiratory allergy usually around the third year of age. We thus designed a prospective study to monitor the outcome of severe AD and to investigate the association between cytokine gene polymorphisms and clinical manifestations. METHODS: Clinical and laboratory follow-up of 94 patients with severe AD and 103 healthy controls was performed using routine methodology. Allele, genotype, and haplotype frequencies of single nucleotide polymorphisms of 13 selected cytokine/receptor genes were analyzed using PCR with sequence-specific primers. RESULTS: In our study, genotypes of 7 polymorphisms--LL-4 -1098G/T and -590C/T, IL-6 -174C/G and nt565A/G, and IL-10 -1082A/G, -819C/T, and -592A/C were significantly associated with atopic AD (P < .05). A significant association was also found for TNF-alpha AA and IL-4 GC haplotypes and AD. We confirm the progressive clinical improvement of AD together with a decrease in the severity index SCORAD (SCORing atopic dermatitis) during childhood (P < .05). We found significant differences between IL-4Ralpha +1902 A/G and positivity of tree pollen-specific IgE (P < .05) in the AD group. Moreover, a weak association was also found between IL-10 -819C/T and IL-10 -590A/C and the appearance of allergic rhinitis (P < 0.1). CONCLUSIONS: We confirmed a clinical shift in allergic phenotype in the first 3 years of life, and showed an association between IL-4, IL-6, and IL-10 polymorphisms and AD. Our data indicate that IL-4alpha and IL-10 polymorphisms may be considered predictive factors of respiratory allergy in children with AD.

Selective increase in blood dendritic cell antigen-3-positive dendritic cells in bronchoalveolar lavage fluid in allergic patients.

Dendritic cells (DCs) are specific antigen-presenting cells that play critical roles in the initiation and polarization of immune responses. DCs residing in the lungs might be detected in the bronchoalveolar lavage fluid (BALF). We analysed DC compartment in the peripheral blood and BALF of patients with allergy and in controls. Plasmacytoid and four distinct subsets of myeloid DCs [characterized by the expression of blood dendritic cell antigen (BDCA)-1+ and -3+ and CD16 positivity or negativity] were detected in both tested compartments. We further evaluated the expression of C-type lectins [mannose receptor (MR), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and dendritic and epithelial cells (DEC)-205] relevant to the pathogenesis of asthma. Interestingly, we found a selective increase in the frequency of myeloid DC-expressing BDCA-3 and MR particularly in BALF from allergic patients. Specific and highly statistically significant increase in BDCA-3+ and/or MR+ DCs brings a novel characteristic to BAL analysis in allergic patients.

Expansion of T helper type 17 lymphocytes in patients with chronic granulomatous disease.

Hyper-immunoglobulin (Ig)E syndrome (HIES) is a primary immunodeficiency associated with mutations in STAT3 resulting in impaired development of T helper type 17 (Th17) lymphocytes. HIES patients with a reduced frequency of Th17 cells present with infections caused by Staphylococcus aureus and/or Candida strains. The same spectrum of pathogens is present in patients with chronic granulomatous disease (CGD).We analysed the characteristics of the Th17 compartment in HIES and CGD. HIES patients showed very low numbers of Th17 cells. By contrast, the frequency of Th17 cells and production of Th17-derived cytokines was significantly higher among CGD patients when compared to both control samples and HIES. Naive CD4(+) cells in CGD patients had a normal capacity to differentiate into IL-17-producing cells and the numbers of Th17 cells in the CGD patients normalized following successful bone marrow transplantation. Our findings complement recent data on the importance of Th17 cells for elimination of infections with C. albicans and S. aureus.

[Schnitzler syndrome: diagnostics and treatment]. / Schnitzler-syndrom: diagnostika a lécba.

BACKGROUNDS: The most important diagnostic criteria for Schnitzler syndrome include chronic urticaria, the presence of monoclonal IgM immunoglobulin, marked inflammation (leukocytosis, elevated CRP and erythrocyte sedimentation rate), subfebrile temperatures or fevers and bone and joint pains. It is a rare idiopathic disease that may lead to potentially life-threatening complications such as development of secondary amyloidosis or transformation into malignant lymphoproliferation. Schnitzler syndrome should be included in differential diagnostics of chronic urticaria and fevers of unknown origin. The diagnostic algorithm is based on clinical presentation and serum and urine electrophoreses to detect monoclonal components. Blockade of interleukin-1 (IL-1), key cytokine in the pathogenesis of the disease, dominates current therapeutic protocols. Anakinra (Kineret), recombinant human IL-1 receptor antagonist, is the most widely used treatment option. According to literature, disease remission was obtained in all treated patients. Therefore, anakinra represents a significant diagnostic possibility to differentiate Schnitzler syndrome from e.g. monoclonal gammopathy of unknown significance (MGUS) associated with urticaria of different aetiology. Biological therapy with rilonacept (Arcalyst) and canakinumab (Ilaris) represents a new treatment alternative for patients, allowing prolonged dosing intervals of 1 and 8 weeks, respectively (compared to 24 hours with anakinra). The review article also presents findings of various imaging methods (conventional radiography, computed tomography, traditional bone scintigraphy) and photographs of patients with Schnitzler syndrome before and after anakinra therapy. DESIGN: The aim of the review is to draw attention to the existence of this rare autoinflammatory and potentially premalignant condition, present a simple diagnostic algorithm and provide an overview of therapeutic options for the patients. CONCLUSIONS: Malign potential of Schnitzler syndrome, possible development into systemic amyloidosis and the fact that patients are frequently referred to oncology clinics for differential diagnostics of monoclonal gammopathy, are the main reasons why clinical oncologists should be aware of Schnitzler syndrome.

Molecular phylogeographic analyses of the loach Oxynoemacheilus bureschi reveal post-glacial range extensions across the Balkans.

Rivers on the Balkan Peninsula can be separated into ichthyofaunistic areas with different endemic fish species. The Vardar River contains a particularly large number of endemics, indicating its complete and long-term isolation from neighbouring river systems. One of the few species shared with other rivers is the loach species Oxynoemacheilus bureschi. In this study, the genetic analyses of 175 individuals of O. bureschi from 17 sites, covering the entire distribution of the species, including the Rivers Vardar (= Axios), Struma (= Strymon), Mesta (= Nestos) and Danube, were performed using one mitochondrial and one nuclear marker. Genetic differentiation among populations was in general low. Shared haplotypes were common and occurred even between distant localities and different river systems. This points to a high degree of gene flow among populations and rejects the hypothesis that the population in the Vardar River represents a relict from an early colonization of the Balkan Peninsula. In contrast, the results suggest that populations in the Vardar River, as well as those in the Danube River, are of recent origin, and a human-mediated introduction cannot be excluded. On the other hand, the populations in the Aggitis River, a left tributary of the lower Struma River, were clearly separated from the rest of the species and represent a long-term isolated lineage. Demographic analyses suggest a recent population expansion for O. bureschi, in which the population in the Aggitis River was not involved.

Serum immunoglobulin free light chains in severe forms of atopic dermatitis.

An increase in immunoglobulin free light chains (FLC) was recently described in several pathological conditions, including asthma. FLC pathology is classically associated with monoclonal gammopathies. Its association with allergic disorders is surprising and unexplained. We therefore tested a cohort of children with severe atopic dermatitis (SCORAD 50-80) to determine the serum levels of free kappa and lambda chains, and correlated the results with clinical status and relevant laboratory markers. Seventy-three patients with severe forms of AD, all children from 3 months to 3 years of age and ninety healthy age-matched controls were included in the study. Light chains in sera were tested using the Freelite assay (Binding Site, Birmingham, UK). There were highly significant differences in both kappa (mean: 7.05 and 3.22 mg/l) and lambda (mean: 10.99 and 9.8 mg/l) serum levels between patients and controls, respectively (P < 0.0001). The kappa/lambda ratio in patients with allergy (mean: 0.64) was significantly higher than in controls (0.33) (P < 0.0001). We further observed significantly increased levels of FLC and their ratio in the group of patients with severe forms of AD in comparison to the group of patients with a resting stage of the disease or healthy controls (P < 0.05 and P < 0.0001, respectively). On the other hand, we could not confirm any association of FLC levels with age or total IgE levels. In conclusion, an increase in FLC reflects disease activity in children with severe atopic dermatitis. FLC might thus represent an additional diagnostic marker independent of total IgE levels.

Exposure to silica and risk of ANCA-associated vasculitis.

BACKGROUND: Exposure to silica dust is considered to be one of etiological factors of antineutrophil cytoplasmic antibodies (ANCA) -associated vasculitis (AAV). METHODS: Subjects exposed to silica dust in Central Bohemia and followed in the Department of Occupational Medicine, Charles University, were selected for study. A group of 86 men exposed to SiO2 for at least 5 years were examined. The association between occupational exposure to silica dust and ANCA positivity is analyzed. RESULTS: The subjects had a mean age of 66.7 years, and mean exposure to silica of 22.3 years. ANCA were detected significantly more frequently in patients group (17.1%; P-ANCA 18x, C-ANCA 3x) than in controls (n = 28, mean age 64.2 years, P-ANCA 1x, i.e., 3.6%). ANCA positivity was found less frequently (7.1%) in the group with history of SiO2 exposure without signs of pronounced silicosis, than in the group with simple (30.3%) or complicated silicosis (36.0%). Odds ratio for ANCA positivity and relative risk estimate in patients with silicosis were highly significant. Among possible predictor factors for ANCA positivity, silicosis and tuberculosis were relevant. No typical AAV was present among the patients. CONCLUSION: Long-term silica exposure may be one of the exogenous factors contributing to ANCA production, however, silica exposure alone, without typical silicosis, was not associated with ANCA positivity.

[Familial haemophagocytic lymphohistiocytosis caused by perforin deficit can be successfully treated by haematopoietic stem cell transplantation--the first diagnosed case in the Czech Republic]. / Familiární hemofagocytující lymfohistiocytóza na podklade deficitu perforinu uspesne lécená transplantací hematopoetických kmenových bunek--první diagnostikovaný prípad v Ceské republice.

Familial haemophagocytic lymphohistiocytosis (FHL) is an inherited disorder characterized by an impaired cytotoxicity of T lymphocytes and NK cells typically manifesting within first few months after birth. If not treated adequately, it is inevitably fatal within several months. The incidence in Caucasians has been estimated to 1: 50 000 births. Haematopoietic stem cell transplantation represents the only curative treatment for FHL. Recently, several genetic defects underlying molecular defects in FHL have been identified. In approximately 30% of patients FHL is caused by mutations in PRF1 gene coding for perforin. Further 30% of patients were found to have mutations in UNC13D coding for hMunc13-4 protein. Very recent report has identified another cause of FHL, mutations in STX11 gene on chromosome 6, coding for syntaxin 11. Absence of any of those proteins severely impairs the process of exocytosis of cytotoxic granules. We describe patient with clinical symptoms of FHL. Immunological and molecular biology methods led to the identification of perforin mutation as a cause of the disease. Patient received an allogeneic SCT from HLA-matched unrelated donor. SCT was followed by rapid normalization of clinical symptoms and laboratory findings. In patient described in this study, FHL manifested with typical clinical and laboratory symptoms. Adequate immunosuppressive treatment and subsequent SCT led to the sustained remission of FHL and correction of molecular defect. This is the first case of FHL in Czech Republic where perforin mutation was identified as a molecular cause both at cellular and molecular level.

[Prevalence of hepatitis G virus infection (HGV) in intravenous immunoglobulin recipients in the Czech Republic]. / Výskyt infekce virem hepatitidy G (HGV) u pacientu lécených intravenózními imunoglobuliny v Ceské republice.

The prevalence of hepatitis G virus (HGV) in the serum of intravenous immunoglobulin (IVIG) recipients was studied and risk related to HGV positivity was considered. Although its pathogenicity is unclear, HGV is likely to cause liver disease or lymphoproliferation. Twenty (23%) of 86 tested MG patients were HGV RNA positive. Of the HGV positive patients, three (15%) showed mild elevation of liver enzymes and one (5%) was diagnosed with chronic lymphatic leukaemia prior to the institution of MG replacement. It can be concluded that the HGV prevalence among IVIG recipients is high but is not associated with signs of either liver disease or lymphoproliferation.

[Primary biliary cirrhosis--specific anti-mitochondrial antibodies]. / Primární biliární cirhóza--specifické antimitochondriální protilátky.

UNLABELLED: Primary biliary cirrhosis is a chronic liver disease, characterized by the destruction of the epithelial cells of the sublobular, interlobular and septal bile ducts and with the development of cirrhosis. The presence of anti-mitochondrial antibodies against the subunits of mitochondrial 2-oxoacids dehydrogenases is characteristic for patients with primary biliary cirrhosis. The aim of this work was to study the effect of anti-mitochondrial antibodies upon activity of the isolated mitochondrial pyruvate dehydrogenase complex after the incubation with serum from patients with primary biliary cirrhosis. GROUP OF PATIENTS AND METHODS: The activity of the purified bovine pyruvate dehydrogenase complex was studied spectrophotometrically in presence of the serum (1: 1000) from five patients with primary biliary cirrhosis and from ten disease free controls. RESULTS: The activity of the pyruvate dehydrogenase was decreased after incubation with the serum from patients with primary biliary cirrhosis. No similar inhibitory effect was found after incubation with serum from controls. DISCUSSION: The inhibitory effect of the anti-mitochondrial antibodies upon activity of pyruvate dehydrogenase may broaden the spectrum of diagnostic methods in patients with primary biliary cirrhosis. Further investigations are necessary to assess the possible application of this method for monitoring of changes during the course of the disease and for assignation of the disease prognosis.

Antineutrophil cytoplasmic antibodies, anti-Saccharomyces cerevisiae antibodies, and specific IgE to food allergens in children with inflammatory bowel diseases.

Differential diagnosis between ulcerative colitis (UC) and Crohn's disease (CD) is difficult in the initial phases in pediatric patients with inflammatory bowel diseases (IBD). This study was performed to determine the significance of anti-neutrophil cytoplasmic antibodies (ANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) in IBD. ANCA were specified with regard to their antigenic specifity, significance to the diagnosis, and correlation of titer with the disease activity. The occurrence of food allergy was questioned, too. Serum samples from 44 children with UC (n = 23) or CD (n = 21) and from disease-control children (coeliac disease, n = 21) were analyzed for IgG ANCA, ANCA target antigens, IgA and IgG ASCA, and IgE to food allergens. Results show that ANCA occur more frequently in UC than in CD and disease-control (74, 24, and 10%, respectively). The presence of ANCA does not reflect disease activity. Antigenic specificity does not differ in any group. IgA-ASCA are found more often in patients with CD (76% versus 17% in UC). The testing for both ANCA and ASCA enabled clear-cut differential diagnosis between UC and CD based on the high specificity (ANCA+ ASCA- 92.5% for UC, ANCA- ASCA+ 93.2% for CD). Specific IgE to food allergens were found in 8.7, 14.3, and 23.8% of patients with UC, CD, and coeliac disease, respectively. We conclude that combined testing of ANCA and ASCA represents a valuable tool in the differential diagnosis between UC and CD in pediatric patients, minimizing invasive diagnostic procedures. Monitoring of ANCA, its specificity, and titer determination does not bring more information. Testing for specific IgE to food allergens may be considered in individual patients.

[Autoimmune enteropathy with onset in early infancy: clinico-morphologic and immunologic manifestations]. / Autoimunní enteropatie se zacátkem v casném kojeneckém veku: klinicko-morfologické a imunologické projevy.

This paper describes a severely affected male infant with serious protracted diarrhoea caused by a rare autoimmune enteropathy. The disease began at 6 weeks of age of the child and it was associated with small bowel villous atrophy and the presence of circulating antienterocyte antibodies. The child was treated with steroids and with parenteral and special enteral nutrition. The patient showed clinical improvement as documented by decreased stool output and possibility to terminate the parenteral nutrition. The small biopsy samples showed a return to normal. Antienterocyte antibodies were negative after the treatment. The patient has been followed up for at least 18 months and was in a clinical remission. We recommend that autoantibodies tests should be performed in all infants with unexplained protracted diarrhoea. The use of potent immunosuppressive drugs and the increasing experience with parenteral and enteral nutrition can improve the perspective of these previously fatal disorders.

Lung transplantation for cystic fibrosis: immune system and autoimmunity.

BACKGROUND: In the current study we focused on changes in the immune parameters of patients with CF after lung transplantation (Tx), with particular emphasis on the interaction of the immune system, infection, the autoimmune phenomenon observed in some CF patients, and immunosuppression. MATERIAL AND METHODS: Seven transplant patients with CF were investigated, 3 men and 4 women; the average age at Tx was 24.2 years (20.2-32.3). The parameters of both humoral immunity (immunoglobulins, complement, CRP, antinuclear and antineutrophil cytoplasmic antibodies) and cellular immunity (T and B lymphocytes, NK cells) were traced. RESULTS: We observed marked initial hyperimmunoglobulinemia, with a sharp drop in immunoglobulin levels within 1 month after Tx. Positivity for antineutrophil cytoplasmic antibodies (ANCA) was found in 3 patients before Tx. A strong ANCA positivity persisted 2 months after Tx despite deep introductory immunosuppression. In one patient ANCA positivity, after a transient negative result at months 2 and 12 after Tx, reappeared one year after Tx. The Burkholderia cepacia infections found in 2 patients proved to be lethal. CONCLUSIONS: In our series of CF lung transplant recipients, we found Burkholderia cepacia infection to be a risk factor. The robust appearance of autoantibodies and their persistent positivity for many months despite deep immunosuppression is a remarkable feature observed in some CF patients.