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Hereditary angioedema (HAE) is a rare genetic disorder with variable expressivity even in carriers of the same underlying genetic defect, suggesting other genetic and epigenetic factors participate in modifying HAE severity. Recent knowledge indicates the role of immune cells in several aspects of HAE pathogenesis, which makes monocytes and macrophages candidates to mediate these effects. Here we combined a search for HAE phenotype modifying gene variants with the characterization of selected genes' mRNA levels in monocyte and macrophages in a symptom-free period. While no such gene variant was found to be associated with a more severe or milder disease, patients revealed a higher number of dysregulated genes and their expression profile was significantly altered, which was typically manifested by changes in individual gene expression or by strengthened or weakened relations in mutually co-expressed gene groups, depending on HAE severity. SERPING1 showed decreased expression in HAE-C1INH patients, but this effect was significant only in patients carrying mutations supposedly activating nonsense-mediated decay. Pro-inflammatory CXC chemokine superfamily members CXCL8, 10 and 11 were downregulated, while other genes such as FCGR1A , or long non-coding RNA NEAT1 were upregulated in patients. Co-expression within some gene groups (such as an NF-kappaB function related group) was strengthened in patients with a severe and/or mild course compared to controls. All these findings show that transcript levels in myeloid cells achieve different activation or depression levels in HAE-C1INH patients than in healthy controls and/or based on disease severity and could participate in determining the HAE phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ballonová, Souček, Slanina, Réblová, Zapletal, Vlková, Hakl, Bíly, Grombiříková, Svobodová, Kulíšková, Štíchová, Sobotková, Zachová, Hanzlíková, Vachová, Králíčková, Krčmová, Jeseňák and Freiberger.)

The existence of eosinophils was documented histopathologically in the first half of the 19th century. However, the term "eosinophils" was first used by Paul Ehrlich in 1878. Since their discovery and description, their existence has been associated with asthma, allergies, and antihelminthic immunity. Eosinophils may also be responsible for various possible tissue pathologies in many eosinophil-associated diseases. Since the beginning of the 21st century, the understanding of the nature of this cell population has undergone a fundamental reassessment, and in 2010, J. J. Lee proposed the concept of "LIAR" (Local Immunity And/or Remodeling/Repair), underlining the extensive immunoregulatory functions of eosinophils in the context of health and disease. It soon became apparent that mature eosinophils (in line with previous morphological studies) are not structurally, functionally, or immunologically homogeneous cell populations. On the contrary, these cells form subtypes characterized by their further development, immunophenotype, sensitivity to growth factors, localization, role and fate in tissues, and contribution to the pathogenesis of various diseases, including asthma. The eosinophil subsets were recently characterized as resident (rEos) and inflammatory (iEos) eosinophils. During the last 20 years, the biological therapy of eosinophil diseases, including asthma, has been significantly revolutionized. Treatment management has been improved through the enhancement of treatment effectiveness and a decrease in the adverse events associated with the formerly ultimately used systemic corticosteroids. However, as we observed from real-life data, the global treatment efficacy is still far from optimal. A fundamental condition, "sine qua non", for correct treatment management is a thorough evaluation of the inflammatory phenotype of the disease. We believe that a better understanding of eosinophils would lead to more precise diagnostics and classification of asthma subtypes, which could further improve treatment outcomes. The currently validated asthma biomarkers (eosinophil count, production of NO in exhaled breath, and IgE synthesis) are insufficient to unveil super-responders among all severe asthma patients and thus give only a blurred picture of the adepts for treatment. We propose an emerging approach consisting of a more precise characterization of pathogenic eosinophils in terms of the definition of their functional status or subset affiliation by flow cytometry. We believe that the effort to find new eosinophil-associated biomarkers and their rational use in treatment algorithms may ameliorate the response rate to biological therapy in patients with severe asthma.

Currently, the approach to a patient with asthma is in accordance with personalized medicine wherein the decision on the treatment pathway is based on the type of asthmatic inflammation and other comorbidities that accompany asthma. For an allergic asthma patient, allergen immunotherapy (AIT), which has a disease-modifying effect and the potential to prevent further progression of allergic symptoms, is one of the treatment modalities. It is an effective treatment that, unlike pharmacotherapy, modifies the course of allergic respiratory diseases and induces allergen specific immune tolerance that persists for up to several years after treatment cessation. Therapeutic allergens of high quality, efficacy, and safety according to European regulatory authorities are an integral part of the treatment of respiratory allergies. It is a safe treatment option which still remains the only causal immuno¬modulatory therapy for allergic eosinophilic asthma.

Background: Omalizumab is an efficient drug for patients with uncontrolled severe allergic asthma (SAA). However, little is known about the differences in omalizumab treatment outcomes among patients with different types of atopic sensitization. Here, we assessed the effect of sensitization to individual allergens or their combinations on the outcomes of anti-IgE therapy in patients with SAA., Methods: We performed a post hoc analysis of data of subgroups of patients enrolled in the Czech Anti-IgE Registry (CAR). The patients were evaluated at baseline and 16 weeks and 12 months after omalizumab treatment initiation. We analyzed the dependence of primary treatment outcomes [global evaluation of treatment effectiveness (GETE) after 16 weeks of treatment, a reduction in severe exacerbation rate (ER), and an improvement in the asthma control test (ACT) result during 12 months of treatment] and secondary outcomes [a reduction in systemic corticosteroid (SCS) use, an improvement in lung functions, and a fraction of exhaled nitric oxide] of patients with SAA treated with omalizumab for 12 months on sensitization to different perennial aeroallergens. We assessed sensitization to house dust mites, molds, and pets at baseline using skin prick tests and/or specific IgE measurement (semiquantitative evaluation). We compared polysensitized patients (sensitized to all tested allergens) with monosensitized (single positivity) or partially polysensitized patients (combined positivity but not to all allergens)., Results: We enrolled 279 patients (58.3% women, mean age 52.9 years). Omalizumab treatment presented an 82.8% response rate (according to GETE). It significantly reduced severe asthma exacerbations and SCS use, and improved the ACT result in 161 responders. We identified a subgroup of responders with distinct sensitization patterns (polysensitization to all tested perennial allergens) with higher odds of being responders (OR = 2.217, p = 0.02) and lower tendency to improve ACT result (OR 0.398, p = 0.023) and reduce ER (OR 0.431, p = 0.034) than non-polysensitized patients., Conclusions: The clinical benefit of sensitization for patients with SAA receiving omalizumab may be particularly dependent on sensitization pattern. Polysensitized patients showed a higher tendency to be responders (GETE), but a lower tendency to improve the ACT result and reduce ER than non-polysensitized patients., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Introduction: The serum periostin level is a promising biomarker of type 2- high inflammation pattern of bronchial asthma. It has been proven that serum periostin levels decrease in response to systemic and inhaled corticosteroid (ICS) therapy. However, we have only limited knowledge about changes in serum periostin levels reflecting omalizumab (OMA) treatment and other variables, such as chronic rhinosinusitis with nasal polyps (CRSwNP)., Aim: To critically appraise clinically relevant parameters influencing periostin levels in asthma patients., Material and Methods: A pilot, cross-sectional, observational study to assess serum periostin levels of 48 asthma patients (38 treated by conventional therapy comprising ICS and 10 treated by ICS and OMA as an add-on therapy) with respect to asthma clinical traits, comorbidities and to other biomarkers of type 2-high asthma phenotype (total IgE, absolute and relative eosinophil count, eosinophilic cationic protein (ECP) and a fraction of exhaled NO (FeNO))., Results: Serum periostin correlates with total IgE levels (Spearman rho = 0.364, p = 0.025) in a subgroup of conventionally treated patients, and with eosinophil count (Spearman rho = 0.401, p = 0.021) in a subgroup of patients with concurrent CRSwNP. Serum periostin levels were decreased in omalizumab-treated patients in comparison to conventionally treated patients ( p = 0.025). This effect was remarkably apparent only if CRSwNP was not present ( p = 0.005). Conversely, we measured elevated periostin levels in OMA-treated patients with concurrent CRSwNP ( p = 0.017)., Conclusions: Serum periostin production is significantly associated with treatment modality (omalizumab vs. conventional) and presence of CRSwNP. These variables need to be taken into account to interpret periostin levels accurately., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2020 Termedia Sp. z o. o.)

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease. The progression from AD to bronchial asthma (AB) and allergic rhinitis (AR) is called atopic march. The aim of this study was to evaluate the difference in the sensitization to molecular components in patients suffering from AD in relation to subgroups of patients with AR and AB., Material and Methods: The complete dermatological and allergological examinations were performed. Specific IgE antibodies against 112 molecular components were measured with the multiplex ImmnoCAP ISAC test., Results: Altogether 104 atopic dermatitis patients (50 men, 54 women) at the average age 40.1 years were examined. The sensitization to molecular components was confirmed in 93.3% of patients. The sensitization to components of mites, grasses, trees, animals, moulds, and shrimps was significantly more frequent in patients with severe form of AD and the sensitization to components of grasses, trees, and moulds was significantly higher in subgroup of patients with AB. In subgroup of patients suffering from AR the higher occurrence of pollen-derived and pollen-food derived PR-10 proteins, grasses, mites, and animals was observed also., Conclusions: We have confirmed the significant differences in the sensitization to molecular components in patients suffering from severe form of AD, and in subgroups of patients suffering from AB and AR. These molecular components may play the important role in the consecutive development of different allergy pathologies called atopic march.

Anaphylactic symptoms and anaphylactic shock are serious, rapidly developing and potentially fatal systemic reactions occurring after contact with the trigger, followed by release of a number of substances that affect vascular permeability, smooth muscle tone of blood vessels and bronchi with activation of the systemic inflammatory cascade. From a pathophysiological point of view, it can be an IgE-mediated immune response followed by massive release of biologically active mediators from mast cells and basophils (IgE dependent). If the mastocyt/basophil is degranulated via a direct IgE-free pathway, it is non-allergic (non-IgE dependent, anaphylactoid anaphylaxis). The diagnosis of anaphylaxis is determined on the basis of clinical criteria, taking into account the need to initiate therapy in a life-threatening condition without delay. Adrenaline is the first-line drug in the treatment of anaphylaxis and there is no contraindication to its use. Early provision of venous intake is essential for the patient to develop hypotension.

Purpose: Omalizumab has demonstrated clinical efficacy in severe allergic asthma by reducing exacerbation rates and increasing quality of life. However, data concerning its sustained effect after treatment discontinuation are still needed., Methods: This analysis was an observational pilot study (simple within-subjects design) of 12 patients experiencing severe asthma, treated with omalizumab, for 1 year after treatment discontinuation. We prospectively analyzed clinical measurements (pulmonary functions, inhaled corticosteroid [ICS] doses, Asthma Control Test [ACT] scores, skin prick test [SPT] positivity, fraction of exhaled nitric oxide, and exacerbation rates) and laboratory test results (eosinophils and total immunoglobulin E levels) at the time of discontinuation and 6 and 12 months thereafter. Baseline data (before the treatment period; range, 11-61 months) were collected retrospectively. The treatment effect until discontinuation was calculated. To determine its persistence, repeated measures were compared with baseline levels and analyzed by using a general linear model for repeated measures or the Friedman ANOVA, and χ 2 tests in case of normality assumption violation or frequencies. Post hoc analysis was applied by using a simple or repeated contrasts analysis or Wilcoxon signed rank test with Bonferroni correction., Findings: We proved a significant reduction in ICS doses and SPT reactivity and an increase in ACT score during the retrospective treatment phase. Moreover, persistence of these statistically significant effects was recorded 6 months after treatment discontinuation. ACT score and ICS doses (but not SPT reactivity) remained improved for 12 months after discontinuation of omalizumab treatment., Implications: Omalizumab treatment exhibited sustained treatment benefit after its discontinuation for patients experiencing severe allergic asthma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Hereditary angioedema (HAE) is a rare disease caused by a C1 inhibitor (C1-INH) deficit. Clinically, HAE is manifested by repeated episodes of localized subcutaneous or submucosal oedema attacks. Managing HAE patients in pregnancy is challenging, since there are only limited data on the safety and efficacy of various therapeutic approaches., Methods: We present our clinical experience treating acute HAE attacks during pregnancy in six consecutive patients., Results: During the pregnancies, 79 HAE attacks occurred. The most frequent were abdominal 53 (67.1%) followed by peripheral 21 (26.6%), facial 10 (12.7%), and laryngeal 10 (12.7%) oedemas; 13 (16.5%) attacks were combined. Fifty (63.3%) attacks were treated with recombinant human C1-INH (rhC1-INH); 17 (21.5%) with plasma-derived, pasteurized, nanofiltered C1-INH (pnfC1-INH); 13 (16.5%) with icatibant; and 1 (1.3%) with plasma-derived, nanofiltered C1-INH (nfC1-INH). Treatment had to be repeated in 5 attacks (6.3%). All six deliveries (one caesarean section and five spontaneous vaginal deliveries) were complication free. All pregnancies went to the full term and the patients delivered healthy babies with a birth weight ranging from 2850 to 3690 g. No congenital abnormalities were detected in the neonates. No abortions occurred., Conclusions: Our results show good C1-INH or icatibant treatment efficacy for HAE attacks in pregnancy. The treatment by the first drug used was effective in 93.7% of all attacks. In 6.3% of attacks, a second treatment had to be used. No adverse effects were observed.

Successful rituximab treatment of granulomatous/lymphocytic interstitial lung disease in common variable immunodeficiency Common variable immunodeficiency, a heterogeneous group of diseases, represents a clinically relevant form of antibody immunodeficiency. Granulomatous/lymphocytic interstitial lung disease is among the most serious complications. A case report is presented of a young women with granulomatous/lymphocytic interstitial lung disease and splenomegaly accompanied by pancytopenia. Intravenous rituximab treatment in monotherapy (at a weekly dose of 375 mg/m2 for four consecutive weeks, repeated six months later) not only led to a significant improvement in clinical symptoms but also to positive morphological and functional lung changes, mitigation of pancytopenia, considerable reduction of alkaline phosphatase level, and disappearance of splenic granulomas. The treatment was well tolerated without any side effects. The case report presented suggests possible efficacy and safety of rituximab monotherapy in patients with a complicated form of common variable immunodeficiency. KEYWORDS Rituximab - antibody immunodeficiency - lung disease - treatment Epidemiol. Mikrobiol. Imunol., 67, 2018, č. 3, s. 142-148.

Complement deficiency represents 5% of primary immunodeficiencies worldwide. A total of seven patients with deficiencies of the classical complement pathway were reported in the Czech Republic by the end of 2015. Typical manifestations of complement deficiency are recurrent meningitis, other bacterial infections, autoimmunity and kidney disease.Two case reports are presented of patients with molecularly confirmed C7 (compound heterozygote, c.663_644del in exon 6 and c.2350+2T:>C in intron 16) and C8 (homozygous c.1282C>T in exon 9) deficiency. The first patient had four attacks of meningococcal meningitis and an episode of pneumonia of unknown aetiology in childhood. The second had six attacks of meningitis. He also suffered from recurrent infections (otitis media, tonsillitis, chronic mucopurulent rhinitis and subsequent pansinusitis complicated by nasal polyposis) since childhood. No autoimmune disease was documented in either patient. They both received meningococcal and pneumococcal vaccines. Antibiotic prophylaxis was used only in the second patient, leading to a decline in the number of ENT infections.Complement deficiency should be suspected in patients with recurrent meningococcal infections, especially if combined with other infections caused by encapsulated bacteria or autoimmunity diseases. Prophylaxis with conjugate polysaccharide vaccines is recommended and antibiotic prophylaxis should be considered in individual cases.

Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune multisystem disease. The aim of our study was to clarify the frequency of decreased serum immunoglobulin levels in SLE patients. There were evaluated 799 results of serum immunoglobulin levels gained from 157 patients fulfilling revised ACR criteria in the retrospective study., Results: The immunoglobulin levels under the normal range were found in 29/157 (18.5 %) patients. The most frequent was isolated reduction of IgG 12/157 (7.6 %), two persons fulfilled criteria for selective IgA deficiency, and one case possible diagnosis of common variable immunodeficiency (CVID). Additionally we report two cases of SLE patients complicated by severe hypogammaglobulinaemia and infectious complications with necessity of long-term immunoglobulin substitution therapy. The diagnosis of CVID is highly probable in the first case. The second case presents sever drug-induced hypogammaglobulinaemia. This female with lymphoma history and multiorgan impairment due to acute SLE was treated with rituximab after convention therapy failure., Conclusion: Humoral immunodeficiency may occur in SLE patients. The monitoring of serum immunoglobulin levels could be a routine in these patients. The CVID diagnosis is possible in patients suffering from recurrent sinopulmonary infections, especially in combination with absence of lupus activity. Rituximab therapy could cause long-term suppression of B lymphocytes with secondary humoral deficiency requiring immunoglobulin substitution therapy.

Cell death is still a matter of debate and scientific opinions have been challenged and are not uniform due to complexity of this issue. Recent research has brought some new evidence about the very subtle border between programmed cell death and necrosis. The concept of their mutual independence, broadly accepted for decades, is now significantly challenged. Lack of unified terminology led to the establishment of the Nomenclature Committee on Cell Death (NCCD) which provides recommendations for clear definition of distinct cell death programs. It also appeals for consistent application of this nomenclature in scientific literature. In this work, some keystone knowledge addressing three specific programmed cell death types - apoptosis, autophagic cell death, and pyroptosis which is recognized as a controversial cell death scenario on the border between programmed cell death and necrosis, is reviewed. These cell death scenarios are discussed in the context of pathogenesis of infectious diseases.

Intracellular parasitism is a phenomenon present in nature for more than one billion years. Its keystone is the intriguing ability of viruses and some bacteria to survive and multiply inside eukaryotic host cells and to parasitize on their metabolic machinery. According to the classical definition, germs are classified as intracellular parasites only if they are able to survive inside macrophages. However, the ability of germs to survive inside eukaryotic cells is much more common than it was expected earlier. Reaction of macrophages to invading microbes is the key point in the complex immunological resistance of the host. The outcome of the host is substantially linked to macrophage reactivity. For example, if an evading microbe with a replication time of 20 minutes survived inside a host for 24 hours without reaction of innate immunity, there would be more than 2 x 1021 microbes at the end of this period. It would be fatal for the host, indeed. The key activities of macrophages in the sense of protection against intracellular parasites are reviewed. Some mechanisms of microbial defence and some new approaches to clinical diagnosis of the functional status of cells of innate immunity are also discussed.