Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort.

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare and life-threatening condition characterized by recurrent localized edema. We conducted a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 families with C1-INH-HAE. Our workflow involved a combined strategy of sequencing extended to UTR and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays. This approach allowed us to detect a causal variant in all families except one and to identify a total of 56 different variants, including 5 novel variants that are likely to be causal. We further investigated the functional impact of two splicing variants, namely c.550 + 3A > C and c.686-7C > G using minigene assays and RT-PCR mRNA analysis. Notably, our cohort showed a considerably higher proportion of detected splicing variants compared to other central European populations and the LOVD database. Moreover, our findings revealed a significant association between HAE type 1 missense variants and a delayed HAE onset when compared to null variants. We also observed a significant correlation between the presence of the SERPING1 variant c.-21 T > C in the trans position to causal variants and the frequency of attacks per year, disease onset, as well as Clinical severity score. Overall, our study provides new insights into the genetic landscape of C1-INH-HAE in the Czech population, including the identification of novel variants and a better understanding of genotype-phenotype correlations. Our findings also highlight the importance of comprehensive screening strategies and functional analyses in improving the C1-INH-HAE diagnosis and management.

Myeloid lineage cells evince distinct steady-state level of certain gene groups in dependence on hereditary angioedema severity.

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.

The role of interleukin 6 in the pathogenesis and therapy of Castleman disease - an immunologist's perspective.

Castleman disease (CD) is a heterogeneous group of diseases characterized by lymphadenopathy and systemic inflammatory manifestations. CD can be divided into uni- (UCD) and multicentric form (MCD) according to the disease extent. MCD is usually accompanied by the features of a systemic inflammatory response including fever, weight loss, hepatosplenomegaly, ascites, and edema. In these patients, we can also observe elevation of inflammatory parameters and anemia within the laboratory assessment. Based on etiological nature, the CD can be further divided into human herpesvirus-8-associated (HHV8-associated) and idiopathic form. Interleukin 6 (IL-6) plays a central role in the disease pathogenesis. Inhibition of IL-6 has been shown to be an effective treatment modality. Currently, siltuximab, a chimeric monoclonal antibody targeting IL-6, is the only approved treatment for MCD. Its short-term and long-term efficacy and safety have been demonstrated in a few clinical studies.

Risk Factors for Severe COVID-19 and Hospital Admission in Patients With Inborn Errors of Immunity - Results From a Multicenter Nationwide Study.

Despite the progress in the understanding how COVID-19 infection may impact immunocompromised patients, the data on inborn errors of immunity (IEI) remain limited and ambiguous. Therefore, we examined the risk of severe infection course and hospital admission in a large cohort of patients with IEI. In this multicenter nationwide retrospective survey-based trial, the demographic, clinical, and laboratory data were collected by investigating physicians from 8 national referral centers for the diagnosis and treatment of IEI using a COVID-19-IEI clinical questionnaire. In total, 81 patients with IEI (including 16 with hereditary angioedema, HAE) and confirmed SARS-CoV-2 infection were enrolled, and were found to have a 2.3-times increased (95%CI: 1.44-3.53) risk ratio for hospital admission and a higher mortality ratio (2.4% vs. 1.7% in the general population). COVID-19 severity was associated with the presence of clinically relevant comorbidities, lymphopenia, and hypogammaglobulinemia, but not with age or BMI. No individuals with HAE developed severe disease, despite a hypothesized increased risk due to perturbed bradykinin metabolism. We also demonstrated a high seroconversion rate in antibody-deficient patients and the safety of anti-spike SARS CoV-2 monoclonal antibodies and convalescent plasma. Thus, IEI except for HAE, represent significant risk factors for a severe COVID-19. Therefore, apart from general risk factors, immune system dysregulation may also be involved in the poor outcomes of COVID-19. Despite the study limitations, our results support the findings from previously published trials.

Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients.

INTRODUCTION: Acquired angioedema with C1 inhibitor deficiency (AAE-C1-INH) is rare but a potentially life-threatening disease. There are no official prevalence data, nor approved therapies for this condition. OBJECTIVE: In this study, we aimed to collect and analyze clinical data on patients with AAE-C1-INH in the Czech Republic. METHODS: We have conducted a retrospective analysis of AAE-C1-INH patients from Czech referral centers for the treatment of hereditary angioedema with C1 inhibitor deficiency. The inclusion criteria involved recurrent episodes of angioedema with the first manifestation at or after the age of 40, negative family history of angioedema, and C1 inhibitor function 50% or less. RESULTS: A total of 14 patients (7 males and 7 females) met the inclusion criteria for AAE-C1-INH. The median age of the symptom onset was 59.5 years, and the median diagnosis delay was 1 year. The most common clinical manifestation was facial edema (100%) and upper airway swelling (85.7%). All patients responded to the acute attack treatment with icatibant and plasma-derived or recombinant C1 inhibitor concentrate. Lymphoid malignancy was identified in 9 patients (64%), monoclonal gammopathy of uncertain significance in 3 (21%), and in 1 patient autoimmune disease (ulcerative colitis) was considered causative (7%). We were not able to identify any underlying disease only in 1 patient (7%). In 6 of 7 patients (86%) treated for lymphoma, either a reduction in the frequency of angioedema attacks or both angioedema symptoms' disappearance and complement parameter normalization was observed. CONCLUSIONS: The prevalence of AAE-C1-INH in the Czech Republic is about 1:760,000. This rare condition occurs in approximately 8% of the patients with angioedema with C1 inhibitor deficiency. AAE-C1-INH is strongly associated with lymphoproliferative disorders, and treating these conditions may improve the control of angioedema symptoms.

Complement deficiencies.

Complement system plays a crucial role in innate imunity. Complement deficiencies are often associated with severe infections, usually meningoccocal, pneumococcal or caused by Haemophilus influenzae, or with autoimmune diseases, especially systemic lupus erythematodes. Inherited complement deficiencies are very rare although their prevalence in population may be underestimated due to lower availability of adequate laboratory testing. Acquired complement deficiencies accompany other underlying diseases and often are caused by increased consumption and only partial.

Current trends in immunosuppressive treatment.

Immunosuppressive agents represent a class of drugs that inhibits activity of the immune system. They are mostly used in autoimmune diseases and other inflammatory conditions treatment and in prevention of recipient´s immune response to donors antigens in transplantations. There is a broad spectrum of different immunosuppressive drugs with various mechanisms of action. This article provides an overview of drugs currently registered as immunosuppressive agents in the Czech Republic and provides some insights what we might expect regarding this group of drugs in the future.

Angiotensin-converting enzyme inhibitor-induced angioedema: epidemiology, pathogenesis and management.

Angiotensin-converting enzyme-induced angioedema occurs in 0.1-0.7 % of recipients. Swelling often affects head and neck and makes it an extremely dangerous adverse effect. Bradykinin is considered to be the main mediator of edema in these cases. There is currently no specific treatment for angioedema of this etiology. Drugs used for treatment of attacks in hereditary angioedema with C1 inhibitor deficiency are tried also in this indication, but there are currently no clinical studies available supporting their effectiveness. Patients using angiotensin-converting enzyme inhibitors with angioedemas of unknown etiology must discontinue using this drug. Swelling episodes may appear even after this arrangement. Key words: angioedema - angiotensin-converting enzyme inhibitors - bradykinin.