Successful rituximab treatment of granulomatous/lymphocytic interstitial lung disease in common variable immunodeficiency.

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, c. 3, s. 142-148.

Sequence variants of the TNFRSF13B gene in Czech CVID and IgAD patients in the context of other populations.

Mutations in the TNFRSF13B gene, encoding TACI, have been found in common variable immunodeficiency (CVID) and selective IgA deficient (IgAD) patients, but only the association with CVID seems to be significant. In this study, Czech CVID, IgAD and primary hypo/dysgammaglobulinemic (HG/DG) patients were screened for all TNFRSF13B sequence variants. The TNFRSF13B gene was mutated in 4/70 CVID patients (5.7%), 9/161 IgAD patients (5.6%), 1/17 HG/DG patient (5.9%) and none of 195 controls. Eight different mutations were detected, including the most frequent p.C104R and p.A181E mutations as well as 1 novel missense mutation, p.R189K. A significant association of TNFRSF13B gene mutations was observed in both CVID (p=0.01) and IgAD (p=0.002) Czech patients. However, when combined with all published data, only the association with CVID remained significant compared with the controls (9.9% vs. 3.2%, p<10(-6)), while statistical significance disappeared for IgAD (5.7% vs. 3.2%, p=0.145). The silent mutation p.P97P was shown to be associated significantly with CVID compared with the controls in both Czech patients (allele frequency 4.3% vs. 0.2%, p=0.01) and in connection with the published data (5.1% vs. 1.8%, p=0.003). The relevance of some TNFRSF13B gene variants remains unclear and needs to be elucidated in future studies.

No evidence for linkage between the hereditary angiooedema clinical phenotype and the BDKR1, BDKR2, ACE or MBL2 gene.

Hereditary angiooedema (HAE) is a life-threatening disease with poor clinical phenotype correlation with its causal mutation in the C1 inhibitor (SERPING1) gene. It is characterized by substantial symptom variability even in affected members of the same family. Therefore, it is likely that genetic factors outside the SERPING1 gene have an influence on disease manifestation. In this study, functional polymorphisms in genes with a possible disease-modifying effect, B1 and B2 bradykinin receptors (BDKR1, BDKR2), angiotensin-converting enzyme (ACE) and mannose-binding lectin (MBL2), were analysed in 36 unrelated HAE patients. The same analysis was carried out in 69 HAE patients regardless of their familial relationship. No significant influence of the studied polymorphisms in the BDKR1, BDKR2, ACE and MBL2 genes on overall disease severity, localization and severity of particular attacks, frequency of oedema episodes or age of disease onset was detected in either group of patients. Other genetic and/or environmental factors should be considered to be responsible for HAE clinical variability in Caucasians.

Association of FcRn expression with lung abnormalities and IVIG catabolism in patients with common variable immunodeficiency.

The neonatal Fc receptor (FcRn) acts as a key regulator of IgG homeostasis and is an important sensor of luminal infection. We analyzed the influence of FcRn expression on disease phenotype and the catabolism of therapeutically administered intravenous immunoglobulins (IVIG) in 28 patients with common variable immunodeficiency (CVID). Patients with generalized bronchiectasis and fibrosis had lower levels of FCRN mRNA compared to patients without these complications (P=0.027 and P=0.041, respectively). Moreover, FCRN mRNA levels correlated negatively with the extent of bronchiectasis and the rate of IgG decline after infusion of IVIG (P=0.027 and P=0.045, respectively). No relationship of FCRN expression with age at disease onset, age at diagnosis, diagnostic delay, IgG levels or frequency of infections before or during replacement immunoglobulin treatment, the presence of lung functional abnormalities, chronic diarrhea, granulomas, lymphadenopathy, splenomegaly or autoimmune phenomena was observed. Our results showed that FcRn might play a role in the development of lung structural abnormalities and in the catabolism of IVIG in patients with CVID.

No association of FCRN promoter VNTR polymorphism with the rate of maternal-fetal IgG transfer.

The neonatal Fc receptor (FcRn) plays a critical role in maternal-fetal IgG transfer. Recently, a functionally active promoter polymorphism in the FCRN gene, represented by variable number of tandem repeats (VNTR), has been described. We analysed 103 single fetal samples and 103 paired maternal and fetal samples collected from umbilical cord blood of full-term neonates born from the 38th to the 41st week of pregnancy and detected no significant influence of maternal FCRN VNTR genotype on maternal IgG levels or of fetal FCRN VNTR genotype on fetal IgG levels or the fetal/maternal IgG ratio.

Analysis of transactivation capability and conformation of p53 temperature-dependent mutants and their reactivation by amifostine in yeast.

The p53 gene is often mutated during cancer development. Frequency and functional consequences of these mutations vary in different tumor types. We analysed conformation and temperature dependency of 23 partially inactivating temperature-dependent (td) p53 mutants derived from various human tumors in yeast. We found considerable differences in transactivation capabilities and discriminative character of various p53 mutants. No correlations in transactivation rates and conformations of the td p53 proteins were detected. Amifostine-induced p53 reactivation occurred only in 13 of 23 td mutants, and this effect was temperature dependent and responsive element specific. The most of the p53 mutations (10/13) reactivated by amifostine were located in the part of the p53 gene coding for hydrophobic beta-sandwich structure of the DNA-binding domain.

[Comparison of various methods of correction of QT intervals during exercise in familial long QT interval syndrome]. / Srovnání ruzných metod korekce QT intervalu pri zátezi v rodinách se syndromem dlouhého QT intervalu.

BACKGROUND: Pathologic prolongation of QT interval is related to increased risk of arrhythmias. Changes of this parameter are influenced by many conditions, the most important is heart rate. Several formulas have been proposed for mathematical description of QT interval/heart rate relationship. The aim of this study was comparison of different QT interval correction formulas in families with congenital long QT syndrome (LQTS). METHODS: In 28 members of 6 families with LQTS occurrence bicycle ergometry testings were performed. QT and RR intervals were measured before exercise, at peak exercise and in the 1st and the 6th minute of restitution. For QT interval correction single-parameter formulas by Bazett, Fridericia, Malik and Framingham study were used. In 3 families the results could be correlated with genetically proved diagnosis (KCNQ1 gene mutations in 2 families, HERG-KCNH2 gene mutation in the other). RESULTS: In the described group the genetically established diagnosis of LQTS correlated at best with values obtained with correction by Bazett. All the mutation carriers were correctly identified only by this method. The Fridericia, Malik and Framingham formulas failed to identify 2 patients--mutation carriers (both KCNQ1 and HERG-KCNH2 mutations). DISCUSSION: Because of simplicity the Bazett formula remains the most common method of QT interval correction. Moreover, in our study this formula appeared to be the most sensitive for clinical diagnosis of LQTS.