CVID-Associated Tumors: Czech Nationwide Study Focused on Epidemiology, Immunology, and Genetic Background in a Cohort of Patients With CVID

Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumorsMethods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background.Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A).Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy

Pusobeni kadmia a zinku na funkce lidskych lymfocytu in vitro.

We tested the effect of metals sulphates added in cell cultures in different concentrations from 10-2 M to 10-10 M. Cell cultures were prepared from the whole human blood without the isolation of lymphocytes. We studied the early cell activation by the expression of the surface antigen CD69, the blast transformation of lymphocytes, changes of CD95 expression, the production of cytokines (intracellular and in the supernate) and the production of immunoglobulins. The duration of cultivation was different in XXXX methods. The analysis of the expression of surface cells antigens (lymphocytes subpopulations, CD69, CD95), blast transformation and intracellular cytokines was made with monoclonal antibodies by flow cytometry. The results of the concentration of produced cytokines were obtained by ELISA, the concentration of immunoglobulines was detected by nephelometry. The result showed more expressive differences in the test of blast transformation. There were stimulating effects of cadmium in concentrations 10-3 M, 10-4 M and 10-8 M, and zinc 10-3 M. The most suppressive effect was in concentrations 10-10 M of cadmium and 10-8 M of zinc. The highest CD69 expression was in concentration 10-4 M and 10-6 M of cadmium and 10-3 M of zinc. The kinetic study of the expression of the surface antigen CD95 (Fas receptor) showed the elevation of the percentage of positive untreated cells after 18 hours of cultivation and a very low expression after 90 hours. In cell cultures with cadmium and zinc was the CD95 expression on lymphocytes after 18 hours lower that results of untreated cells. After 90 hours of cultivation we found difference between the effect of both metals, with a great individal variability in the number of positive cells upon the influence of zinc.In the test of cytokine production there were significant differences between the groups of studied persons, patients with autoimmune diseases showed high levels of IL-6 in all cell cultures, the group of heavy smokers produced IL-10 after the stimulation with PHA. In the detected concentrations of produced cytokines and immunoglobulins (very low levels) we found high individual variability. The results obtained by our experiments show the importance of the study of the influence of metals on the functions of immune system. Our investigation shows possibilities for further research.Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Oral Microbiota Composition and Antimicrobial Antibody Response in Patients with Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis (RAS) is the most common disease of the oral mucosa, and it has been recently associated with bacterial and fungal dysbiosis. To study this link further, we investigated microbial shifts during RAS manifestation at an ulcer site, in its surroundings, and at an unaffected site, compared with healed mucosa in RAS patients and healthy controls. We sampled microbes from five distinct sites in the oral cavity. The one site with the most pronounced differences in microbial alpha and beta diversity between RAS patients and healthy controls was the lower labial mucosa. Detailed analysis of this particular oral site revealed strict association of the genus Selenomonas with healed mucosa of RAS patients, whereas the class Clostridia and genera Lachnoanaerobaculum, Cardiobacterium, Leptotrichia, and Fusobacterium were associated with the presence of an active ulcer. Furthermore, active ulcers were dominated by Malassezia, which were negatively correlated with Streptococcus and Haemophilus and positively correlated with Porphyromonas species. In addition, RAS patients showed increased serum levels of IgG against Mogibacterium timidum compared with healthy controls. Our study demonstrates that the composition of bacteria and fungi colonizing healthy oral mucosa is changed in active RAS ulcers, and that this alteration persists to some extent even after the ulcer is healed