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Abstract: A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra®, a 20% human IgG for subcutaneous administration, in 51 primary immunodeficiency patients over 40weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra® at doses equivalent to their previous treatment. IgG levels achieved with Hizentra® were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient, the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra®-related adverse events were reported. Individual median infusion durations ranged between 1.14 and 1.27h. Hizentra® maintained or improved serum IgG levels without dose increases and effectively protected patients against infections. [Copyright &y& Elsevier]

We studied the efficacy, safety and pharmacokinetic profiles of Intratect®, a recently developed polyvalent intravenous immunoglobulin (IVIG) preparation. Fifty-one patients (aged 6–48 years) with primary immunodeficiencies (PID) and established replacement therapy using a licensed IVIG were enrolled and treated for 12 months with Intratect®. Retrospective patient data served as prestudy controls. The primary efficacy variable was the annual rate of acute serious bacterial infection (ASBI) per patient. Secondary parameters were annual rate of acute relevant infection (ARI), days with antibiotic use, fever, absence from school/work and hospitalization. The average IVIG dose was 0·49 g/kg, with an average infusion rate of 2·4 ml/kg/h. The annual ASBI rate/patient was 0·02 and ARIs were detected 128 times during the 630 adverse events in 40 patients, specified mainly as bronchitis, sinusitis, respiratory tract infection, rhinitis and pharyngitis. The annual rate of respiratory ARIs/patient was 2·0 and the rates/patient for days with fever >38°C, school/work absence and hospitalization were 1·81, 3·99 and 0·36, respectively. A total of 630 adverse events (AEs) were observed in 50 of 51 (98·0%) of patients. In 46 of 51 patients the AEs were not related to infusion. Pharmacokinetic studies after the first infusion revealed a mean elimination half-life of 50·8 ± 30·3 days. During this study, 19 of 649 (2·9%) IgG trough levels were below 6 g/l, better than that of reference IVIGs during the 6 months before study start (10 of 201). These data suggest that Intratect® is a well tolerated, safe and effective IgG concentrate for the treatment of patients with PID. [ABSTRACT FROM AUTHOR]

The opsonisation of four different campylobacter species for human neutrophils was studied using a chemiluminescence system and electron microscopy. Opsonisation of Campylobacter fetus, Campylobacter coli, and Campylobacter jejuni was mediated by antibody and enhanced by complement. Antibody was not, however, required for the phagocytosis of Campylobacter pylori because it activates the classical pathway of complement directly. This unusual property may be important in the pathogenesis of C pylori associated gastritis and duodenal ulcer. [ABSTRACT FROM PUBLISHER]

Bolted connections are willingly used in steel structures because of their easiness of fabrication and assembly, but often they are the weakest component in the construction. In case of tensile lap connections, fracture of net cross section usually determines a joint capacity. Additionally, possible eccentricities can affect the distribution of stresses in the cross section and hence its load capacity. Analysis of fracture is a completely different issue compared to well-known and established problems of stability or plastic resistance. Paper relates to steel angle tension members connected by one bolt. It starts from the description of experimental investigations which results were used for hierarchical validation of computational models. Choice between two types of material models (elastic-plastic and Gurson–Tvergaard–Needleman) and building of FE models, representing different degrees of complexity, were described. Paper ends with parametric study taking into account influence of the edge distance from the centre of a fastener hole to the adjacent edge of angle. The paper’s aim is to verify and present the methodology for fracture prediction in steel angle tension members, which can be next extended for bolted joints with larger number of bolts and different geometrical configurations.

The paper presents results of investigation carried out on structure of the cultural center building in Dębica in Poland. Technical condition of mentioned building after 40 years of exploitation did not allow for its further use. In order to check the reliability of the structure, the authorities of the city commissioned an expertise. This study included basic structure measurements, loads statement and static analysis as well as check of limit states. As a result of the conducted analyses, it was found that the roof structure made of steel girder with web openings did not comply with resistant conditions. The paper presents brief description of building structure, numerical analyses and proposals of strengthening the roof girder.

Abstract: Chronic graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). After the skin, the liver is the second, most frequent target of GVHD, which presenting with hyperbilirubinemia, elevated liver enzymes, and coagulopathy. Progressive destruction of small intrahepatic bile ducts causes vanishing bile duct syndrome and leads to end-stage liver disease. We report 2 successful cases of orthotopic liver transplantation performed in children with severe GVHD after hematopoietic stem cell transplantation from a matched unrelated donor (HSCT-MUD). [Copyright &y& Elsevier]

Introduction: Deficiency of adenosine deaminase (ADA) manifests as severe combined immunodeficiency (SCID), caused by accumulation of toxic purine degradation by-products. Untreated patients develop immune and non-immune symptoms with fatal clinical course. According to ESID and EBMT recommendations enzyme replacement therapy (ERT) should be implemented as soon as possible to stabilize the patient's general condition, normalize transaminases, treat pulmonary proteinosis, bone dysplasia, and protect from neurological damage. Hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) is a treatment of choice. In absence of such donor, gene therapy (GT) should be considered. HSCT from a matched unrelated donor (MUD) and haploidentical hematopoietic stem cell transplantation (hHSCT) are associated with worse prognosis., Material and Methods: We retrospectively evaluated the clinical course and results of biochemical, immunological and genetic tests of 7 patients diagnosed in Poland with ADA deficiency since 2010 to 2022., Results: All patients demonstrated lymphopenia affecting of T, B and NK cells. Diagnosis was made on the basis of ADA activity in red blood cells and/or genetic testing. Patients manifested with various non-immunological symptoms including: lung proteinosis, skeletal dysplasia, liver dysfunction, atypical hemolytic-uremic syndrome, and psychomotor development disorders. Five patients underwent successful HSCT: 3 patients from matched unrelated donor, 2 from matched sibling donor, and 1 haploidentical from a parental donor. In 4 patients HSCT was preceded by enzyme therapy (lasting from 2 to 5 months). One patient with multiple organ failure died shortly after admission, before the diagnosis was confirmed. None of the patients had undergone gene therapy., Conclusions: It is important to diagnose ADA SCID as early as possible, before irreversible multi-organ failure occurs. In Poland HSCT are performed according to international immunological societies recommendations, while ERT and GT are less accessible. Implementation of Newborn Screening (NBS) for SCID in Poland could enable recognition of SCID, including ADA-SCID., 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 Dąbrowska-Leonik, Piątosa, Słomińska, Bohynikova, Bernat-Sitarz, Bernatowska, Wolska-Kuśnierz, Kałwak, Kołtan, Dąbrowska, Goździk, Ussowicz and Pac.)

Introduction: The J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI., Results: In this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients' data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174)., Conclusions: 1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries., 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 © 2022 Abolhassani, Avcin, Bahceciler, Balashov, Bata, Bataneant, Belevtsev, Bernatowska, Bidló, Blazsó, Boisson, Bolkov, Bondarenko, Boyarchuk, Bundschu, Casanova, Chernishova, Ciznar, Csürke, Erdős, Farkas, Fomina, Galal, Goda, Guner, Hauser, Ilyina, Iremadze, Iritsyan, Ismaili-Jaha, Jesenak, Kelecic, Keles, Kindle, Kondratenko, Kostyuchenko, Kovzel, Kriván, Kuli-Lito, Kumánovics, Kurjane, Latysheva, Latysheva, Lázár, Markelj, Markovic, Maródi, Mammadova, Medvecz, Miltner, Mironska, Modell, Modell, Mosdósi, Mukhina, Murdjeva, Műzes, Nabieva, Nasrullayeva, Naumova, Nagy, Onozó, Orozbekova, Pac, Pagava, Pampura, Pasic, Petrosyan, Petrovic, Pocek, Prodeus, Reisli, Ress, Rezaei, Rodina, Rumyantsev, Sciuca, Sediva, Serban, Sharapova, Shcherbina, Sitkauskiene, Snimshchikova, Spahiu-Konjusha, Szolnoky, Szűcs, Toplak, Tóth, Tsyvkina, Tuzankina, Vlasova and Volokha.)

The effect of vitamin D levels on the response to the hepatitis B vaccine in childhood and the induced levels of antibodies against the hepatitis B surface antigen (anti-HBs) is not yet well understood. The study aimed to investigate the relationship between age, serum 25-hydroxyvitamin D (25(OH)D) concentration and anti-HBs titer among children under 12 years old. Serum 25(OH)D concentration and anti-HBs titer were determined in 352 healthy Caucasian children with the average age of 4.2 (2.5; 6.3) years. All children were vaccinated with 3 doses of hepatitis B vaccine (Engerix-B, GlaxoSmithKline Pharmaceuticals Limited) in infancy according to the Centers for Disease Control and Prevention recommendations. Only 14.5% of children had an optimal concentration of 25(OH)D ≥ 30 ng/mL and 71.9% children had a seroprotective anti-HBs titer ≥ 10 mIU/mL. Significant negative correlations were found between 25(OH)D, anti-HBs titer and age (r = -0.420, p = 0.000; r = -0.425, p = 0.000, respectively), and a weak positive correlation between 25(OH)D concentration and anti-HBs titer (r = 0.243, p = 0.000). Analysis of six clusters of children demonstrated that age is the main factor affecting anti-HBs titer. One third of children under 12 years of age had nonprotective anti-HBs titer < 10 mIU/mL and around 40% had vitamin D deficiency. We conclude that vitamin D status has no impact on anti-HBs titer in children vaccinated against hepatitis B virus in infancy. Age, so time since the receipt of the last dose of hepatitis B vaccine, is the main factor influencing a decline in anti-HBs titer., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Dabrowska-Leonik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: We aimed to assess BCG (Bacillus Calmette-Guérin) complications in patients with Inborn Errors of Immunity (IEI), according to the inherited disorders and associated immunological defects, as well as the different BCG substrains., Material: We studied adverse reactions to the locally-produced BCG Moreau vaccine, analyzed in patients with IEI diagnosed between 1980 and 2020 in the Department of Immunology, Children's Memorial Health Institute (CMHI), Warsaw. These results were compared with previously published studies., Results: Significantly fewer disseminated BCG infections (BCGosis) were found in 11 of 72 (15%) SCID (Severe Combined Immunodeficiency) NK (Natural Killer)-phenotype patients, when compared with the 119 out of 349 (34%) ( p = 0.0012) patients with SCID with BCG in other countries. Significantly fewer deaths caused by BCGosis were observed ( p = 0.0402). A significantly higher number of hematopoietic stem cell transplantations (HSCTs) were performed in the CMHI study ( p = 0.00001). BCGosis was found in six patients with Mendelian susceptibility to mycobacterial diseases (MSMD). Other patients with IEI prone to BCG complications, such as CGD (Chronic Granulomatous Disease), showed no case of BCGosis., Conclusion: The BCG Moreau substrain vaccine, produced in Poland since 1955, showed genetic differences with its parental Brazilian substrain together with a superior clinical safety profile in comparison with the other BCG substrains, with no BCGosis in patients with IEI other than SCID and MSMD. Our data also confirmed significantly fewer cases of BCGosis and deaths caused by BCG infection in patients with SCID with this vaccine substrain. Finally, they confirmed the protecting role of NK cells, probably via their production of IFN-γ., 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 © 2022 Bernatowska, Pac, Heropolitańska-Pliszka, Pietrucha, Dąbrowska-Leonik, Skomska-Pawliszak, Bernat-Sitarz, Krzysztopa-Grzybowska, Wolska-Kuśnierz, Bohynikova, Augustynowicz, Augustynowicz-Kopeć, Korzeniewska-Koseła, Wieteska-Klimczak, Książyk, Jackowska, van den Burg, Casanova, Picard and Mikołuć.)

Purpose: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI)., Methods: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured., Results: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate., Conclusions: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI., (© 2021. The Author(s).)

This paper presents the results of experimental and numerical tests on angle members connected by one leg with a single row of bolts. This study was designed to determine which failure mode governs the resistance of such joints: net section rupture or block tearing rupture. Experimental tests were insufficient to completely identify the failure modes, and it was necessary to conduct numerical simulations. Finite element analysis of steel element resistance based on rupture required advanced material modelling, taking into account ductile initiation and propagation of fractures. This was realised using the Gurson-Tvergaard-Needleman porous material model, which allows for analysis of the joint across the full scope of its behaviour, from unloaded state to failure. Through experimental testing and numerical simulations, both failure mechanisms (net section and block tearing) were examined, and an approach to identify the failure mode was proposed. The obtained results provided experimental and numerical evidence to validate the strength function used in design standards. Finally, the obtained results of the load capacity were compared with the design procedures given in the Eurocode 3's current and 2021 proposed editions.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to systemic autoinflammatory diseases (AIDs). Many of these syndromes are genetically conditioned and can be inherited. Diagnosis relies on clinical symptoms and should be confirmed by genetic testing. One of the most serious complications is AA amyloidosis. We present the diagnostic route of a 33-year-old male with AA amyloidosis and his children, leading to diagnosis of monogenic autoinflammatory syndrome, confirmed by genetic analysis. A novel variant of the in-frame insertion type in one allele of TNFRSF1A gene was found by whole exome sequencing and confirmed by Sanger sequencing, which allowed a diagnosis of TRAPS. Three-dimensional modeling was used to assess the structural changes introduced into TNFR1 molecule by the insertion. The analysis of the 3D model revealed that accommodation of the 4AA insert induces misalignment of three cysteine bridges (especially the C70-C96 bridge) in the extracellular domain, leading to putatively misfolded and improperly functioning TNFR1. Three of the patient's daughters inherited the same variant of the TNFRSF1A gene and presented TRAPS symptoms. TRAPS is a very rare disease, but in the presence of suggestive symptoms the genetic diagnostic workout should be undertaken. Early diagnosis followed by appropriate clinical management can prevent irreversible complications.

Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD - the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary., (Copyright © 2020 Pac, Bielecka, Grzela, Komarnicka, Langfort, Koltan, Dabrowska-Leonik, Bernat-Sitarz, Pronicki, Dmenska, Pituch-Noworolska, Mikoluc, Piatosa, Tkaczyk, Bernatowska, Wojsyk-Banaszak and Krenke.)

Background: Variants in recombination-activating genes ( RAG ) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries. Methods: Demographic, clinical, and laboratory data were collected from RAG -deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay. Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID ( n = 20), OS ( n = 37), and LS/CID ( n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% ( n = 47) of patients with RAG1 variants carried p.K86Vfs * 33 (c.256&#95;257delAA) allele, either in homozygous ( n = 18, 27%) or in compound heterozygous ( n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs * 33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs * 33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion: We propose that RAG1 p.K86Vfs * 33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival., (Copyright © 2020 Sharapova, Skomska-Pawliszak, Rodina, Wolska-Kuśnierz, Dabrowska-Leonik, Mikołuć, Pashchenko, Pasic, Freiberger, Milota, Formánková, Szaflarska, Siedlar, Avčin, Markelj, Ciznar, Kalwak, Kołtan, Jackowska, Drabko, Gagro, Pac, Naumova, Kandilarova, Babol-Pokora, Varabyou, Barendregt, Raykina, Varlamova, Pavlova, Grombirikova, Debeljak, Mersiyanova, Bondarenko, Chernyshova, Kostyuchenko, Guseva, Rascon, Muleviciene, Preiksaitiene, Geier, Leiss-Piller, Yamazaki, Kawai, Walter, Kondratenko, Šedivá, van der Burg, Kuzmenko, Notarangelo, Bernatowska and Aleinikova.)

The aim of our study was to evaluate redox status, enzymatic and non-enzymatic antioxidant barriers, oxidative damage of proteins, lipids and DNA, as well as concentration of coenzyme Q10 and vitamins A and E in patients with chronic granulomatous disease (CGD). The study was performed on fifteen Caucasian individuals (median age 24 years and seven months) diagnosed with CGD. The mutation in the NCF1 gene was confirmed in ten patients, and in the CYBB gene in five patients. We demonstrated high levels of total oxidant status (TOS) and oxidative stress index (OSI), lipids (↑8-isoprostanes (8-isoP), ↑4-hydroxynonenal (4-HNE)), proteins (↑advanced oxidation protein products (AOPP)) and DNA (↑8-hydroxy-2'-deoxyguanosine (8-OHdG)) oxidation products in CGD individuals as compared to sex- and age-matched healthy controls. We showed enhanced serum enzymatic activity of catalase (CAT) and superoxide dismutase-1 (SOD) and significantly decreased coenzyme Q10 concentration. Our study confirmed redox disturbances and increased oxidative damage in CGD patients, and indicated the need to compare redox imbalance depending on the type of mutation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The question regarding effectiveness of antioxidant therapy in patients with CGD is open, and the need to establish guidelines in this area remains to be addressed.

Objectives: The aim of the study was to estimate the rate of adverse reactions to live BCG Moreau vaccine, manufactured by Biomed in Poland, in severe combined immunodeficiency (SCID) patients., Material: The profiles of 52 SCID patients vaccinated at birth with BCG, hospitalized in Children's Memorial Health Institute, Warsaw (CMHI), in the years 1980-2015 were compared with those of 349 BCG-vaccinated SCID patients from other countries analyzed by Beatriz E. Marciano et al. in a retrospective study (Marciano et al. J Allergy Clin Immunol. 2014;133(4):1134-1141)., Results: Significantly less disseminated BCG infections (10 out of 52 SCID, 19%) occurred in comparison with Marciano study-119 out of 349, 34% (p = 0.0028), with no death in patients treated with SCID anti-TB drug, except one in lethal condition. In our study, disseminated BCG infection was observed only in SCID with T-B+NK- phenotype and significantly lower NK cell counts (p = 0.0161). NK cells do not influence on the frequency of local BCG reaction. A significantly higher number of hematopoietic stem cells transplantations (HSCT) were performed in CMHI study (p = 0.0001). Anti-TB treatment with at least two medicines was provided., Conclusion: The BCG Moreau vaccine produced in Poland, with well-documented genetic characteristics, seems to be safer than other BCG substrains used in other regions of the world. Importantly, NK cells seem to play a role in protecting SCID patients against disseminated BCG complications, which NK- SCID patients are more prone to. HSCT and TB therapy could be relevant due to the patients' survival and the fact that they protect against BCG infection.

Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) belong to a group of primary immunodeficiency diseases (PI) characterized by premature aging, cerebral degeneration, immunoglobulin deficiency and higher cancer susceptibility. Despite the fact that oxidative stress has been demonstrated in vitro and in animal models of AT and NBS, the involvement of redox homeostasis disorders is still unclear in the in vivo phenotype of AT and NBS patients. Our study is the first to compare both enzymatic and non-enzymatic antioxidants as well as oxidative damage between AT and NBS subjects. Twenty two Caucasian children with AT and twelve patients with NBS were studied. Enzymatic and non-enzymatic antioxidants - glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase-1 (SOD) and uric acid (UA); redox status-total antioxidant capacity (TAC) and ferric reducing ability of plasma (FRAP); and oxidative damage products-8-hydroxy-2'-deoxyguanosine (8-OHdG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE) protein adducts, and 8-isoprostanes (8-isop) were evaluated in serum or plasma samples. We showed that CAT, SOD and UA were significantly increased, while TAC and FRAP levels were statistically lower in the plasma of AT patients compared to controls. In NBS patients, only CAT activity was significantly elevated, while TAC was significantly decreased as compared to healthy children. We also showed higher oxidative damage to DNA (↑8-OHdG), proteins (↑AGE, ↑AOPP), and lipids (↑4-HNE, ↑8-isop) in both AT and NBS patients. Interestingly, we did not demonstrate any significant differences in the antioxidant defense and oxidative damage between AT and NBS patients. However, in AT children, we showed a positive correlation between 8-OHdG and the α-fetoprotein level as well as a negative correlation between 8-OHdG and IgA. In NBS, AGE was positively correlated with IgM and negatively with the IgG level. Summarizing, we demonstrated an imbalance in cellular redox homeostasis and higher oxidative damage in AT and NBS patients. Despite an increase in the activity/concentration of some antioxidants, the total antioxidant capacity is overwhelmed in children with AT and NBS and predisposes them to more considerable oxidative damage. Oxidative stress may play a major role in AT and NBS phenotype., (Copyright © 2019 Maciejczyk, Heropolitanska-Pliszka, Pietrucha, Sawicka-Powierza, Bernatowska, Wolska-Kusnierz, Pac, Car, Zalewska and Mikoluc.)

Background: The capsular group B meningococcal vaccine (4CMenB) is recommended for children with complement deficiencies, asplenia, and splenic dysfunction; however, data on the immunogenicity of 4CMenB in these "at-risk" children are missing., Methods: Participants aged 2 to 17 years in Italy, Spain, Poland, the United Kingdom, and Russia with complement deficiencies, asplenia, or splenic dysfunction received 2 doses of 4CMenB 2 months apart, as did healthy children in the control group. Exogenous and endogenous human complement serum bactericidal activity (SBA) was determined at baseline and 1 month after the second immunization against 4 test strains: H44/76 (assessing vaccine antigen factor H binding protein), 5/99 (Neisserial adhesion A), NZ98/254 (Porin A), and M10713 (Neisserial heparin binding antigen)., Results: Of 239 participants (mean age 10.3 years, 45% female), 40 children were complement deficient (9 eculizumab therapy, 4 terminal-chain deficiencies, 27 "other"), 112 children had asplenia or splenic dysfunction (8 congenital asplenia, 8 functional asplenia, 96 splenectomy), and 87 children were in the control group. After immunization, the proportions of complement-deficient participants with exogenous complement SBA titers ≥1:5 were 87% (H44/76), 95% (5/99), 68% (NZ98/254), and 73% (M10713), compared with 97%, 100%, 86%, and 94%, respectively, for asplenic children and 98%, 99%, 83%, and 99% for children in the control group. When testing with endogenous complement, strain-specific bactericidal activity was evident in only 1 eculizumab-treated participant and 1 terminal chain complement-deficient participant., Conclusions: 4CMenB administration is similarly immunogenic in healthy children and those with asplenia or splenic dysfunction. The significance of the trend to lower responses of SBA titers in complement-deficient children (especially those with terminal chain complement deficiency or those on eculizumab therapy) must be determined by ongoing surveillance for vaccine failures., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The institution of Dr Martinón-Torres received clinical trial fees from Novartis during the conduct of this study, and he received personal fees and/or nonfinancial support and/or grants and/or other from Novartis, Pfizer, Sanofi-Pasteur MSD (SPMSD), the GlaxoSmithKline (GSK) group of companies, and/or Merck outside the submitted work. Prof Esposito reports grants from Novartis, the GSK group of companies, Pfizer, Sanofi-Pasteur, and Valeas, and personal fees from Novartis, the GSK group of companies, Pfizer, Sanofi-Pasteur, Novavax, and Vifor outside the submitted work. Prof Szenborn received personal fees from Novartis and the GSK group of companies during the conduct of the study. The institution of Prof Marti received clinical trial fees from Novartis during the conduct of the study, and she received grants from Novartis, GSK, and Pfizer outside of the submitted work. The institution of Prof Faust received grants from GSK group of companies during the conduct of the study and received grants for his participation in advisory boards (Astra Zeneca and Cubist) and speaking engagements (Pfizer). Prof Faust acts as an investigator for clinical studies from both noncommercial funding bodies and commercial sponsors (ie, some or all of Novartis Vaccines, the GSK group of companies, MedImmune and/or AstraZeneca, and Pfizer Vaccines) conducted on behalf of Southampton University Hospital NHS Foundation Trust and the University of Southampton. The institution of Prof Gonzalez-Granado received clinical trial fees from Novartis during the conduct of the study and he has received grants for his participation in advisory boards and speaking engagements (CSL Behring and Baxter). Dr Calabresi and Mr D’Agostino were employees and Dr Toneatto is an employee of the GSK group of companies. Dr Toneatto owns stock and/or stock options in the GSK group of companies. Dr Snape acts as an investigator for clinical studies from both noncommercial funding bodies and commercial sponsors (ie, some or all of Novartis Vaccines, the GSK group of companies, Sanofi-Aventis, SPMSD, MedImmune, and Pfizer Vaccines) conducted on behalf of the University of Oxford and Oxford University Hospitals NHS trust. The NIHR Oxford Biomedical Research Centre provides salary support for Dr Snape, who is a Jenner Investigator; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Purpose: The objective of this study was to evaluate thevitamin D concentration in patients with recurrent respiratory infections with or without immunoglobulin G, A or M (IgG, IgA, IgM) deficiency, and to find a correlation between the vitamin D concentration and the response to hepatitis B vaccination., Materials and Method: The study involved 730 patients with recurrent respiratory infections. The concentration of 25-hydroxyvitamin D (25(OH)D), immunoglobulins G, A and M, anti-HBs was determined., Results: The tests showed that 11% of patients presented IgG levels below the age related reference values. Children with reduced IgG concentration were also found to have significantly lower vitamin D concentrations in comparison to children with normal IgG. Vitamin D deficiency was observed in schoolchildren between 7 and 18 years of age. No correlation was found between 25(OH)D concentration and Hbs antibody levels., Conclusions: An investigation of a large group of patients who have recurrent infection found patients with IgG deficiency to whom special proceeding have to be performed: 1. Significantly lower vitamin D concentration observed in the group of children with IgG deficiency implicated in long-lasting monitoring of vitamin D level require adding to the practice guidelines for Central Europe 2013. 2. Intervention treatment with suitable doses of vitamin D to clarified metabolism of vitamin D has to be plan for children with IgG deficiency and significant lower vitamin D concentration., (Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Immunoglobulin replacement therapy (IRT) is standard treatment for patients with primary immunodeficiency (PID). Because most of the patients with PID will require long life-time immunoglobulin replacement therapy, the quality of the prescribed products is of utmost importance. The IRT is generally administered either intravenously (abbreviated IVIG), or subcutaneously (abbreviated SCIG). Both routes have been demonstrated to be effective. The preferred route may vary at different times during a given patient's life. Options are therefore not fixed and the choice of route for immunoglobulin therapy will depend on several factors, including patient characteristics, clinical indication, venous access, side effects, rural or remote location, treatment compliance and patient preference. Many years ago, immunoglobulin therapy was associated with side effects which may compromise patient's compliance and quality of life of the patients. Most of the side effects were related to impurities. Recently, major advances in the manufacturing process have been made and new processes, such as the Quality by design (QbD) approach were added into the manufacturing steps to ensure patients tolerability and safety. Due to the improved purity of the immunoglobulin products obtained by these processes, the incidence of side effects is lower, while the ways of administration of Ig therapy and the choice of the regimen has widened to suit patient's preference and needs., Competing Interests: None.

This multicentre, open-label, prospective, single-arm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune®, a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune® was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L (p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The pharmacokinetic profile of IqYmune® was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune® was shown to be effective and well tolerated in patients with primary immunodeficiency.

Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame.

Background: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway., Methods: We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis., Results: We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal. Basal AKT phosphorylation was increased in lymphocytes from APDS patients and natural effector B cells where most affected. PI3K mutations resulted in altered SHM and CSR and increased apoptosis., Conclusions: The B-cell compartment in APDS patients is affected by the mutations in PI3K. There is reduced differentiation beyond the transitional stage, increased AKT phosphorylation and increased apoptosis. This B-cell phenotype contributes to the clinical phenotype., (Copyright © 2017. Published by Elsevier Inc.)

This study compared the antioxidant status and major lipophilic antioxidants in patients with ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). Total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), and concentrations of coenzyme Q10 (CoQ10) and vitamins A and E were estimated in the plasma of 22 patients with AT, 12 children with NBS, and the healthy controls. In AT patients, TAS (median 261.7  μ mol/L) was statistically lower but TOS (496.8  μ mol/L) was significantly elevated in comparison with the healthy group (312.7  μ mol/L and 311.2  μ mol/L, resp.). Tocopherol (0.8  μ g/mL) and CoQ10 (0.1  μ g/mL) were reduced in AT patients versus control (1.4  μ g/mL and 0.3  μ g/mL, resp.). NBS patients also displayed statistically lower TAS levels (290.3  μ mol/L), while TOS (404.8  μ mol/L) was comparable to the controls. We found that in NBS patients retinol concentration (0.1  μ g/mL) was highly elevated and CoQ10 (0.1  μ g/mL) was significantly lower in comparison with those in the healthy group. Our study confirms disturbances in redox homeostasis in AT and NBS patients and indicates a need for diagnosing oxidative stress in those cases as a potential disease biomarker. Decreased CoQ10 concentration found in NBS and AT indicates a need for possible supplementation.

Unlabelled: The study presents an overview on current situation of primary immunodeficiency (PID) patients in Poland and the 2014 annual report of the Polish Working Group for Immunodeficiency (PWGID). The group was set up in 2005 to improve diagnosis, treatment, and care of patients with immunodeficiencies and currently includes 15 pediatric and 13 adult centers. According to PWGID report 4099, PID patients are recognized in Poland, with the prevalence 10.6/100,000. The majority of them (54.2 %) have predominantly antibody deficiency (PAD). In 2014 alone, a total number of 731 newly diagnosed individuals are reported. As predicted, the vast majority (70 %) of them have PAD. Approximately one third of PAD patients require immunoglobulin replacement therapy. Within the entire cohort, an intravenous route of immunoglobulin therapy dominates (67.3 %). However, within the age groups, distribution of immunoglobulin therapy varies and seems to be age related. Among children, 36 % receive subcutaneous immunoglobulin, while with adults 26 %., Conclusion: Analysis of numbers of either newly recognized or treated patients indicates its dynamic increase in recent years. This is the result of comprehensive activities by PWGID supported by governmental institutions, outstanding foundations, and patient's organization., What Is Known: • Immunoglobulins' treatment has substantially changed the life of individuals with PAD. Patients with common variable immunodeficiency (CVID) or X-linked agammaglobulinemia (XLA) can live and lead a near normal life. Early diagnosis of the disease followed by earlier implementation of appropriate treatment, including gammaglobulin replacement therapy, improves the quality of life. • Targeted efforts of health care professionals and government are required to optimize diagnostic and therapeutic approach for PAD. What is New: • Comprehensive activities of PWGID lead to better recognition of PID individuals and should improve reporting Polish PIDs to the ESID database. • Following the joint efforts of immunologists, patient's, and governmental organizations in the end of 2014, the Therapeutic Program for Treatment Adults with PID was introduced, leading to universal access to currently available treatment options and to improve the quality of life.

Purpose: Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation., Methods: The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed., Results: Of the 149 NBS patients, 91 (61%), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin's lymphomas), were diagnosed in 42% of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35%, respectively, and were significantly lower in patients with than without malignancies., Conclusions: The extremely high incidence of malignancies, mostly non-Hodgkin's lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.

Introduction: Münchausen syndrome by proxy (MSBP) describes a pattern in which a caregiver induces a disease in a child. The symptoms may manifest in the oral cavity., Material and Methods: PubMed was researched for articles between 1990-2014, presenting manifestations of MSPB, following PRISMA 2009 guidelines, and an in-house case of MSBP with oral manifestations was presented., Review: Among 66 articles presenting MSBP symptoms, four included descriptions of oral lesions in five children. They included: tooth loss, ulcerations and ulcers on oral mucosa, scars due to old, healed lesions, bleeding, black tongue, polysialia, and discolouration and swelling in the lips. Münchausen syndrome by proxy with participation of the mother was diagnosed in four cases., Case: A 13-year-old girl was hospitalised because of a non-healing ulcer of the septum, loose and lost mandibular teeth, skin lesions, and suspected immunodeficiency. She had been hospitalised numerous times at other facilities. Consultations and diagnostic tests did not confirm an organic disease. The patient and her mother agreed to undergo all examinations, and some symptoms 'went away' during the examinations. The behaviour of the patient and her mother during hospital stays, ambulatory care, and the psychiatric observations all pointed towards MPSB. They refused further treatment at the present facility., Conclusions: A dentist should take into account the potential 'fabrication' of symptoms in a child by the latter or by a caregiver. Consultations with a paediatrician or psychiatrist enable a diagnosis and treatment.

Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of "next generation" sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons.

Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott-Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21(low) B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells. In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Common variable immune deficiency (CVID) is a heterogeneous disease associated with ineffective production of antibodies. It is usually diagnosed in adulthood, but a variable proportion of children develop CVID. Early identification of patients with potentially worse prognosis may help to avoid serious complications. The goal of this study was to associate the clinical phenotype of patients with early onset CVID with peripheral B-cell maturation profile. Four color flow cytometry was used to define distribution of peripheral B-cell subsets in 49 children with early-onset CVID. All clinical data were extracted from medical records. A proportion of patients demonstrated diminishing with time total B-lymphocytes pool, beyond physiological age-related changes. Irrespective from duration of the follow-up period the B-cell maturation profile in individual patients remained unchanged. We identified six different aberrant peripheral B cell maturation profiles associated with different clinical characteristics. Patients with an early B-cell maturation block earlier required replacement therapy and were at significantly greater risk of enteropathy, granuloma formation, cytopenia, and lymphoproliferation. B-cell maturation inhibited at the natural effector stage was associated with higher risk of autoimmune manifestations other than autoimmune cytopenia. Prevalence of male patients was observed among patients with B-cell maturation inhibited at naïve B-cell stage. In conclusion, the diagnostic process in patients with suspected early-onset CVID shall include routine analysis of peripheral B-cell maturation to provide surrogate markers identifying patients at greater risk of developing certain complications.

The aim of the current study was to examine whether a congenital lack of the spleen changes distribution, state of activation and function of peripheral lymphocyte T subsets. Seven children with congenital asplenia (CA) aged 1.5-17 years and seven age-matched controls were tested. By triple-color flow cytometry we examined: (1) the expression of CD3(+), CD4(+), CD8(+), CD19(+), and CD56(+) on lymphocytes; (2) the distribution of CD45RA(+) and CD45RO(+) in CD4(+) and CD8(+); (3) the expression of CD27(+) in the CD4(+) and CD8(+) T-cell-bearing CD45RA(+), CD45RO(+), or CD45RB(+). Lymphocyte proliferative responses and cytokines production (IFN-gamma, IL-6, TNF-alfa, and IL-10) in anti-CD3-induced peripheral blood mononuclear cells were tested. The results indicate (1) a normal distribution of the basic lymphocyte subsets, (2) low CD3(+)/CD8(+) percentage but expressing CD8(+high) and non-significantly elevated CD4(+)/CD8(+) ratio, (3) CD45RA(+high) and CD27(+high) in the CD4(+) and CD8(+) T cell, and (4) CD45RB(+high) in the CD4(+) and CD45RO(+high) in the CD8(+). The distribution of CD27(+) in the CD45RA(+) and CD45RO(+) CD4(+) T cells remained unchanged. However, the percentage of CD8(+)/CD45RO(+)/CD27(+) T cells tended to be elevated. Altogether, these data indicate that CA is connected with (1) the presence CD4(+) T cells expressing the "naive" phenotype (CD45RA(+high) RB(+high) and CD27(+high)), (2) high numbers of activated CD8(+) T cells shifted toward the memory phenotype (CD45RO(+high)) but still showing high CD27(+) expression, which may indicate failure in T CD8(+) cytotoxic effectors differentiation, and (3) a tendency to the rather pro-inflammatory status of cells, low IL-10 expression, and suboptimal lymphocytes responses to mitogenic stimulation., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)