BACKGROUND: RTX, an anti-CD20 monoclonal antibody, added to chemotherapy has proven to be effective in children and adolescents with high-grade, high-risk and matured non-Hodgkin lymphoma. RTX leads to prompt CD19+ B lymphocyte depletion. However, despite preserved immunoglobulin production by long-lived plasmablasts after treatment, patients remain at risk of prolonged hypogammaglobulinemia. Further, there are few general guidelines for immunology laboratories and clinical feature monitoring after B cell-targeted therapies. The aim of this paper is to describe B cell reconstitution and immunoglobulin levels after pediatric B-NHL protocols, that included a single RTX dose and to review the literature. METHODS: A retrospective single-center study on the impact of a single RTX dose included in a chemotherapeutic pediatric B Non-Hodgkin Lymphoma (B-NHL) treatment protocols. Immunology laboratory and clinical features were evaluated over an eight hundred days follow-up (FU) period, after completing B-NHL treatment. RESULTS: Nineteen patients (fifteen Burkitt lymphoma, three Diffuse large B cell lymphoma, and one Marginal zone B cell lymphoma) fulfilled the inclusion criteria. Initiation of B cell subset reconstitution occurred a median of three months after B-NHL treatment. Naïve and transitional B cells declined over the FU in contrast to the marginal zone and the switched memory B cell increase. The percentage of patients with IgG, IgA, and IgM hypogammaglobulinemia declined consistently over the FU. Prolonged IgG hypogammaglobulinemia was detectable in 9%, IgM in 13%, and IgA in 25%. All revaccinated patients responded to protein-based vaccines by specific IgG antibody production increase. Following antibiotic prophylaxes, none of the patients with hypogammaglobulinemia manifested with either a severe or opportunistic infection course. CONCLUSION: The addition of a single RTX dose to the chemotherapeutic treatment protocols was not shown to increase the risk of developing secondary antibody deficiency in B-NHL pediatric patients. Observed prolonged hypogammaglobulinemia remained clinically silent. However interdisciplinary agreement on regular long-term immunology FU after anti-CD20 agent treatment is required.

• MeSH
• B-buněčný lymfom farmakoterapie   imunologie   MeSH
• dítě MeSH
• imunoglobuliny aplikace a dávkování   MeSH
• lidé MeSH
• mladiství MeSH
• nehodgkinský lymfom farmakoterapie   imunologie   MeSH
• podskupiny B-lymfocytů imunologie   účinky léků   MeSH
• předškolní dítě MeSH
• protinádorové látky imunologicky aktivní aplikace a dávkování   terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• retrospektivní studie MeSH
• rituximab * terapeutické užití   aplikace a dávkování   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Tumor Necrosis Factor Receptor 2 (TNFR2) expression is increasingly being linked to tolerogenic immune reactions and cells with suppressor function including a subset of T-regulatory cells. B-regulatory cells play an important role in control of T-cell responses and inflammation. Recently, we described TNFR2 as a marker for IL-10-producing B cells, a hallmark of this cell subset. Here, we demonstrate that proliferation of T cells is reduced in the presence of TNFR2 positive human memory B cells generated with TLR9 ligand, while TNFR2- and TNFR2+CD27- B cells display costimulatory activity. Our data further reveal that IL-10 secretion is characteristic of IgM+ naïve and memory B cells but suppressive activity is not restricted to IL-10: (i) the inhibitory effect of TNFR2+ switched memory B cells was comparable to that exerted by TNFR2+ IgM+ memory B cells although IL-10 secretion levels in the cocultures were lower; (ii) supernatants from TNFR2+ memory B cells failed to suppress T-cell proliferation. Based on our findings, we propose that formation of Breg is a specific characteristic of human memory B cells undergoing terminal differentiation. Our data further corroborate that TNFR2 represents a viable marker for identification of memory B cells with regulatory function.

• MeSH
• aktivace lymfocytů genetika   imunologie   MeSH
• B-lymfocyty imunologie   metabolismus   MeSH
• běžná variabilní imunodeficience etiologie   metabolismus   MeSH
• buněčná diferenciace imunologie   MeSH
• cytokiny metabolismus   MeSH
• imunologická paměť * MeSH
• imunomodulace genetika   MeSH
• interleukin-10 metabolismus   MeSH
• lidé MeSH
• mezibuněčná komunikace imunologie   MeSH
• receptory TNF - typ II genetika   metabolismus   MeSH
• regulace genové exprese * MeSH
• regulační B-lymfocyty imunologie   metabolismus   MeSH
• studie případů a kontrol MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• toll-like receptor 9 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: Epstein-Barr virus (EBV) targets predominantly B cells and these cells could acquire new phenotype characteristics. Here we analyzed whether EBV-infected and -uninfected B cells from healthy subjects differ in proportion of dominant phenotypes, maturation stage, and homing receptors expression. METHODS: EBV-infected and -uninfected cells were identified by flow cytometry using fluorophore-labeled EBV RNA-specific DNA probes combined with fluorophore-labeled antibody to surface lineage markers, integrins, chemokine receptors, and immunoglobulin isotypes, including intracellular ones. RESULTS: Our results show that the trafficking characteristics of EBERpos B cells are distinct from EBERneg B cells with most dominant differences detected for α4β1 and α4β7 and CCR5 and CCR7. EBV-positive cells are predominantly memory IgM+ B cells or plasmablasts/plasma cells (PB/PC) positive for IgA or less for IgM. In comparison to uninfected B cells, less EBV-positive B cells express α4β7 and almost no cells express α4β1. EBV-positive B cells contained significantly higher proportion of CCR5+ and CCR7+ cells in comparison to EBV-negative cells. In vitro exposure of blood mononuclear cells to pro-inflammatory cytokine IL-6 reduces population of EBV-positive B cell. CONCLUSION: Although EBV-infected B cells represent only a minor subpopulation, their atypical functions could contribute in predisposed person to development abnormities such as some autoimmune diseases or tumors. Using multi-parameter flow cytometry we characterized differences in migration of EBV-positive and -negative B cells of various maturation stage and isotype of produced antibodies particularly different targeting to mucosal tissues of gastrointestinal and respiratory tracts.

• MeSH
• B-lymfocyty imunologie   MeSH
• dospělí MeSH
• infekce virem Epsteina-Barrové imunologie   patofyziologie   MeSH
• krev imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• průtoková cytometrie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vezikulární transportní proteiny imunologie   metabolismus   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Systémový lupus erythematodes (SLE) je chronické zánětlivé autoimunitní onemocnění s variabilní manifestací a průběhem včetně rizika závažné prognózy. V době milénia mělo standardizované riziko mortality u SLE hodnotu 2,4 a v následujících letech nedošlo ke zřejmému pokroku. Podle projektu Euro-lupus jsou největším nebezpečím fatální prognózy aktivita nemoci, infekce a cévní okluze. Z celonárodních registrů (USA, Švédsko aj.) vyplynulo, že SLE se závažnou infekcí (zvl. bakteriální pneumonie a/nebo sepse) je významně častějším důvodem hospitalizace než u adjustované non SLE populace. SLE pacienty lze všeobecně považovat za imunokompromitované osoby, speciálně pak ve vztahu k aktivitě (nefrotický syndrom u lupusové nefritidy aj.), komorbiditám, post OP stavu (splenektomie) a terapii (glukokortikoidy, cyto-statika aj.), s výjimkou antimalarik. V širokém spektru poruch B buněčné imunity u SLE byly předmětem cílené analýzy paměťové B buňky marginální zóny. U kohorty SLE byl metodou průtokové cytometrie zjištěn signifikantní deficit paměťových B buněk marginální zóny (CD 19+CD27+ IgM+) v absolutních hodnotách (x106/l) všech lymfocytů periferní krve i s perzistencí při kontrole za 12 měsíců, vždy u SLE na úrovni nízké aktivity nemoci. Lze předpokládat, že detekce skrytého deficitu paměťových B buněk marginální zóny v periferní krvi může být přínosem i v hodnocení rizika závažných infekcí u SLE.

Systemic lupus erythermatosus (SLE) is a chronic inflammatory autoimmune disease with variable manifestation and course, incl. a risk of serious prognosis. In time of milenium, the overall standardized mortality ratio was in SLE 2.4, and the following up-years without evident progress. Euro-lupus project expressed the most frequent risk of fatal prognosis as follows: disease activity, infections and thrombosis. Nati-onwide registers (USA, Sweden etc.) demonstrated that SLE with serious infections (espec. bacterial pneumonia and/or sepsis) is significantly more frequent reason for hospitalization in comparison to adjusted non-SLE population. SLE patients are immunocompromised subjects in general, but especially in relation to disease activity (nephrotic syndrom in lupus nephritis etc.), comorbidities, post-OP state (splenectomy), and therapy (glucocorticoids, cytostatics, etc.), except antimalarials. In a large amount of B cell immunity disorders in SLE, an analysis of memory marginal-zone B cells was made more in detail. A cohort of SLE was examined by means of flow cytometry with detection a significant deficiency of memory marginal-zone (CD 19+ CD27+ IgM+) B cells in absolute values (x106/L) of whole lymphocytes in peripheral blood (PB), incl. with persistence after a twelve-months control, always in lupus low disease activity state. Is supposed, that investigation of unapparent deficiency of memory marginal-zone B cells in PB should be useful in evaluation the risk of serious infections in SLE.

• MeSH
• B-lymfocyty imunologie   patologie   MeSH
• lidé MeSH
• průtoková cytometrie MeSH
• systémový lupus erythematodes * epidemiologie   imunologie   mortalita   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Funkční hyposplenizmus je stav provázející řadu chorob, vč. autoimunitních onemocnění a lymfomů. Hyposplenizmus se běžně vyskytuje také u celiakie (až ve 20 % nekomplikované a 80 % komplikované nemoci). Hyposplenizmus je spojen se zvýšeným rizikem závažných infekcí (Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae). Cílem této prospektivní pilotní studie bylo vyšetřit paměťové B lymfocyty coby nepřímý biomarker funkčního hyposplenizmu. Bylo vyšetřeno 42 pacientů s celiakií (11 mužů, 31 žen, průměrný věk 49 ± 14 let) a 10 kontrolních osob, dárců krve (2 muži, 8 žen, průměrný věk 39 ± 7 let). Pomocí panelu DuraClone IM byly průtokovou cytometrií (Navios, Beckman Coulter) vyšetřeny jednotlivé subpopulace B lymfocytů v periferní krvi. Imunoglobulin (Ig) M a IgD paměťové B lymfocyty byly u nemocných s celiakií signifikantně nižší ve srovnání s kontrolními osobami. Dysfunkce paměťových B lymfocytů může být zodpovědná za zvýšené riziko bakteriálních infekcí u celiakie. Pacienti s celiakií s prokázanou dysfunkcí paměťových B lymfocytů jsou indikováni k pneumokokové vakcinaci.

Functional hyposplenism is a condition accompanying many diseases including autoimmune disorders and lymphomas. Hyposplenism is also commonly found in adult coeliac disease (up to 20% of non-complicated and up to 80% of complicated disease). Hyposplenism is associated with an increased risk of severe infections (Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae). The aim of this prospective study was to investigate memory B lymphocytes as an indirect biomarker of functional hyposplenism. A total of 42 patients with coeliac disease (11 men, 31 women; mean age 49 ± 14 years) and 10 healthy controls, blood donors (2 men, 8 women; mean age 39 ± 7 years) were enrolled into the study. None of the patients had a history of splenectomy and none of them suffered. from immunodeficiency. The DuraClone IM panel was used to identify B lymphocytes subpopulations in peripheral blood samples by flow cytometry Navios (Beckman Coulter) with software analysis using Kaluza version 1.2. Patients with coeliac disease and controls did not differ in basic parameters of leukocyte and total lymphocyte blood count. Switched memory B lymphocytes (CD19+CD27+IgD-), non-switched memory/marginal-zone-like B lymphocytes (CD19+CD27+IgD+) and immunoglobulin (Ig) M memory B lymphocytes (CD19+CD27+IgM++) were significantly lower in patients with coeliac compared to controls. Follicular (naïve) B lymphocytes were not significantly different between coeliac disease and controls. In conclusion, dysfunction of memory B lymphocytes can be responsible for an increased risk of severe bacterial infections in coeliac disease. Patients with coeliac disease with dysfunction of memory B lymphocytes are clearly indicated for pneumococcal vaccination.

• Klíčová slova
• funkční hyposplenizmus, paměťové B lymfocyty,
• MeSH
• B-lymfocyty * MeSH
• celiakie komplikace   krev   MeSH
• lidé MeSH
• pilotní projekty MeSH
• pneumokokové vakcíny MeSH
• průtoková cytometrie MeSH
• slezina * imunologie   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Chronic lymphocytic leukemia is a disease with up-regulated expression of the transmembrane tyrosine-protein kinase ROR1, a member of the Wnt/planar cell polarity pathway. In this study, we identified COBLL1 as a novel interaction partner of ROR1. COBLL1 shows clear bimodal expression with high levels in chronic lymphocytic leukemia patients with mutated IGHV and approximately 30% of chronic lymphocytic leukemia patients with unmutated IGHV. In the remaining 70% of chronic lymphocytic leukemia patients with unmutated IGHV, COBLL1 expression is low. Importantly, chronic lymphocytic leukemia patients with unmutated IGHV and high COBLL1 have an unfavorable disease course with short overall survival and time to second treatment. COBLL1 serves as an independent molecular marker for overall survival in chronic lymphocytic leukemia patients with unmutated IGHV. In addition, chronic lymphocytic leukemia patients with unmutated IGHV and high COBLL1 show impaired motility and chemotaxis towards CCL19 and CXCL12 as well as enhanced B-cell receptor signaling pathway activation demonstrated by increased PLCγ2 and SYK phosphorylation after IgM stimulation. COBLL1 expression also changes during B-cell maturation in non-malignant secondary lymphoid tissue with a higher expression in germinal center B cells than naïve and memory B cells. Our data thus suggest COBLL1 involvement not only in chronic lymphocytic leukemia but also in B-cell development. In summary, we show that expression of COBLL1, encoding novel ROR1-binding partner, defines chronic lymphocytic leukemia subgroups with a distinct response to microenvironmental stimuli, and independently predicts survival of chronic lymphocytic leukemia with unmutated IGHV.

• MeSH
• analýza přežití MeSH
• chronická lymfatická leukemie klasifikace   diagnóza   genetika   mortalita   MeSH
• lidé MeSH
• mutace MeSH
• pohyb buněk MeSH
• polarita buněk MeSH
• prognóza MeSH
• signální dráha Wnt MeSH
• sirotčí receptory podobné receptoru tyrosinkinasy metabolismus   MeSH
• těžké řetězce imunoglobulinů genetika   MeSH
• transkripční faktory metabolismus   MeSH
• variabilní oblast imunoglobulinu genetika   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Surface IgD is coexpressed with IgM on naive mature B cells. Still, the role of surface IgD remains enigmatic even 50 y after its initial discovery. In this study, we examined the in vivo role of surface IgD in human B cell homeostasis and Ab responses in four individuals with heterozygous nonsense mutations in IGHD All IGHD heterozygous individuals had normal numbers of B cells and serum Igs and did not show signs of immunodeficiency or immune dysregulation. IgD+ and IgD- naive mature B cells were present in equal numbers and showed similar immunophenotypes, except for decreased expression of CD79b in the IgD- subset. Furthermore, both IgD+ and IgD- naive mature B cells had normal replication histories and similar capacities to differentiate into plasma cells upon in vitro stimulation, and Ig class-switched memory B cells showed similar levels of somatic hypermutations. Thus, human B cells lacking IgD expression develop normally and generate immunological memory in vivo, suggesting that surface IgD might function more restrictedly in regulating of B cell activation to specific antigenic structures.

• MeSH
• aktivace lymfocytů MeSH
• B-lymfocyty imunologie   MeSH
• buněčná diferenciace MeSH
• haploinsuficience MeSH
• homeostáza MeSH
• imunoglobulin D genetika   metabolismus   MeSH
• imunoglobulin M metabolismus   MeSH
• imunologická paměť MeSH
• kultivované buňky MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• plazmatické buňky imunologie   MeSH
• podskupiny B-lymfocytů imunologie   MeSH
• přesmyk imunoglobulinových tříd MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Humoral immunocompetence develops stepwise throughout life and contributes to individual susceptibility to infection, immunodeficiency, autoimmunity, and neoplasia. Immunoglobulin heavy chain (IgH) isotype serum levels can partly explain such age-related differences, but their relationship with the IgH isotype distribution within memory B-cell (MBC) and plasma cell (PCs) compartments remains to be investigated. OBJECTIVE: We studied the age-related distribution of MBCs and PCs expressing different IgH isotypes in addition to the immature/transitional and naive B-cell compartments. METHODS: B-cell and PC subsets and plasma IgH isotype levels were studied in cord blood (n = 19) and peripheral blood (n = 215) from healthy donors aged 0 to 90 years by using flow cytometry and nephelometry, respectively. RESULTS: IgH-switched MBCs expressing IgG1, IgG2, IgG3, IgA1, and IgA2 were already detected in cord blood and newborns at very low counts, whereas CD27+IgM++IgD+ MBCs only became detectable at 1 to 5 months and remained stable until 2 to 4 years, and IgD MBCs peaked at 2 to 4 years, with both populations decreasing thereafter. MBCs expressing IgH isotypes of the second immunoglobulin heavy chain constant region (IGHC) gene block (IgG1, IgG3, and IgA1) peaked later during childhood (2-4 years), whereas MBCs expressing third IGHC gene block immunoglobulin isotypes (IgG2, IgG4, and IgA2) reached maximum values during adulthood. PCs were already detected in newborns, increasing in number until 6 to 11 months for IgM, IgG1, IgG2, IgG3, IgA1, and IgA2; until 2 to 4 years for IgD; and until 5 to 9 years for IgG4 and decreasing thereafter. For most IgH isotypes (except IgD and IgG4), maximum plasma levels were reached after PC and MBC counts peaked. CONCLUSIONS: PC counts reach maximum values early in life, followed by MBC counts and plasma IgH isotypes. Importantly, IgH isotypes from different IGHC gene blocks show different patterns, probably reflecting consecutive cycles of IgH isotype switch recombination through life.

• MeSH
• B-lymfocyty imunologie   MeSH
• dítě MeSH
• dospělí MeSH
• humorální imunita imunologie   MeSH
• imunoglobulinové izotypy krev   imunologie   MeSH
• imunologická paměť imunologie   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• novorozenec MeSH
• plazmatické buňky imunologie   MeSH
• předškolní dítě MeSH
• přesmyk imunoglobulinových tříd imunologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stárnutí imunologie   MeSH
• těžké řetězce imunoglobulinů imunologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

HIV-1 infection is associated with an early and profound depletion of mucosal memory CD4+ T cells, a population that plays an indispensable role in the regulation of isotype switching and transepithelial transport of antibodies. In this study, we addressed whether the depletion of CD4+ T cell in HIV-1-infected individuals results in altered humoral responses specific to antigens encountered at mucosal surfaces. Comprehensive protein microarray of systemic humoral responses to intestinal microbiota demonstrated reduced IgG responses to antigens derived from Proteobacteria and Firmicutes but not Bacteroidetes. Importantly, intestinal secretions of antiretroviral therapy-treated HIV-1-infected individuals exhibited a significant elevation of IgM levels and decreased IgA/IgM and IgG/IgM ratios of antibodies specific to a variety of microbial and food antigens. The presented findings indicate reduced competence of mucosal B cells for class switch recombination from IgM to other isotypes limiting their capacity to react to changing antigenic variety in the gut lumen. Decreased availability of microbiota-specific IgA and IgG may be an important factor contributing to the translocation of microbial antigens across the intestinal mucosal barrier and their systemic dissemination that drives chronic inflammation in HIV-1-infected individuals.

• MeSH
• antigeny imunologie   MeSH
• B-lymfocyty imunologie   MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• chronická nemoc MeSH
• HIV infekce imunologie   virologie   MeSH
• HIV-1 imunologie   MeSH
• humorální imunita MeSH
• imunoglobulin A imunologie   MeSH
• imunoglobulin G imunologie   MeSH
• lidé MeSH
• mikrobiota imunologie   MeSH
• potraviny MeSH
• přesmyk imunoglobulinových tříd MeSH
• regulace genové exprese MeSH
• střevní sliznice imunologie   virologie   MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The ileal Peyers patches (IPP) of newborn germfree (GF) piglets were isolated into blind loops and the piglets colonized with a defined probiotic microflora. After 5 weeks, IgA levels in the intestinal lavage (IL) of loop piglets remained at GF levels and IgM comprised ∼70% while in controls, IgA levels were elevated 5-fold and comprised ∼70% of total Igs. Loop piglets also had reduced serum IgA levels suggesting the source of serum IgA had been interrupted. The isotype profile for loop contents was intermediate between that in the IL of GF and probiotic controls. Surprisingly, colonization alone did not result in repertoire diversification in the IPP. Rather, colonization promoted pronounced proliferation of fully switched IgA(+)IgM(-) B cells in the IPP that supply early, non-diversified "natural" SIgA antibodies to the gut lumen and a primary IgA response in serum.

• MeSH
• aktivace lymfocytů MeSH
• B-lymfocyty fyziologie   MeSH
• buněčná diferenciace MeSH
• gnotobiologické modely MeSH
• ileum imunologie   MeSH
• imunoglobulin A sekreční genetika   MeSH
• imunoglobulin M genetika   MeSH
• imunologická paměť MeSH
• kultivované buňky MeSH
• novorozená zvířata MeSH
• Peyerovy pláty imunologie   MeSH
• prasata imunologie   MeSH
• přesmyk imunoglobulinových tříd MeSH
• probiotika aplikace a dávkování   MeSH
• proliferace buněk MeSH
• rozmanitost protilátek MeSH
• střevní mikroflóra imunologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH