Common variable immunodeficiency disorder (CVID) is the most common form of primary antibody immunodeficiency. Due to low antibody levels, CVID patients receive intravenous or subcutaneous immunoglobulin replacement therapy as treatment. CVID is associated with the chronic activation of granulocytes, including an increased percentage of low-density neutrophils (LDNs). In this study, we examined changes in the percentage of LDNs and the expression of their surface markers in 25 patients with CVID and 27 healthy donors (HD) after in vitro stimulation of whole blood using IVIg. An oxidative burst assay was used to assess the functionality of LDNs. CVID patients had increased both relative and absolute LDN counts with a higher proportion of mLDNs compared to iLDNs, distinguished based on the expression of CD10 and CD16. Immature LDNs in the CVID and HD groups had significantly reduced oxidative burst capacity compared to mature LDNs. Interestingly we observed reduced oxidative burst capacity, reduced expression of CD10 after stimulation of WB, and higher expression of PD-L1 in mature LDNs in CVID patients compared to HD cells. Our data indicate that that the functional characteristics of LDNs are closely linked to their developmental stage. The observed reduction in oxidative burst capacity in mLDNs in CVID patients could contribute to an increased susceptibility to recurrent bacterial infections among CVID patients.
- MeSH
- Common Variable Immunodeficiency * MeSH
- Phenotype MeSH
- Humans MeSH
- Neutrophils * MeSH
- Flow Cytometry MeSH
- Respiratory Burst MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Many forms of immunodeficiency have been described. There may be about 150 different types, some with inherited or genetic causes, some with recognized specific molecular defects. Most can be classified as affecting the humoral or cellular, sometimes both, immune systems. In adults, the most common symptomatic form, albeit rare, is common variable immunodeficiency, or CVID. In recent years, it has also been suggested that rather than a single disease, CVID represents a heterogeneous group marked by panhypogammaglobulinemia and variable clinical features. In most, intestinal symptoms predominate, including, but not limited to sprue-like intestinal disease, a disorder that fails to respond to a gluten-free diet. Also, several types of colonic disease may occur similar to ulcerative colitis, Crohn’s disease and, most recently reported, collagenous colitis. Treatment of these disorders remains largely empirical and based on disease seen in the absence of CVID. Added molecular genetic studies are needed to more fully characterize the immune defects in CVID and, ultimately, to provide more evidence-based treatments.
Běžná variabilní imunodeficience (common variable immunodeficiency, CVID) představuje heterogenní skupinu primárních protilátkových poruch imunity. V klinickém obrazu dominují bakteriální infekce, autoimunitní / dysregulanční komplikace a nádory. Zatímco infekční komplikace jsou poměrně dobře ovlivnitelné substituční léčbou imunoglobuliny, neinfekční komplikace významně negativně ovlivňují prognózu pacientů. Mezi nejzávažnější patří granulomatózně/lymfocytární intersticiální plicní nemoc, enteropatie vedoucí k malabsorpci a hepatopatie provázená portální hypertenzí. Léčebné strategie zahrnují kromě klasické imunosuprese i biologickou léčbu, především rituximab. Nádorová onemocnění postihují významně mladší jedince. Jedná se především o lymfomy a adenokarcinom žaludku. Z těchto důvodů je proto nezbytné pravidelné provádění screeningových vyšetření. Provedení genetického vyšetření je indikováno u všech nemocných, především však u těch, kteří trpí neinfekčními komplikacemi, což může pomoci při správné volbě cílené terapie.
Common variable immunodeficiency (CVID) represents a heterogeneous group of primary antibody immunodeficiencies. Bacterial infections, autoimmune/dysregulatory complications and tumours dominate in the clinical picture. While infectious complications are satisfactory controlled with immunoglobulin substitution therapy, non-infectious complications significantly negatively affect patients’ prognosis. The most serious include granulomatous/lymphocytic interstitial lung disease, enteropathy leading to malabsorption, and hepatopathy with portal hypertension. Treatment strategies include, in addition to convention immunosuppression, biological treatment, especially rituximab. The most common types of cancer are lymphoma and gastric adenocarcinoma, which affect patients at a significantly younger age. It is therefore necessary to carry out regular screening examinations. All patients, especially those with non-infectious complications, should undergo genetic testing, which can help to provide the most suitable targeted therapy.
Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.
- MeSH
- Apoptosis genetics MeSH
- Hypergammaglobulinemia * MeSH
- Humans MeSH
- Lymphoproliferative Disorders * genetics MeSH
- TOR Serine-Threonine Kinases MeSH
- Germinal Center MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Common variable immunodeficiency (CVID) is characterized by an impaired postvaccination response, high susceptibility to respiratory tract infections, and a broad spectrum of noninfectious complications. Thus, patients with CVID may be at high risk for COVID-19, and vaccination's role in prevention is questionable. OBJECTIVE: We evaluated the clinical outcomes, safety, and dynamics of humoral and T-cell immune responses induced by the mRNA vaccine BNT162b2 in CVID. METHODS: This prospective observational cohort study focused on the clinical outcomes (proportion of infected patients and disease severity), safety (incidences of adverse events and changes in laboratory parameters), and dynamics of humoral (specific postvaccination and virus-neutralizing antibody assessment) and T-cell immune responses (anti-SARS-CoV-2-specific T-cell detection) in 21 patients with CVID after a two-dose administration of BNT162b2. The patients were observed for 6 months. RESULTS: Humoral response was observed in 52% of patients (11 of 21) at month 1 after vaccination but continuously decreased to 33.3% at month 6 (five of 15). Nevertheless, they had a remarkably lower anti-SARS-CoV-2 neutralizing antibody titer compared with healthy controls. The T-cell response was measurable in 46% of patients with CVID (six of 13) at month 1 and persisted over the study period. Mild infection occurred in three patients within the follow-up period (14.3%). The vaccine also exhibited a favorable safety profile. CONCLUSIONS: The BNT162b2 vaccine elicited a measurable antibody response in a high proportion of patients, but it was limited by low titer of virus-neutralizing antibodies and rapid waning of anti-receptor-binding domain SARS-CoV-2-specific antibodies. T-cell response was detected in one-third of patients and remained stable within the follow-up period. Vaccination has favorable safety and clinical-related outcomes in preventing severe COVID-19.
- MeSH
- Common Variable Immunodeficiency * MeSH
- COVID-19 * prevention & control MeSH
- Humans MeSH
- Antibodies, Neutralizing MeSH
- Primary Immunodeficiency Diseases * MeSH
- Prospective Studies MeSH
- Antibodies, Blocking MeSH
- Antibodies, Viral MeSH
- SARS-CoV-2 MeSH
- BNT162 Vaccine MeSH
- Vaccines * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Observational Study MeSH
- Research Support, Non-U.S. Gov't MeSH
PURPOSE: About 15% of patients with common variable immunodeficiency (CVID) develop a small intestinal enteropathy, which resembles celiac disease with regard to histopathology but evolves from a distinct, poorly defined pathogenesis that has been linked in some cases to chronic norovirus (NV) infection. Interferon-driven inflammation is a prominent feature of CVID enteropathy, but it remains unknown how NV infection may contribute. METHODS: Duodenal biopsies of CVID patients, stratified according to the presence of villous atrophy (VA), IgA plasma cells (PCs), and chronic NV infection, were investigated by flow cytometry, multi-epitope-ligand cartography, bulk RNA-sequencing, and RT-qPCR of genes of interest. RESULTS: VA development was connected to the lack of intestinal (IgA+) PC, a T helper 1/T helper 17 cell imbalance, and increased recruitment of granzyme+CD8+ T cells and pro-inflammatory macrophages to the affected site. A mixed interferon type I/III and II signature occurred already in the absence of histopathological changes and increased with the severity of the disease and in the absence of (IgA+) PCs. Chronic NV infection exacerbated this signature when compared to stage-matched NV-negative samples. CONCLUSIONS: Our study suggests that increased IFN signaling and T-cell cytotoxicity are present already in mild and are aggravated in severe stages (VA) of CVID enteropathy. NV infection preempts local high IFN-driven inflammation, usually only seen in VA, at milder disease stages. Thus, revealing the impact of different drivers of the pathological mixed IFN type I/III and II signature may allow for more targeted treatment strategies in CVID enteropathy and supports the goal of viral elimination.
- MeSH
- Atrophy complications pathology MeSH
- Common Variable Immunodeficiency * complications immunology MeSH
- CD8-Positive T-Lymphocytes MeSH
- Immunoglobulin A MeSH
- Caliciviridae Infections * immunology MeSH
- Interferons MeSH
- Humans MeSH
- Norovirus * physiology MeSH
- Inflammation complications MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Agammaglobulinemia diagnosis drug therapy MeSH
- Common Variable Immunodeficiency diagnosis immunology therapy MeSH
- IgA Deficiency MeSH
- Hyper-IgM Immunodeficiency Syndrome diagnosis therapy MeSH
- Immunologic Tests methods MeSH
- Humans MeSH
- Neonatal Screening MeSH
- Primary Immunodeficiency Diseases diagnosis therapy MeSH
- Antibodies analysis blood MeSH
- Immunologic Deficiency Syndromes * diagnosis therapy MeSH
- Vaccination methods MeSH
- Check Tag
- Humans MeSH
Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.
Úvod: Běžná variabilní imunodeficience (CVID) je heterogenním souborem onemocnění představující nejčastější symptomatickou skupinu vrozených poruch tvorby protilátek. Toto onemocnění je charakterizované hypogamaglobulinémií ve třídě IgG, IgA a/nebo IgM doprovázenou porušenou protilátkovou odpovědí po antigenní stimulaci. Kromě infekčních komplikací vycházejících ze snížené funkce imunitního systému je toto onemocnění často komplikováno klinickými projevy dysregulace funkce imunitního systému. Mezi tyto komplikace patří také granulomatózně-lymfocytární intersticiální plicní nemoc (GLILD). Jedná se o multisystémové granulomatózní a/nebo zánětlivé onemocnění klinicky významně ovlivňující mortalitu a morbiditu těchto pacientů. Materiál a metody: Na našem pracovišti bylo v letech 2012−2023 sledováno celkem 8 pacientů s CVID/GLILD (5 žen, věkové rozmezí 20‒33, medián věku v době stanovení diagnózy 23 let; 3 muži, věkové rozmezí 23‒49 let; medián věku při stanovení diagnózy 23 let). Všichni sledovaní pacienti byli nekuřáci. U většiny pacientů diagnóza CVID předcházela diagnózu CVID/GLILD. Histologický průkaz GLILD byl potvrzen u 6/8 nemocných (75 %). Plicní postižení bylo hodnoceno na základě plicních funkčních parametrů a zobrazovacích metod (zadopředního snímku hrudníku a HRCT hrudníku). Výsledky: CVID/GLILD je prezentován na osmi případech s různým charakterem plicního a mimoplicního postižení. Rozsah postižení plicního parenchymu na HRCT hrudníku hodnocený při vstupním vyšetření metodou automatické analýzy byl u sledovaných pacientů v rozmezí 6‒33 % (s průměrem 18 %). Všichni pacienti byli léčeni imunosupresivy, 3 z nich monoterapií kortikosteroidy (GK), zbylí kombinovanou imunosupresí. Medián follow-up od stanovení diagnózy CVID/GLILD byl 9,5 let. Nebyl dosažen medián přežití, zemřel jen 1 pacient. Závěr: Společná mezioborová spolupráce pneumologa, hematologa a imunologa je základem naší péče o pacienty s CVID/GLILD. Terapie imunosupresivy je dlouhodobá, s rizikem relapsů, ale bez většího rizika infekčních komplikací. Monoterapie GK je ve většině případů nedostatečná a jako efektivnější z pohledu klinických potíží, funkčního vyšetření a zobrazovacích metod se jeví kombinovaná terapie rituximabem s dalším imunosupresivem (rituximab s kortikoidy, rituximab s GK a mykofenol mofetilem).
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- MeSH
- Autoantibodies * MeSH
- Common Variable Immunodeficiency * diagnosis epidemiology MeSH
- Immunologic Tests MeSH
- Humans MeSH
- Prevalence MeSH
- Check Tag
- Humans MeSH
- Publication type
- Letter MeSH
- Research Support, Non-U.S. Gov't MeSH
