The immune response type organized against viral infection is determinant in the prognosis of some infections. This work has aimed to study Th polarization in acute COVID-19 and its possible ...association with the outcome through an observational prospective study. Fifty-eight COVID-19 patients were recruited in the Medicine Department of the hospital "12 de Octubre," 55 patients remaining after losses to follow-up. Four groups were established according to maximum degree of disease progression. T-helper cell percentages and phenotypes, analyzed by flow cytometer, and serum cytokines levels, analyzed by Luminex, were evaluated when the microbiological diagnosis (acute phase) of the disease was obtained. Our study found a significant reduction of %Th1 and %Th17 cells with higher activated %Th2 cells in the COVID-19 patients compared with reference population. A higher percent of senescent Th2 cells was found in the patients who died than in those who survived. Senescent Th2 cell percentage was an independent risk factor for death (OR: 13.88) accompanied by the numbers of total lymphocytes (OR: 0.15) with an AUC of 0.879. COVID-19 patients showed a profile of pro-inflammatory serum cytokines compared to controls, with higher levels of IL-2, IL-6, IL-15, and IP-10. IL-10 and IL-13 were also elevated in patients compared to controls. Patients who did not survive presented significantly higher levels of IL-15 than those who recovered. No significant differences were observed according to disease progression groups. The study has shown that increased levels of IL-15 and a high Th2 response are associated with a fatal outcome of the disease.
Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD ...due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (
NRAS, KRAS
), susceptibility to EBV (
MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9
), antibody deficiency (
PIK3CD
gain of function (GOF)
, PIK3R1
loss of function (LOF)
, CARD11
GOF), regulatory T-cells defects (
CTLA4, LRBA, STAT3
GOF
, IL2RA, IL2RB, DEF6
), combined immunodeficiencies (
ITK, STK4
), defects in intrinsic and innate immunity and predisposition to infection (
STAT1
GOF,
IL12RB1
) and autoimmunity/autoinflammation (
ADA2, TNFAIP3,TPP2, TET2
). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.
Analysis of genetically defined immunodeficient patients allows study of the effect of the absence of specific proteins on human immune function in real‐world conditions. Here we have addressed the ...importance of type I interferon signalling for human NK cell development by studying the phenotype and function of circulating NK cells isolated from patients suffering primary immunodeficiency disease due to mutation of either the human interferon regulatory factor 9 (IRF9) or the signal transducer and activator of transcription 2 (STAT2) genes. IRF9, together with phosphorylated STAT1 and STAT2, form a heterotrimer called interferon stimulated gene factor 3 (ISGF3) which promotes the expression of hundreds of IFN‐stimulated genes that mediate antiviral function triggered by exposure to type I interferons. IRF9‐ and STAT2‐deficient patients are unable to respond efficiently to stimulation by type I interferons and so our experiments provide insights into the importance of type I interferon signalling and the consequences of its impairment on human NK cell biology. Surprisingly, the NK cells of these patients display essentially normal phenotype and function.
Mutations in IRF9 and STAT2 that render an individual unable to respond to Type I interferons have no discernible effect on human natural killer cell development and function.
Mortality of patients on hemodialysis (HD) remains very high despite recent improvements in HD techniques. Cardiovascular (CV) complications and infections are the main causes of death. Some studies ...suggest that disturbances in the immune system could play a role in this disproportionate mortality, through the links of immunity with inflammation and propensity to infections. However, few studies have addressed the role of lymphocyte populations and the global and CV mortality of HD patients.
To analyze the relationship of peripheral blood lymphocyte populations (PBLP) and all-cause and CV mortality of HD patients.
We design a prospective observational single center study in a cohort of HD prevalent patients. PBLP were analyzed at baseline and after 1 year and patients were followed for a 5-year period. Main outcomes were all-cause and CV mortality.
One hundred and four patients (51% male, mean age 64.8 ± 15 years) were included. Follow-up was 18 (7-47) months. Fifty-five patients (52.8%) died, main causes of death being CVD (40%) and infections (29.1%). Low total lymphocyte counts were found in 47 patients (45.2%), and the most frequency lymphopenias were CD19
B-cell (57.7%), CD3
(40.4%), and CD4
(36.5%). After 1 year, all determinations were lower except CD56
CD16
CD3
natural killer. Patient survival was significantly lower in patients with a CD19
B-cell count < 100 cells/μL at baseline as compared to patients with CD19
B-cell ≥ 100 cells/μL counts at the end of follow-up (16.5 vs 54%,
= 0.003). By multivariable analysis, age, history of CV disease, Charlson index, a KT/V < 1.2, and a CD19
B-cell count < 100 cells/μL at baseline and after 1-year were factors associated with of all-cause mortality. A CD19
B-cell count < 100 cells/μL at baseline was associated with CV mortality.
CD19
B-cell lymphopenia is very common among HD patients, and it could be an independent predictor of all-cause and CV mortality. More studies are needed to confirm these findings.
NK degranulation plays an important role in the cytotoxic activity of innate immunity in the clearance of intracellular infections and is an important factor in the outcome of the disease. This work ...has studied NK degranulation and innate immunological profiles and functionalities in COVID-19 patients and its association with the severity of the disease. A prospective observational study with 99 COVID-19 patients was conducted. Patients were grouped according to hospital requirements and severity. Innate immune cell subpopulations and functionalities were analyzed. The profile and functionality of innate immune cells differ between healthy controls and severe patients; CD56dim NK cells increased and MAIT cells and NK degranulation rates decreased in the COVID-19 subjects. Higher degranulation rates were observed in the non-severe patients and in the healthy controls compared to the severe patients. Benign forms of the disease had a higher granzymeA/granzymeB ratio than complex forms. In a multivariate analysis, the degranulation capacity resulted in a protective factor against severe forms of the disease (OR: 0.86), whereas the permanent expression of NKG2D in NKT cells was an independent risk factor (OR: 3.81; AUC: 0.84). In conclusion, a prompt and efficient degranulation functionality in the early stages of infection could be used as a tool to identify patients who will have a better evolution.
Human inborn errors of immunity (IEI) affecting the type I interferon (IFN-I) induction pathway have been associated with predisposition to severe viral infections. Hemophagocytic lymphohistiocytosis ...(HLH) is a life-threatening systemic hyperinflammatory syndrome that has been increasingly associated with inborn errors of IFN-I-mediated innate immunity. Here is reported a novel case of complete deficiency of STAT2 in a 3-year-old child that presented with typical features of HLH after mumps, measles, and rubella vaccination at the age of 12 months. Due to the life-threatening risk of viral infection, she received SARS-CoV-2 mRNA vaccination. Unfortunately, she developed multisystem inflammatory syndrome in children (MIS-C) after SARS-CoV-2 infection, 4 months after the last dose. Functional studies showed an impaired IFN-I-induced response and a defective IFNα expression at later stages of STAT2 pathway induction. These results suggest a possible more complex mechanism for hyperinflammatory reactions in this type of patients involving a possible defect in the IFN-I production. Understanding the cellular and molecular links between IFN-I-induced signaling and hyperinflammatory syndromes can be critical for the diagnosis and tailored management of these patients with predisposition to severe viral infection.
Apoptosis plays an important role in controlling the adaptive immune response and general homeostasis of the immune cells, and impaired apoptosis in the immune system results in autoimmunity and ...immune dysregulation. In the last 25 years, inherited human diseases of the Fas-FasL pathway have been recognized. Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity, characterized clinically by nonmalignant and noninfectious lymphoproliferation, autoimmunity, and increased risk of lymphoma due to a defect in lymphocyte apoptosis. The laboratory hallmarks of ALPS are an elevated percentage of T-cell receptor αβ double negative T cells (DNTs), elevated levels of vitamin B12, soluble FasL, IL-10, IL-18 and IgG, and defective in vitro Fas-mediated apoptosis. In order of frequency, the genetic defects associated with ALPS are germinal and somatic ALPS-FAS, ALPS-FASLG, ALPS-CASP10, ALPS-FADD, and ALPS-CASP8. Partial disease penetrance and severity suggest the combination of germline and somatic FAS mutations as well as other risk factor genes. In this report, we summarize human defects of apoptosis leading to ALPS and defects that are known as ALPS-like syndromes that can be clinically similar to, but are genetically distinct from, ALPS. An efficient genetic and immunological diagnostic approach to patients suspected of having ALPS or ALPS-like syndromes is essential because this enables the establishment of specific therapeutic strategies for improving the prognosis and quality of life of patients.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause ...a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance.
We sought to define TCF3 haploinsufficiency (HI) biology and its association with immunodeficiency.
Patient clinical data and blood samples were analyzed. Flow cytometry, Western blot analysis, plasmablast differentiation, immunoglobulin secretion, and transcriptional activity studies were conducted on individuals carrying TCF3 variants. Mice with a heterozygous Tcf3 deletion were analyzed for lymphocyte development and phenotyping.
Individuals carrying monoallelic LOF TCF3 variants showed B-cell defects (eg, reduced total, class-switched memory, and/or plasmablasts) and reduced serum immunoglobulin levels; most but not all presented with recurrent but nonsevere infections. These TCF3 LOF variants were either not transcribed or translated, resulting in reduced wild-type TCF3 protein expression, strongly suggesting HI pathophysiology for the disease. Targeted RNA sequencing analysis of T-cell blasts from TCF3-null, dominant negative, or HI individuals clustered away from healthy donors, implying that 2 WT copies of TCF3 are needed to sustain a tightly regulated TCF3 gene–dosage effect. Murine TCF3 HI resulted in a reduction of circulating B cells but overall normal humoral immune responses.
Monoallelic LOF TCF3 mutations cause a gene-dosage–dependent reduction in wild-type protein expression, B-cell defects, and a dysregulated transcriptome, resulting in immunodeficiency. Tcf3+/- mice partially recapitulate the human phenotype, underscoring the differences between TCF3 in humans and mice.
Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans,
...,
, and
gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast,
mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in
associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor β (TRB) repertoire in regulatory T cells (T
s), conventional CD4
(T
), and CD8
T cells from 6 patients with
mutations and healthy controls. T
function was assessed by studying its ability to suppress proliferation of T
cells. T
cells of patients with
defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of T
cells from patients with
deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with
mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.
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