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Genes Dec 2021Mutations of the gene, which encodes for the interleukin-2 receptor common gamma chain (γ, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID)...
Mutations of the gene, which encodes for the interleukin-2 receptor common gamma chain (γ, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID) associated with a TBNK phenotype as a result of dysfunctional γ-JAK3-STAT5 signaling. Lately, hypomorphic mutations of the gene have been described causing atypical SCID with a milder phenotype. Here, we report three brothers with low-normal lymphocyte counts and susceptibility to recurrent respiratory infections and cutaneous warts. The clinical presentation combined with dysgammaglobulinemia suspected an inherited immunity disorder, which has been proven by Next Generation Sequencing as a novel c.458T > C; p.Ile153Thr missense-mutation. Subsequent functional characterization revealed impaired T-cell proliferation, low TREC levels and a skewed TCR Vβ repertoire in all three patients. Interestingly, investigation of various subpopulations showed normal expression of CD132 but with partially impaired STAT5 phosphorylation compared to healthy controls. Additionally, we performed precise genetic analysis of subpopulations revealing spontaneous somatic reversion, predominately in lymphoid derived CD3, CD4 and CD8 T cells. Our data demonstrate that the atypical SCID phenotype noticed in these three brothers is due to the combination of hypomorphic IL-2RG function and somatic reversion.
Topics: Adult; CD8-Positive T-Lymphocytes; Cell Proliferation; Humans; Interleukin Receptor Common gamma Subunit; Male; Mutation; Phenotype; X-Linked Combined Immunodeficiency Diseases; Young Adult
PubMed: 35052377
DOI: 10.3390/genes13010035 -
Clinical Reviews in Allergy & Immunology Aug 2022The field of Immunology is one that has undergone great expansion in recent years. With the advent of new diagnostic modalities including a variety of genetic tests... (Review)
Review
The field of Immunology is one that has undergone great expansion in recent years. With the advent of new diagnostic modalities including a variety of genetic tests (discussed elsewhere in this journal), the ability to diagnose a patient with a primary immunodeficiency disorder (PIDD) has become a more streamlined process. With increased availability of genetic testing for those with suspected or known PIDD, there has been a significant increase in the number of genes associated with this group of disorders. This is of great importance as a misdiagnosis of these rare diseases can lead to a delay in what can be critical treatment options. At times, those options can include life-saving medications or procedures. Presentation of patients with PIDD can vary greatly based on the specific genetic defect and the part(s) of the immune system that is affected by the variation. PIDD disorders lead to varying levels of increased risk of infection ranging from a mild increase such as with selective IgA deficiency to a profound risk with severe combined immunodeficiency. These diseases can also cause a variety of other clinical findings including autoimmunity and gastrointestinal disease.
Topics: Autoimmunity; Genetic Testing; Humans; IgA Deficiency; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases
PubMed: 35020168
DOI: 10.1007/s12016-021-08881-2 -
Iranian Journal of Allergy, Asthma, and... Dec 2021Respiratory diseases are considered as significant causes of morbidity and mortality in primary immunodeficiencies. This study aimed to reveal the radiologic patterns of...
Respiratory diseases are considered as significant causes of morbidity and mortality in primary immunodeficiencies. This study aimed to reveal the radiologic patterns of thoracic involvement in these disorders. A total of 58 patients, including 38 cases with combined cellular-humoral and 20 cases with humoral immunodeficiencies, were enrolled in this study. The "combined" group consisted of 12 cases with severe combined immunodeficiency (SCID) and 26 cases with combined immunodeficiency. The "humoral" group included seven patients with Hyper IgM syndrome (HIGMs), seven cases with common variable immunodeficiency (CVID), three patients with X-linked agammaglobulinemia, and three patients with other types of humoral primary immunodeficiencies (PIDs). The mean age of patients at the time of evaluation was 3.3±3.8 and 5.3±3.9 years in combined and humoral groups, respectively. The findings of chest X-rays and CT scans were interpreted and compared. There was a significant difference for alveolar opacification between combined and humoral immunodeficiencies (58% vs. 30%). The bronchopneumonia-like pattern was detected as a significant finding in patients with SCID (42%) and HIGMs (43%). Atrophy of the thymus was detected significantly often in cases of SCID (67%). Two patients with CVID and lipopolysaccharide-responsive and beige-like anchor protein deficiency showed parenchymal changes of granulomatous lymphocytic interstitial lung disease. No significant difference was detected for bronchiectasis, bronchitis/bronchiolitis patterns, pleural effusion, and thoracic lymphadenopathy. Distinct subtypes of primary immunodeficiency may provoke differing and comparable radiological patterns of thoracic involvement; which can clue the clinician and radiologist to the diagnosis of the disease.
Topics: Agammaglobulinemia; Child; Child, Preschool; Common Variable Immunodeficiency; Diagnosis, Differential; Early Diagnosis; Female; Genetic Diseases, X-Linked; Humans; Hyper-IgM Immunodeficiency Syndrome; Infant; Lung; Male; Retrospective Studies; Severe Combined Immunodeficiency; Tomography, X-Ray Computed
PubMed: 34920652
DOI: 10.18502/ijaai.v20i6.8020 -
Hematology. American Society of... Dec 2021As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of...
As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of immunity (IEI) and the consequences of immunotherapy. The facile recognition of IEI presenting with neutropenia provides an avenue for hematologists to facilitate early diagnosis and expedite biologically rationale care. Moreover, enhancing the understanding of the molecular mechanisms driving neutropenia in IEI-decreased bone marrow reserves, diminished egress from the bone marrow, and decreased survival-offers an opportunity to further dissect the pathophysiology driving neutropenia secondary to iatrogenic immune dysregulation, eg, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.
Topics: Chediak-Higashi Syndrome; Female; Humans; Hyper-IgM Immunodeficiency Syndrome; Iatrogenic Disease; Immune Checkpoint Inhibitors; Immunotherapy; Middle Aged; Neutropenia; Primary Immunodeficiency Diseases
PubMed: 34889406
DOI: 10.1182/hematology.2021000285 -
Japanese Journal of Infectious Diseases May 2022The prevalence and mortality rates of coronavirus disease 2019 (COVID-19) widely vary among populations. Mucosal immunity is the first barrier to the pathogen's entry...
The prevalence and mortality rates of coronavirus disease 2019 (COVID-19) widely vary among populations. Mucosal immunity is the first barrier to the pathogen's entry into the body. Immunoglobulin A (IgA) is the primary antibody responsible for mucosal immunity. We explored the relationship between selective IgA deficiency (SIgAD) and COVID-19 severity. We included 424 patients (203 women) with COVID-19. Eleven patients had SIgAD. Laboratory data of patients with SIgAD and normal IgA levels were compared. The relationship between SIgAD and severe COVID-19 infection was explored using logistic regression analysis. In the univariate logistic regression analysis, the risk of severe COVID-19 disease in patients with SIgAD was approximately 7.7-fold higher than that in other patients (odds ratio [OR], 7.789; 95% confidence interval [CI], 1.665-36.690, P = 0.008), while it was 4-fold (OR, 4.053; 95% CI, 1.182-13.903, P = 0.026) higher in the multivariate logistic regression analysis. Serum IgA levels were positively correlated with total lymphocyte counts and negatively correlated with C-reactive protein levels, which was a risk factor for severe COVID-19. In patients with SIgAD, the number of severe acute respiratory coronaviruses 2 that pass through mucosal membranes may be increased, leading to complications such as cytokine storm syndrome and acute respiratory distress syndrome.
Topics: COVID-19; Female; Humans; IgA Deficiency; Immunoglobulin A; Prognosis
PubMed: 34588364
DOI: 10.7883/yoken.JJID.2021.281 -
Frontiers in Immunology 2021Patients with antibody deficiency may experience exceptionally long diagnostic delays, increasing the risk of life-threatening infections, end-organ damage, mortality,... (Clinical Trial)
Clinical Trial Comparative Study
BACKGROUND
Patients with antibody deficiency may experience exceptionally long diagnostic delays, increasing the risk of life-threatening infections, end-organ damage, mortality, and health costs.
OBJECTIVE
This study aimed to analyze serum protein electrophoresis and verify the correlation between calculated globulin (CG, total protein minus albumin levels) or electrophoretically determined serum gamma globulin fraction (Gamma) with IgG levels in children and adolescents under 18 years old (yo).
METHODS
We analyzed serum protein electrophoresis (GC or Gamma) and IgG levels from 1215 children and adolescents under 18 yo, classified into 5 age groups. We verified the correlation between CG or Gamma with serum IgG levels.
RESULTS
Serum IgG levels varied according to age groups (from 4.3 ± 2.3 g/l in children under 6 months old to 11.4 ± 3.2 g/l in adolescents in the 10-<18 yo group). CG sensitivity and specificity to detect IgG below the reference range for all patients were 93.1% and 81.8%, respectively, and varied according to age group. Gamma sensitivity and specificity for all patients were 100% and 87.8%, respectively, and varied according to age group as well. We found serum IgG levels below the age reference level in 29 patients (2.4% of the cases) using CG or Gamma levels.
CONCLUSION
Both CG and Gamma levels may be of utility as a screening tool for earlier diagnosis of antibody deficiency in children and adolescents under 18 yo.
Topics: Adolescent; Age Factors; Antibodies; Area Under Curve; Blood Protein Electrophoresis; Brazil; Child; Child, Preschool; Dysgammaglobulinemia; Female; Humans; IgA Deficiency; IgG Deficiency; Immunoglobulin M; Infant; Infant, Newborn; Male; Mass Screening; ROC Curve; Serum Globulins
PubMed: 34497609
DOI: 10.3389/fimmu.2021.712637 -
Journal of Clinical Immunology Nov 2021Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical... (Clinical Trial)
Clinical Trial
Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).
Topics: Adolescent; Adult; Ataxia Telangiectasia; B-Lymphocytes; Child; Child, Preschool; Female; Humans; IgA Deficiency; IgG Deficiency; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Infant; Lymphocyte Count; Male; Middle Aged; T-Lymphocyte Subsets; Young Adult
PubMed: 34477998
DOI: 10.1007/s10875-021-01090-8 -
Respiratory Research Aug 2021The innate and adaptive immune system is involved in the airway inflammation associated with acute exacerbations in patients with chronic obstructive pulmonary disease... (Randomized Controlled Trial)
Randomized Controlled Trial
Association of mannose-binding lectin, ficolin-2 and immunoglobulin concentrations with future exacerbations in patients with chronic obstructive pulmonary disease: secondary analysis of the randomized controlled REDUCE trial.
BACKGROUND
The innate and adaptive immune system is involved in the airway inflammation associated with acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). We evaluated the association of mannose-binding lectin (MBL), immunoglobulin (Ig) and ficolin-2 concentrations with COPD exacerbations and according to the glucocorticoid treatment duration for an index exacerbation.
METHODS
Post-hoc analysis of the randomized, double-blind, placebo-controlled REDUCE trial of 5 vs. 14 days of glucocorticoid treatment for an index exacerbation. MBL, ficolin-2 and total IgG/IgA and subclass concentrations were determined in stored samples drawn (n = 178) 30 days after the index exacerbation and associated with the risk of re-exacerbation during a 180-day follow-up period.
RESULTS
IgG and subclass concentrations were significantly lower after 14 days vs. 5 days of glucocorticoid treatment. Patients with higher MBL concentrations were more likely to suffer from a future exacerbation (multivariable hazard ratio 1.03 per 200 ng/ml increase (95% confidence interval (CI) 1.00-1.06), p = 0.048), whereas ficolin-2 and IgG deficiency were not associated. The risk was most pronounced in patients with high MBL concentrations, IgG deficiency and 14 days of glucocorticoid treatment pointing towards an interactive effect of MBL and IgG deficiency in the presence of prolonged glucocorticoid treatment duration [Relative excess risk due to interaction 2.13 (95% CI - 0.41-4.66, p = 0.10)]. IgG concentrations were significantly lower in patients with frequent re-exacerbations (IgG, 7.81 g/L vs. 9.53 g/L, p = 0.03).
CONCLUSIONS
MBL modified the short-term exacerbation risk after a recent acute exacerbation of COPD, particularly in the setting of concurrent IgG deficiency and recent prolonged systemic glucocorticoid treatment. Ficolin-2 did not emerge as a predictor of a future exacerbation risk.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Forecasting; Humans; IgG Deficiency; Immunoglobulin G; Lectins; Male; Mannose-Binding Lectin; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Factors; Ficolins
PubMed: 34391418
DOI: 10.1186/s12931-021-01822-9 -
Veterinary Medicine and Science Nov 2021Immunoglobulin A (IgA) deficiency, chronic enteropathies and exocrine pancreatic insufficiency (EPI) have a high prevalence in German Shepherd dogs (GSD). This...
BACKGROUND
Immunoglobulin A (IgA) deficiency, chronic enteropathies and exocrine pancreatic insufficiency (EPI) have a high prevalence in German Shepherd dogs (GSD). This prospective study determined the prevalence of faecal IgA deficiency (IgAD) in GSD and investigated several candidate genes and the canine genome for a region or locus co-segregating with IgAD in GSD. Faecal IgA concentrations were quantified and genomic DNA was extracted from 8 GSD with an undetectable faecal IgA (classified as IgAD) and 80 non-IgAD GSD. The canine minimal screening set II microsatellite markers were genotyped, with evidence of an association at p < 1.0 × 10 . Faecal IgA concentrations were also tested for an association with patient clinical and biochemical variables.
RESULTS
Allele frequencies observed using the candidate gene approach were not associated with faecal IgAD in GSD. In the genome-wide association study (GWAS), the microsatellite marker FH2361 on canine chromosome 33 approached statistical significance for a link with IgAD in GSD (p = 1.2 × 10 ). A subsequent GWAS in 11 GSD with EPI and 80 control GSD revealed a significant association between EPI and FH2361 (p = 8.2 × 10 ).
CONCLUSIONS
The lack of an association with the phenotype of faecal IgAD in GSD using the candidate gene approach and GWAS might suggests that faecal IgAD in GSD is a relative or transient state of deficiency. However, the prevalence of faecal IgAD in GSD appears to be low (<3%). The relationship between faecal IgAD, EPI and loci close to FH2361 on canine chromosome 33 in GSD warrants further investigation.
Topics: Animals; Dog Diseases; Dogs; Genome-Wide Association Study; Genomics; IgA Deficiency; Immunoglobulin A; Prospective Studies
PubMed: 34390535
DOI: 10.1002/vms3.603 -
BMC Immunology Aug 2021Factors associated with IgG levels in adults with IgG subclass deficiency (IgGSD) are incompletely understood. We studied adults with IgGSD with subnormal IgG1 only,...
BACKGROUND
Factors associated with IgG levels in adults with IgG subclass deficiency (IgGSD) are incompletely understood. We studied adults with IgGSD with subnormal IgG1 only, subnormal IgG1/IgG3, or subnormal IgG3 only without other subnormal IgG subclasses, IgA, or IgM. We compiled: age; sex; autoimmune condition(s) (AC); atopy; IgG, IgG subclasses, IgA, IgM; IgGsum (IgG1 + IgG2 + IgG3 + IgG4); and D (percentage difference between IgGsum and IgG). We compared attributes of patients with/without subnormal IgG (< 7.00 g/L; subnormal IgG1 subclass groups only) and analyzed IgGsum and IgG relationships. We performed backward stepwise regressions on IgG using independent variables IgG subclasses, age, and sex and on D using independent variables age and sex.
RESULTS
There were 39 patients with subnormal IgG1 only (89.7% women), 53 with subnormal IgG1/IgG3 (88.7% women), and 115 with subnormal IgG3 only (91.3% women). Fifteen patients (38.5%) and 32 patients (60.4%) in the respective subnormal IgG1 subclass groups had subnormal IgG. Attributes of patients with/without IgG < 7.00 g/L were similar, except that AC prevalence was lower in patients with subnormal IgG1 only and IgG < 7.00 g/L than ≥ 7.00 g/L (p = 0.0484). Mean/median IgG1 and IgG2 were significantly lower in patients with IgG < 7.00 g/L in both subnormal IgG1 subclass groups (p < 0.0001, all comparisons). Regressions on IgG in three subclass groups revealed positive associations with IgG1 and IgG2 (p < 0.0001 each association). Regressions on D revealed no significant association. IgG1 percentages of IgGsum were lower and IgG2 percentages were higher in patients with subnormal IgG1 subclass levels than subnormal IgG3 only (p < 0.0001 all comparisons).
CONCLUSIONS
We conclude that both IgG1 and IgG2 are major determinants of IgG in patients with subnormal IgG1, combined subnormal IgG1/IgG3, or subnormal IgG3 and that in patients with subnormal IgG1 or combined subnormal IgG1/IgG3, median IgG2 levels are significantly lower in those with IgG < 7.00 g/L than those with IgG ≥ 7.00 g/L.
Topics: Adult; Aged; Autoimmune Diseases; Female; Humans; IgG Deficiency; Immunoglobulin G; Immunoglobulin Isotypes; Male; Middle Aged; Seroepidemiologic Studies; United States
PubMed: 34372773
DOI: 10.1186/s12865-021-00447-3