Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

Zielen, Stefan; Duecker, Ruth Pia; Woelke, Sandra; Donath, H; Bakhtiar, Sharhzad; Buecker, Aileen; Kreyenberg, Hermann; Huenecke, Sabine; Bader, Peter; Mahlaoui, Nizar; Ehl, Stephan; El-Helou, Sabine M.; Pietrucha, Barbara; Plebani, Alessandro; Flier, Michiel van der; Aerde, Koen van; Kılıç, Sara Şebnem; Reda, Shereen M.; Kostyuchenko, Larysa; McDermott, Elizabeth; Galal, Nermeen; Pignata, Claudio; Pérez, Juan Luis Santos; Laws, Hans-Juergen; Niehues, Tim; Kütükçüler, Necil; Seidel, Markus G.; Marquès, Laura; Čižnár, Peter; Edgar, J. D. M.; Soler‐Palacín, Pere; Bernuth, Horst von; Krueger, Renate; Meyts, Isabelle; Baumann, Ulrich; Kanariou, Maria; Grimbacher, Bodo; Hauck, Fabian; Graf, Dagmar; Granado, L.I. González; Prader, Seraina; Reisli, İsmail; Slatter, Mary; Rodríguez-Gallego, Carlos; Arkwright, Peter D.; Bethune, Claire; Deripapa, Elena; Sharapova, Svetlana O.; Lehmberg, Kai; Davies, E. Graham; Schuetz, Catharina; Kindle, Gerhard; Schubert, Ralf

doi:10.1007/s10875-021-01090-8

Cited by 19 publications

(8 citation statements)

References 52 publications

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“…The switched-memory B cells have been depleted in three out of six HIGM and four out of six non-HIGM children, which is an unexpected finding in individuals with elevated serum IgM levels reflecting an impaired class switch recombination (CSR) (31)(32)(33)(34) being the major criterion for stratifying our patients with A-T. We have also noted that IgA serum levels were admittedly higher in the non-HIGM group with normal or partially deficient IgA in as many as four patients. Referring to the recent report (44) on the predictive role of IgA as a simple, surrogate marker in anticipating the poorer prognosis in A-T patients, our five HIGM A-T presented with a complete IgA deficiency. The HIGM group also more frequently presented a deficit in IgG subclass generation and this parameter has also been shown to correlate with shorter survival in A-T (45).…”

Section: Discussionmentioning

confidence: 73%

Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience

et al. 2022

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Ataxia-telangiectasia (A-T) is a severe syndromic neurodegenerative inborn error of immunity characterized by DNA reparation defect, chromosomal instability, and hypersensitivity to ionizing radiation, thereby predisposing affected individuals to malignant transformation. While the leading disease symptomatology is associated with progressively debilitating cerebellar ataxia accompanied by central and peripheral nervous system dysfunctions, A-T is a multisystemic disorder manifesting with the heterogeneity of phenotypic features. These include airway and interstitial lung disease, chronic liver disease, endocrine abnormalities, and cutaneous and deep-organ granulomatosis. The impaired thymic T cell production, defective B cell development and antibody production, as well as bone marrow failure, contribute to a combined immunodeficiency predisposing to infectious complications, immune dysregulation, and organ-specific immunopathology, with the A-T hyper-IgM (HIGM) phenotype determining the more severe disease course. This study aimed to clarify the immunodeficiency and associated immune dysregulation as well as organ-specific immunopathology in children with A-T. We also sought to determine whether the hyper-IgM and non-hyper-IgM phenotypes play a discriminatory role and have prognostic significance in anticipating the clinical course and outcome of the disease. We retrospectively reviewed the medical records of twelve A-T patients, aged from two to eighteen years. The patients' infectious history, organ-specific symptomatology, and immunological workup including serum alpha-fetoprotein, immunoglobulin isotypes, IgG subclasses, and lymphocyte compartments were examined. For further comparative analysis, all the subjects were divided into two groups, HIGM A-T and non-HIGM A-T. The clinical evaluation of the study group showed that recurrent respiratory tract infections due to viral and bacterial pathogens and a chronic obstructive airway disease along with impaired humoral immunity, in particular complete IgA deficiency, were noted in all the A-T patients, with both HIGM and non-HIGM phenotypes. The most important features with the discriminatory role between groups, were autoimmune disorders, observable four times more frequently in HIGM than in non-HIGM A-T. Two patients with the HIGM A-T phenotype were deceased due to liver failure and chronic Epstein-Barr virus (EBV) infection. It may therefore be assumed that the HIGM form of A-T is associated with more profound T cell dysfunction, defective immunoglobulin class switching, chronic EBV expansion, and poorer prognosis.

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Section: Discussionmentioning

confidence: 73%

Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience

et al. 2022

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“…Interestingly, in a cohort of AT, 7 out of 8 patients with granulomas showed IgA deficiency ( 9 ). In addition, IgA deficiency has been identified as a surrogate marker for immunodeficiency and mortality in AT patients ( 10 ). However, transient IgA deficiency is also common in healthy infants and thus not useful for risk assessment prior to MMR vaccination in patients with AT.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Rubella Virus-Induced Cutaneous Granulomas in Two Pediatric Patients With DNA Double Strand Breakage Repair Disorders – Outcome After Hematopoietic Stem Cell Transplantation

et al. 2022

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We report two patients with DNA repair disorders (Artemis deficiency, Ataxia telangiectasia) with destructive skin granulomas, presumably triggered by live-attenuated rubella vaccinations. Both patients showed reduced naïve T cells. Rapid resolution of skin lesions was observed following hematopoietic stem cell transplantation. However, the patient with AT died due to complications of severe hepatic veno-occlusive disease 6 month after HSCT. Dried blood spots obtained after birth were available from this patient and showed absent T-cell receptor excision circles (TRECs). Therefore, newborn screening may help to prevent patients with moderate T-cell deficiency from receiving live-attenuated rubella vaccine potentially causing granulomas.

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“…In addition, growth failure, poor pubertal development, gonadal atrophy, skin abnormalities, and cardiovascular disorders have also been reported in A-T patients 17,18 . However, the clinical picture exhibits high variability that correlates with residual ATM kinase activity 19 . In 2006, a prospective study reported a median survival of 25 years 20 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of T Cell Repertoire in Primary Immunodeficiencies With Dna Repair Defects

Karaaslan¹,

Demirkale²,

Turan³

et al. 2023

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Inborn errors of immunity include multiple genetic abnormalities affecting different components of the innate and adaptive immune systems. More than 450 genes have been described so far including DNA repair defects which may result in predisposition to infections, but also malignancies, neurologic abnormalities and growth retardation. The group of patients with DNA repair and methylation defects exhibit impaired adaptive immunity, which increases susceptibility to infections due to impaired repertoire diversity. In this context, we aimed to investigate the TCRvβ repertoire and its interaction with clinical entities in a group of IEI patients with DNA repair defects including ATM, DCLRE1C, DNA-PRKDC, DNA ligase-4, and BLM. Thirty-nine patients with evidence of DNA repair defects and radiosensitivity and 15 age-matched healthy controls were included in this study. Peripheral lymphocyte subset and TCR-vβ repertoire analyses were performed by flow cytometry. To contrast TCR-repertoire in patients with DNA repair defects to healthy controls, we extracted data on lymphocyte phenotype, thymic function, immunoglobulins, and analysis of the TCRvβ repertoire from a prior study. The entire TCR-vβ repertoire was detected in all patients. However, compared with the control group, 9 of 24 clones (37.5%) were statistically significantly lower, whereas only 3 clones had high levels (p < 0.05). In addition, 62.5% of all clones had lower values than the control group. Some unique vβ clones have been associated with some clinical entities. Clonotypes associated with infections, autoimmunity and lymphoid proliferation were detected in the patient group. Lower TCR-vβ-9 and TCR-vβ23, higher TCR-vβ7.2 were detected in the patients with pneumonia (n = 13) (respectively p = 0.018, p = 0.044 p = 0.032). In addition, AT patients with pneumonia (n = 10) had a lower TCR-vβ-9 clone than patients without pneumonia (n = 25) (p = 0.008). In summary, we observed skewed clonal proliferation of most TCR-vβ clones in DNA repair defects, especially AT. In addition, our study demonstrated that some TCR-vβ clones might be predictive of some clinical entities. To further investigate the impact of the diversity of the TCR repertoire on the clinical phenotype, future studies should focus on the analysis of naïve and memory T cells, the detection of the source of oligoclonality, and the relationship between clonality and clinical entities.

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Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

Cited by 19 publications

References 52 publications

Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience

Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience

Case Report: Rubella Virus-Induced Cutaneous Granulomas in Two Pediatric Patients With DNA Double Strand Breakage Repair Disorders – Outcome After Hematopoietic Stem Cell Transplantation

Evaluation of T Cell Repertoire in Primary Immunodeficiencies With Dna Repair Defects

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