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Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature
(American Association for the Advancement of Science (AAAS), 2025-01-10)
Marita Bosticardo
;
Kerry Dobbs
;
Ottavia M. Delmonte
;
Andrew J. Martins
;
Francesca Pala
<jats:p> Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of <jats:italic>RAG</jats:italic> -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic <jats:italic>RAG</jats:italic> variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (T <jats:sub>H</jats:sub> 2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease. </jats:p>
Scopus© Citations 2 1
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Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency
(2023)
Tom Le Voyer
;
Audrey V. Parent
;
Xian Liu
;
Axel Cederholm
;
Adrian Gervais
<jats:title>Abstract</jats:title><jats:p>Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)<jats:sup>1,2</jats:sup>, conferring a predisposition to life-threatening COVID-19 pneumonia<jats:sup>3</jats:sup>. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52<jats:sup>LOF</jats:sup>/IκBδ<jats:sup>GOF</jats:sup>). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for <jats:italic>NFKB2</jats:italic> variants causing haploinsufficiency of p100 and p52 (hereafter, p52<jats:sup>LOF</jats:sup>/IκBδ<jats:sup>LOF</jats:sup>) or gain-of-function of p52 (hereafter, p52<jats:sup>GOF</jats:sup>/IκBδ<jats:sup>LOF</jats:sup>). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.</jats:p>
3Scopus© Citations 90
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Lupus eritematoso sistémico buloso: Una manifestación infrecuente en población pediátrica
(2021)
María Trinidad Hasbún Z.
;
ROLLAN MARZOLO, MARIA PAZ
;
Ximena Chaparro R.
;
Cecilia Fischer S.
;
Adriana Castrillón V.
<jats:p>El lupus eritematoso sistémico buloso (LESB) es una enfermedad ampollar subepidérmica autoinmune secundaria a la presencia de autoanticuerpos contra el colágeno VII de la membrana basal. Es considerada una variante de lupus eritematoso sistémico (LES), siendo infrecuente en la población pediátrica.Objetivo: Describir caso de paciente pediátrica con erupción ampollar compatible con LESB.Caso Clínico: Paciente de sexo femenino de 16 años de ascendencia mapuche, con antecedentes de LES diagnosticado a los 10 años de edad, en tratamiento. Consultó por erupción vesiculobulosa generalizada de 6 semanas de evolución, sin sintomatología sistémica. Se realizó biopsia para estudio histológico e inmunofluorescencia directa (IFD), confirmándose el diagnóstico de LESB. La paciente respondió favorablemente al tratamiento con dapsona en dosis de 100 mg/día (asociado a su tratamiento de base), sin nuevas reactivaciones a 8 años de seguimiento.Conclusión: El LESB es una manifestación infrecuente de LES. Aunque la clínica es similar a la de otras dermatosis ampollares, la correlación entre la presencia de LES, los hallazgos histopatológicos y de IFD permiten confirmar el diagnóstico. Si bien se ha reportado mayor riesgo de LES en población de ascendencia indígena, faltan estudios respecto a la asociación de LESB en esta etnia.</jats:p>
Scopus© Citations 2 1
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Therapeutic strategies in NMOSD and MOGAD patients: A multicenter cohort study in Latin America
(2023)
Juan Ignacio Rojas
;
Pablo A. López
;
Juan Criniti
;
Juan Pablo Pettinicchi
;
Alejandro Caride
46Scopus© Citations 7
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Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C
(2022)
Peter D. Burbelo
;
Riccardo Castagnoli
;
Chisato Shimizu
;
Ottavia M. Delmonte
;
Kerry Dobbs
<jats:p>The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring <jats:italic>in vivo</jats:italic> decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring &gt;100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.</jats:p>
Scopus© Citations 25 1
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Diagnosis and classification of optic neuritis
(2022)
Axel Petzold
;
Clare L Fraser
;
Mathias Abegg
;
Raed Alroughani
;
Daniah Alshowaeir
Scopus© Citations 81 2
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Encefalitis autoinmunes: criterios diagnósticos y pautas terapéuticas
(2018)
Juan Pablo Collao-Parra
;
César Romero-Urra
;
Carolina Delgado-Derio
;
RICARDO PABLO JAVIER ERAZO TORRICELLI
Scopus© Citations 18 11

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