Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency

Walter, Jolán E.; Rosen, Lindsey B.; Csomós, Krisztián; Rosenberg, Jacob M.; Mathew, Divij; Keszei, Márton; Ujházi, Boglárka; Chen, Karin; Lee, Yu Nee; Tirosh, Irit; Dobbs, Kerry; Al‐Herz, Waleed; Cowan, Morton J.; Puck, Jennifer M.; Bleesing, Jack J.; Grimley, Michael; Malech, Harry L.; Ravin, Suk See De; Gennery, Andrew R.; Abraham, Roshini S.; Joshi, Avni Y.; Boyce, Thomas G.; Butte, Manish J.; Nadeau, Kari; Balboni, Imelda; Sullivan, Kathleen E.; Akhter, Javeed; Adeli, Mehdi; Elfeky, Reem; El‐Ghoneimy, Dalia; Dbaibo, Ghassan; Wakim, Rima Hanna; Azzari, Chiara; Palma, Paolo; Cancrini, Caterina; Capuder, Kelly; Condino‐Neto, Antônio; Costa‐Carvalho, Beatriz Tavares; Oliveira, João Bosco; Roifman, Chaim M.; Buchbinder, David; Kumánovics, Attila; Franco, José Luis; Niehues, Tim; Schuetz, Catharina; Kuijpers, Taco W.; Yee, Christina S.K.; Chou, Janet; Masaad, Michel J.; Geha, Raif S.; Uzel, Gülbû; Gelman, Rebecca; Holland, Steven M.; Recher, Mike; Utz, Paul J.; Browne, Sarah K.; Notarangelo, Luigi D.

doi:10.1172/jci91162

Cited by 46 publications

(58 citation statements)

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“…Other complications were also seen (Fig E1E). Similar to recent reports (21–77%) 5, 9 cytopenias occurred in 40% of patients; autoimmune hemolytic anemia (27%), immune thrombocytopenic purpura (20%), and autoimmune neutropenia in one patient.…”

Section: To the Editorsupporting

confidence: 90%

“…3, 4 Hypomorphic RAG1/2 mutations with more preserved residual V(D)J recombination activity (5–30%) result in a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A). 1, 2, 5 Beyond CID, RAG deficiency has been found in patients with predominantly primary antibody deficiencies 6, 7 and naïve CD4 + T cell lymphopenia in most cases. Currently there is no published systematic evaluation for the presence of an underlying RAG deficiency in patients with primary antibody deficiencies.…”

Section: To the Editormentioning

confidence: 99%

“…Organ-specific manifestations were most common (73%) and similar to previously described reports of 48–77%. 5, 9 Granulomatous disease was seen in 40% of patients, with five out of six patients showing granuloma localization within interstitial lung tissue. Other complications were also seen (Fig E1E).…”

Section: To the Editormentioning

confidence: 99%

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Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Lawless

Geier²,

Farmer

et al. 2018

Journal of Allergy and Clinical Immunology

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Section: To the Editorsupporting

confidence: 90%

Section: To the Editormentioning

confidence: 99%

See 1 more Smart Citation

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Lawless

Geier²,

Farmer

et al. 2018

Journal of Allergy and Clinical Immunology

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“…However, RAG1/2 function is also necessary for elimination of autoreactive T and B cells as well as development of both central and peripheral tolerance 34. Therefore, it is not entirely surprising that patients with RAG deficiency are found to have a broad spectrum of antibodies against self-antigens, including cytokines 35. In the case of chronic granulomatous disease, mutations in anyone of the five components of the nicotinamide adenine dinucleotide phosphate oxidase complex in phagocytes lead to a defective oxidative burst and susceptibility to invasive bacterial and fungal infections.…”

Section: Expanding the Concept Of Autoinflammationmentioning

confidence: 99%

Autoinflammatory diseases: update on classification diagnosis and management

2016

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The spectrum of systemic autoinflammatory disorders broadens continually. In part, this is due to the more widespread application of massive parallel sequencing, helping with novel gene discovery in this and other areas of rare diseases. Some of the conditions that have been described fit neatly into a conventional idea of autoinflammation. Others, such as Interferon-mediated autoinflammatory diseases, are broadening the concept which we consider to be autoinflammatory disorders. There is also a widening of the clinical phenotypes associated with certain genetic mutations, as genetic testing is used more regularly and increasing numbers of patients are screened. It is also increasingly evident that both autoinflammatory and autoimmune problems are frequently seen as complications of primary immunodeficiency disorders.The aim of this review is to provide an update on some recently discovered conditions, and to discuss how these disorders help to define the concept of autoinflammation. The review will also cover recent discoveries in the biology of innate-immune mediated inflammation, and describe how this has provided the biological rationale for using anti-IL-1 therapies in the treatment of many such conditions. Finally, we discuss the importance of recognising somatic mutations as causes of autoinflammatory clinical phenotypes, and provide practical advice on how this could be tackled in everyday clinical practice.

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“…Since the discovery of monogenic causes of primary immunodeficiency (PID), we have experienced many nuances but also seismic changes in our understanding of the manifestation of genetically inherited PID. We should no longer be surprised that defects in single genes can manifest in a variety of clinical manifestations, perhaps best typified by defects in recombination activating genes 1 and 2 (RAG1/2) [1]. First described as causing T-B-NK+ severe combined immunodeficiency (SCID), we learned that hypereosinophilia with immunodeficiency (Omenn syndrome) was caused, not only by hypomorphic mutations in the same genes, but in some families, the same mutation could manifest as these two extreme phenotypes in different individuals, emphasizing the co-influence of environmental factors on a genetic background in phenotypic evolution.…”

mentioning

confidence: 99%