Untitled

Harville, Terry; Adams, Denise M.; Howard, Thad A.; Ware, Russell E.

doi:10.1023/a:1027330800085

Cited by 43 publications

(5 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Puzzlingly, the phenotypes of the three individuals are highly similar in Vβ families that are missing and those reduced to a single peak they are almost completely identical. Moreover, many families reduced to single peaks and highly overexpressed is highly suggestive for oligo or even monoclonal expansion as reported before [ 32 , 33 ]. We speculate that the skewed TCR repertoire may mainly consist of public TCRs that are virus specific.…”

Section: Discussionsupporting

confidence: 61%

Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency

Hou

Gratz

Ureña-Bailén

et al. 2021

Genes

View full text Add to dashboard Cite

Mutations of the IL2RG gene, which encodes for the interleukin-2 receptor common gamma chain (γC, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID) associated with a T−B+NK− phenotype as a result of dysfunctional γC-JAK3-STAT5 signaling. Lately, hypomorphic mutations of the IL2RG 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 IL2RG 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.

show abstract

Section: Discussionsupporting

confidence: 61%

Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency

Hou

Gratz

Ureña-Bailén

et al. 2021

Genes

View full text Add to dashboard Cite

show abstract

“…The hallmark of OS, as a consequence of residual recombinase activity, is a peculiar immune phenotype made up of normal or elevated numbers of activated yet poorly functional T cells, with a highly restricted oligoclonal TCR repertoire. Such T cells infiltrate various organs, including skin, gut, spleen, and liver, resulting in profound tissue damage (Harville et al, 1997;Rieux-Laucat et al, 1998;Signorini et al, 1999). More recently, we and others have reported hypomorphic Rag mouse mutants that mimic many features of human OS (Khiong et al, 2007;Marrella et al, 2007); the study of these mice has led to a better understanding of the complexity of OS pathogenesis.…”

Section: Detection Of Plasma Cells In Lymphoid Organs Of Os Patientsmentioning

confidence: 99%

Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome

Cassani

Poliani

Marrella

et al. 2010

Journal of Experimental Medicine

View full text Add to dashboard Cite

Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells in lymphoid organs of OS patients, in which circulating B cells are undetectable. Hypomorphic Rag2R229Q knock-in mice, which recapitulate OS, revealed, beyond severe B cell developmental arrest, a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC). The size of this ISC compartment correlated with increased expression of Blimp1 and Xbp1, and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines. The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction. We hypothesize that impaired B cell receptor (BCR) editing and a serum B cell activating factor (BAFF) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag2R229Q knock-in mice. BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage. These findings highlight a role for B cells in OS pathogenesis.

show abstract

“…As the major clinical OS manifestations are caused by an aberrant activation of T-cells in the periphery, with preferential localization in skin and gut 8,12,33,34 , we looked more closely at peripheral T-cell compartments in adult Rag2 R229Q OS mice. In Rag2 R229Q large intestines, the overall proportion of T-lymphocytes amongst hematopoietic cells was increased by 2-fold compared to Rag2 +/+ controls (Figure S1C) and composed by both TCRβ T-cells, representing the major T-cell type with a 2-fold increased frequency compared to Rag2 +/+ , and TCRγδ T-cells (Figures 1E and 1F).…”

Section: Resultsmentioning

confidence: 99%

Embryonic lymphocytes contribute to a genetic form of autoimmune inflammation

Cascione,

Fontana,

Scarfò

et al. 2023

Preprint

View full text Add to dashboard Cite

Omenn Syndrome (OS) is a rare hematological disorder, caused by hypomorphic mutations in genes involved in B-/T-cell receptor (BCR/TCR) rearrangement that result in impaired lymphocyte development and immunodeficiency. Notwithstanding, few T-cell clones enriched in self-reactive specificities expand in peripheral tissues, where they trigger severe inflammation and autoimmune reactions. Interestingly, residual OS lymphocytes display characteristics proper of embryonic lymphocytes that emerge before, and independently from, hematopoietic stem cells (HSCs). This prompted us to hypothesize whether OS autoreactive T-cells are generated in the embryo independently from HSCs. Here we show that in theRag2R229Q/R229QOS mouse model, embryonic but not adult bone marrow-derived hematopoietic progenitors can generate T-cells. T-lymphopoiesis can be rescued in adult OS blood progenitors via their Lin28-mediated reprogramming to an embryonic-like state. Remarkably, when transplanted in immunodeficient mice, embryonic-like OS progenitors trigger tissue morphological alterations and inflammation in the large intestine of the recipients, recapitulating the typical OS inflammatory phenotype. Our study describes the previously unappreciated contribution of embryonic progenitors to the pool of autoreactive infilitrating T-cells, providing a novel platform for both the detailed study of human autoimmune disorders and the design of more targeted therapies.

show abstract

Untitled

Cited by 43 publications

References 63 publications

Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency

Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency

Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome

Embryonic lymphocytes contribute to a genetic form of autoimmune inflammation

Contact Info

Product

Resources

About