Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells

Csomós, Krisztián; Ujházi, Boglárka; Blazsó, Péter; Herrera, Juan López de; Tipton, Christopher; Gordon, Sumai; Ellison, Maryssa; Wu, Kevin; Stowell, Matthew; Haynes, Lauren; Cruz, Rachel; Zakota, Bence; Nguyen, Jenny; Altrich, Michelle; Geier, Christoph; Sharapova, Svetlana O.; Dasso, Joseph F.; Leiding, Jennifer W.; Smith, Grace; Al‐Herz, Waleed; Dorna, Mayra de Barros; Fadugba, Olajumoke; Froňková, Eva; Kanderová, Veronika; Svatoň, Michael; Henrickson, Sarah E.; Hernandez, Joseph D.; Kuijpers, Taco W.; Kandilarova, Snezhina Mihailova; Наумова, Е. А.; Milota, Tomáš; Šedivá, Anna; Moshous, Despina; Neven, Bénédicte; Saco, Tara; Sargur, Ravishankar; Savic, Sinisa; Sleasman, John W.; Sunkersett, Gauri; Ward, Brant R.; Komatsu, Masanobu; Pittaluga, Stefania; Kumánovics, Attila; Butte, Manish J.; Cancro, Michael P.; Pillai, Shiv; Meffre, Eric; Notarangelo, Luigi D.; Walter, Jolán E.

doi:10.1038/s41590-022-01271-6

Cited by 21 publications

(37 citation statements)

References 66 publications

(84 reference statements)

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“…In proportion, all populations were preserved including Bregs, but there was a relative increase in autoreactive B-cells. As described elsewhere, an alteration of BLNK could lead to a dysregulation of B-cells with activation and selection of autoreactive B clones responsible for autoimmune manifestations ( 20 ). As her mutation appears to be somatic but is not expected to give a proliferative advantage, we believe that it may have occurred early in development.…”

Section: Discussionmentioning

confidence: 94%

BLNK mutation associated with T-cell LGL leukemia and autoimmune diseases: Case report in hematology

et al. 2022

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We present the case of a female patient with a heterozygous somatic BLNK mutation, a T-cell LGL (large granular lymphocyte) leukemia, and multiple autoimmune diseases. Although this mutation seems uncommon especially in this kind of clinical observation, it could represent a new mechanism for autoimmune diseases associated with LGL leukemia. The patient developed several autoimmune diseases: pure red blood cell apalsia, thyroiditis, oophoritis, and alopecia areata. She also presented a T-cell LGL leukemia which required treatment with corticosteroids and cyclophosphamide, with good efficacy. Interestingly, she had no notable infectious history. The erythroblastopenia also resolved, the alopecia evolves by flare-ups, and the patient is still under hormonal supplementation for thyroiditis and oophoritis. We wanted to try to understand the unusual clinical picture presented by this patient. We therefore performed whole-genome sequencing, identifying a heterozygous somatic BLNK mutation. Her total gamma globulin level was slightly decreased. Regarding the lymphocyte subpopulations, she presented a B-cell deficiency with increased autoreactive B-cells and a CD4+ and Treg deficiency. This B-cell deficiency persisted after complete remission of erythroblastopenia and LGL leukemia. We propose that the persistent B-cell deficiency linked to the BLNK mutation can explain her clinical phenotype.

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Section: Discussionmentioning

confidence: 94%

BLNK mutation associated with T-cell LGL leukemia and autoimmune diseases: Case report in hematology

et al. 2022

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“…Another exciting development is that whole-genome sequencing of patients diagnosed with autoimmune disease has recently identified novel rare mutations. These mutations have provided evidence for a critical pathogenic role of various genes, including partial RAG deficiency [ 350 ] and gain-of-function mutations in the IKFZ1 gene, encoding the Ikaros transcription factor [ 351 ] and the TLR7 gene [ 308 ]. Single-cell technology will be instrumental to uncover drivers of interindividual variation in immune cells, which will help to interpret and prioritize risk variants identified by GWAS and to identify critical cell types in autoimmune diseases [ 352 ].…”

Section: Concluding Remarks and Future Perspectivementioning

confidence: 99%

Aberrant B Cell Signaling in Autoimmune Diseases

Corneth

Neys

Hendriks

2022

Cells

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Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells.

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“…A 2022 study by Csomos et al [38 ▪▪ ] examined 16 patients with confirmed pRD, ranging from an asymptomatic infant to adults with recurrent infections ( n = 15) and autoimmune ( n = 10) and/or granulomatous ( n = 3) conditions. As the reported infant patient underwent haematopoietic stem cell transplantation prior to developing symptoms, the study population was subdivided into antigen-naive (pRD-N, n = 1) and antigen-experienced (pRD-Ag, n = 15), with the majority of subsequent analyses limited to the latter subpopulation.…”

Section: Newly Described Mechanisms Of Autoimmunity and Inflammation ...mentioning

confidence: 99%

Autoimmune and autoinflammatory manifestations in inborn errors of immunity

Kačar

Markelj

Avčin

2022

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewAutoimmune and inflammatory complications have been shown to arise in all age groups and across the spectrum of inborn errors of immunity (IEI). This review aims to highlight recent ground-breaking research and its impact on our understanding of IEI.Recent findingsThree registry-based studies of unprecedented size revealed the high prevalence of autoimmune, inflammatory and malignant complications in IEI. Two novel IEI were discovered: an autoinflammatory relopathy, cleavage-resistant RIPK1-induced autoinflammatory syndrome, as well as an inheritable phenocopy of PD-1 blockade-associated complication (as seen in cancer therapy) manifesting with multiorgan autoimmunity and Mycobacterium tuberculosis infection. A study examining patients with partial RAG deficiency pinpointed the specific defects leading to the failure of central and peripheral tolerance resulting in wide-ranging autoimmunity. A novel variant of Immunodeficiency Polyendocrinopathy Enteropathy X-linked syndrome was described, associated with preferential expression of a FOXP3 isoform lacking exon 2, linking exon-specific functions and the phenotypes corresponding to their absence. Lastly, we touch on recent findings pertaining actinopathies, the prototypical IEI with autoimmune, inflammatory and atopic complications.SummaryDysregulated immunity has been associated with IEI since their discovery. Recently, large concerted efforts have shown how common these complications actually are while providing insight into normal and dysregulated molecular mechanisms, as well as describing novel diseases.

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Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells

Cited by 21 publications

References 66 publications

BLNK mutation associated with T-cell LGL leukemia and autoimmune diseases: Case report in hematology

BLNK mutation associated with T-cell LGL leukemia and autoimmune diseases: Case report in hematology

Aberrant B Cell Signaling in Autoimmune Diseases

Autoimmune and autoinflammatory manifestations in inborn errors of immunity

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