Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency

Geier, Christoph; Farmer, Jocelyn R.; Foldvari, Zsofia; Ujházi, Boglárka; Steininger, Jolanda; Sleasman, John W.; Parikh, Suhag; Dilley, Meredith A.; Henderson, Lauren A.; Hazen, Melissa; Neven, Bénédicte; Moshous, Despina; Sharapova, Svetlana O.; Mihailova, Snezhina; Yankova, Petya; Naumova, Elisaveta; Özen, Seza; Byram, Kevin; Fernandez, James; Wolf, Hermann M.; Eibl, Martha M.; Notarangelo, Luigi D.; Calabrese, Leonard H.; Walter, Jolán E.

doi:10.3389/fimmu.2020.574738

Cited by 10 publications

(8 citation statements)

References 41 publications

(45 reference statements)

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“…In addition, our findings might support the role of HHV-7 as a possible trigger in the pathogenesis of cerebral vasculitis. Recent findings indicate that various forms of PIDs are associated with CNS manifestations and vasculitis (17). We therefore suggest that children with unexplained autoimmune CNS inflammation as a primary clinical manifestation should be investigated for an underlying primary immunodeficiency.…”

Section: Discussionmentioning

confidence: 95%

“…Due to diverse clinical symptoms and EBV-seronegativity in approximately 10% of the patients, early diagnosis of SH2D1A deficiency as the causative condition is challenging (5). Central nervous system (CNS) manifestations are a rare but severe complication of primary immunodeficiencies (PIDs) that range from predispositions to viral or bacterial infections of the CNS leading to meningitis or encephalitis (11)(12)(13)(14), accumulation of toxic metabolites in the CNS (15,16), CNS vasculitis (5,(17)(18)(19)(20)(21)(22)(23) as well as CNS involvement in hemophagocytic lymphohistiocytosis (24,25). In XLP1 11 patients with CNS vasculitis have been described in the past (STable 1).…”

Section: Introductionmentioning

confidence: 99%

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Case Report: Meningoencephalitis With Thrombotic Occlusive Vasculopathy in a Young EBV-Naïve Boy Is Associated With a Novel SH2D1A Mutation

Steininger¹,

Rossmanith

Geier³

et al. 2021

Front. Immunol.

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X-linked lymphoproliferative disease (XLP1) is a combined immunodeficiency characterized by severe immune dysregulation caused by mutations in the SH2D1A/SAP gene. Loss or dysfunction of SH2D1A is associated with the inability in clearing Epstein-Barr-Virus (EBV) infections. Clinical manifestation is diverse and ranges from life-threatening hemophagocytic lymphohistiocytosis (HLH) and fulminant infectious mononucleosis (FIM) to lymphoma and antibody deficiency. Rare manifestations include aplastic anemia, chronic gastritis and vasculitis. Herein, we describe the case of a previously healthy eight-year old boy diagnosed with XLP1 presenting with acute non-EBV acute meningoencephalitis with thrombotic occlusive vasculopathy. The patient developed multiple cerebral aneurysms leading to repeated intracerebral hemorrhage and severe cerebral damage. Immunological examination was initiated after development of a susceptibility to infections with recurrent bronchitis and one episode of severe pneumonia and showed antibody deficiency with pronounced IgG1-3-4 subclass deficiency. We could identify a novel hemizygous SH2D1A point mutation affecting the start codon. Basal levels of SAP protein seemed to be detectable in CD8+ and CD4+ T- and CD56+ NK-cells of the patient what indicated an incomplete absence of SAP. In conclusion, we could demonstrate a novel SH2D1A mutation leading to deficient SAP protein expression and a rare clinical phenotype of non-EBV associated acute meningoencephalitis with thrombotic occlusive vasculopathy.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Case Report: Meningoencephalitis With Thrombotic Occlusive Vasculopathy in a Young EBV-Naïve Boy Is Associated With a Novel SH2D1A Mutation

Steininger¹,

Rossmanith

Geier³

et al. 2021

Front. Immunol.

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“…2d ). IgG autoantibodies to interferon (IFN)-α, IFN-ω and/or interleukin (IL)-12, a hallmark of pRD 5 , 26 , were present in ten patients with pRD-Ag (newly detected in four patients and previously published in six cases 5 ) but not in pRD-N (Extended Data Fig. 2e ).…”

Section: Resultsmentioning

confidence: 89%

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

et al. 2022

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The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an ‘experiment of nature’ to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent ‘domino effect’ that impacts stringency of tolerance and B cell fate in the periphery.

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“…Treatment-refractory autoimmune cytopenias are a common manifestation of RAG-dependent CID [51]. Vasculitis and organspecific autoimmunity have been also frequently reported [34,51,59]. Noncaseating granulomas involving the skin or any other organ often develop starting in late childhood or young adulthood.…”

Section: Combined and Common Variable Immunodeficienciesmentioning

confidence: 99%

RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

2021

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The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the RAG genes cause severe combined immune deficiency with lack of T and B cells (T − B − SCID) and susceptibility to life-threatening, early-onset infections, studies in humans and mice have demonstrated that hypomorphic RAG mutations are associated with defects of central and peripheral tolerance resulting in immune dysregulation. In this review, we provide an overview of the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans. We discuss recent advances in the mechanisms that control RAG expression and function, the effects of perturbed RAG activity on lymphoid development and immune homeostasis, and propose novel approaches to correct this group of disorders.

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Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency

Cited by 10 publications

References 41 publications

Case Report: Meningoencephalitis With Thrombotic Occlusive Vasculopathy in a Young EBV-Naïve Boy Is Associated With a Novel SH2D1A Mutation

Case Report: Meningoencephalitis With Thrombotic Occlusive Vasculopathy in a Young EBV-Naïve Boy Is Associated With a Novel SH2D1A Mutation

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

RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

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