Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the <i>Rag2</i> mouse model of Omenn syndrome

Cassani, Barbara; Poliani, Pietro Luigi; Marrella, Veronica; Schena, Francesca; Sauer, Aisha V.; Ravanini, Maria; Strina, Dario; Busse, Christian E.; Regenass, Stephan; Wardemann, Hedda; Martini, Alberto; Facchetti, Fabio; Burg, Mirjam van der; Rolink, Antonius; Vezzoni, Paolo; Grassi, Fabio; Traggiai, Elisabetta; Villa, Anna

doi:10.1084/jem.20091928

Cited by 64 publications

(95 citation statements)

References 70 publications

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“…Analysis of peripheral tissue infiltration demonstrated a significant decrease of organ infiltrates in target tissues such as skin, liver, lung, and gut, thereby demonstrating that anti-CD3ε mAb treatment has a beneficial impact on RAG2 R229Q mice immunopathology. Consistently, serum IgE levels, which have been widely described as important in the pathogenesis of OS, 14,34 were barely detectable in anti-CD3ε mAb-treated mice. The treatment proved to be effective and did not provoke any clinical signs of autoimmunity or tissue infiltration or other adverse effects in mice followed up to 5 months (data not shown).…”

Section: Discussionsupporting

confidence: 59%

Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Marrella

Poliani

Fontana

et al. 2012

Blood

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Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3 monoclonal antibody (mAb) treatment in RAG2 ؊/؊ mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3 mAb administration in the RAG2 R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. IntroductionAs opposed to the classic T Ϫ B Ϫ severe combined immunodeficiencies (SCIDs), Omenn syndrome (OS) represents an atypical type of primary immunodeficiency (PID) associated with autoimmune manifestations because of activated oligoclonal T cells that infiltrate peripheral tissues and provoke generalized erythroderma, alopecia, lymphadenopathy, hepatosplenomegaly, and intractable diarrhea. 1 Patients have high levels of serum IgE despite the absence of circulating B cells. From the genetic point of view, most OS cases result from hypomorphic mutations in RAG genes 2,3 that decrease but do not completely abolish V(D)J recombination activity, allowing the generation of an oligoclonal autoreactive T-cell repertoire. [4][5][6][7] To date, allogeneic hematopoietic stem cell transplantation (HSCT) is the only beneficial therapeutic approach, although at high risk because of the myeloablative conditioning regimens necessary to eliminate autoreactive T lymphocytes and achieve successful engraftment. [8][9][10] We have recently generated and characterized a knock-in Rag2 R229Q mouse model, carrying a hypomorphic mutation in the Rag2 gene (R229Q), initially identified in patients with OS or with leaky SCID. [10][11][12] The RAG2 R229Q mouse model closely recapitulates the human disease as mice display an expansion of oligoclonal and activated T cells which infiltrate target organs including skin, gut, liver, and lung, 13 and high levels of serum IgE, despite a severe arrest of B-cell development in the bone marrow. 14 This mouse model shows an arrest at the CD4 Ϫ CD8 Ϫ CD44 Ϫ CD25 ϩ double-negative 3 (DN3) stage of thymocyte differentiation, resulting in thymic atrophy and severe depletion of CD4 ϩ CD8 ϩ double-positive (DP) and mature CD4 ϩ or CD8 ϩ single-positive (SP) cells. As previously observed in OS patients, 15,16 thymi from RAG2 R229Q mice are small, lack corticomedullary demarcation, and show a significant decrease in the expression of autoimmune regulator (AIRE), which induce the transcription of tissue-restricted antigens (TRAs) and plays a key role in the negative selection of autoreactive thymocytes. 17,18 This observation has raised the hypothesis that a defe...

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Section: Discussionsupporting

confidence: 59%

Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Marrella

Poliani

Fontana

et al. 2012

Blood

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“…The expression of AIRE and AIREdependent tissue-restricted antigens is severely reduced [34]. In addition, nTreg cells from OS patients showed impaired suppressive activity on comparison with similarly phenotyped cells from healthy donors [35], a result consistent with that observed in the OS animal models.…”

Section: Evidence In Os Patientssupporting

confidence: 80%

Tight Interdigitating Developmental Processes within the Thymus; Lessons from Primary Immunodeficiency with Autoimmunity

Han¹,

Choi²

2014

Am. J. Biomed. Sci.

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The underlying cause of the enigmatic coexistence of immunodeficiency and autoimmune disorders in patients with primary immunodeficiency such as Omenn syndrome is largely due to the inefficient negative selection within thymus where T cells develop. Recent advances in molecular biology and animal models answered one of the key questions on the relationship between the partially impaired T cell development at early stages and the presence of autoreactive T cells in periphery. T cell development and thymic organogenesis are tightly coupled to each other. The maturing T cells induce thymic epithelial cell development and AIRE (Autoimmune regulator) expression in thymic medullary epithelial cells. Without thymic medullary epithelial cells and AIRE protein in the patients with primary immunodeficiency, a few autoreactive T cells survive through the complete thymic selection processes and expand to form oligoclonal T cell pools in the periphery. The induction of thymic medullary epithelial cell development may be considered as an alternative therapeutic approach in addition to the current standard therapy for primary immunodeficiency -stem cell transplantation.

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“…Moreover, self-reactive B cells that escape deletion compete with nonself-reactive B cells for survival signals, such as BAFF. This key factor modulating the survival of peripheral B cells is elevated under lymphopenic conditions, such as SCID, and may therefore also contribute to the abnormal accumulation of autoreactive and ANA-expressing B cells, as suggested by mouse models and hyper-IgM patients (41,43).…”

Section: Discussionmentioning

confidence: 99%

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy

Sauer¹,

Morbach²,

Brigida³

et al. 2012

J. Clin. Invest.

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Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell tolerance checkpoints. We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell tolerance. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions

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

Cited by 64 publications

References 70 publications

Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Tight Interdigitating Developmental Processes within the Thymus; Lessons from Primary Immunodeficiency with Autoimmunity

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy

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