Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-50650
Cassani, B; Poliani, P L; Marrella, V; Schena, F; Sauer, A V; Ravanini, M; Strina, D; Busse, C E; Regenass, S; Wardemann, H; Martini, A; Facchetti, F; van der Burg, M; Rolink, A G; Vezzoni, P; Grassi, F; Traggiai, E; Villa, A (2010). Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. Journal of Experimental Medicine, 207(7):1525-1540.
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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 Rag2(R229Q) 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 Rag2(R229Q) 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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology|
|Dewey Decimal Classification:||610 Medicine & health|
|Deposited On:||10 Nov 2011 15:26|
|Last Modified:||27 Nov 2013 20:52|
|Publisher:||Rockefeller University Press|
|Additional Information:||Copyright: Cassani et al.|
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