The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity

Genton, Celine; Wang, Ying; Izui, Shozo; Malissen, Bernard; Delsol, Georges; Fournie, G. J.; Malissen, Marie; Acha-Orbea, Hans

doi:10.4049/jimmunol.177.4.2285

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Title		The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity
Authors		Genton, Celine Wang, Ying Izui, Shozo Malissen, Bernard Delsol, Georges Fournie, G. J. Malissen, Marie Acha-Orbea, Hans
Published in		The Journal of immunology. 2006, vol. 177, no. 4, p. 2285-2293
Abstract		Lat(Y136F) knock-in mice harbor a point mutation in Tyr(136) of the linker for activation of T cells and show accumulation of Th2 effector cells and IgG1 and IgE hypergammaglobulinemia. B cell activation is not a direct effect of the mutation on B cells since in the absence of T cells, mutant B cells do not show an activated phenotype. After adoptive transfer of linker for activation of T cell mutant T cells into wild-type, T cell-deficient recipients, recipient B cells become activated. We show in vivo and in vitro that the Lat(Y136F) mutation promotes T cell-dependent B cell activation leading to germinal center, memory, and plasma cell formation even in an MHC class II-independent manner. All the plasma and memory B cell populations found in physiological T cell-dependent B cell responses are found. Characterization of the abundant plasmablasts found in secondary lymphoid organs of Lat(Y136F) mice revealed the presence of a previously uncharacterized CD93-expressing subpopulation, whose presence was confirmed in wild-type mice after immunization. In Lat(Y136F) mice, B cell activation was polyclonal and not Ag-driven because the increase in serum IgG1 and IgE concentrations involved Abs and autoantibodies with different specificities equally. Although the noncomplement-fixing IgG1 and IgE are the only isotypes significantly increased in Lat(Y136F) serum, we observed early-onset systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria. These results show that Th2 cells developing in Lat(Y136F) mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease.
Keywords		Adaptor Proteins, Signal Transducing/genetics/physiology — Amino Acid Substitution/genetics — Animals — Autoimmune Diseases/genetics/immunology/pathology — B-Lymphocytes/cytology/immunology/pathology — Clone Cells — Lymphocyte Activation/genetics — Lymphoproliferative Disorders/genetics/immunology — Membrane Proteins/genetics/physiology — Mice — Mice, Inbred C57BL — Mice, Knockout — Mice, Mutant Strains — Phenylalanine/genetics — Phosphoproteins/genetics/physiology — Th2 Cells/immunology/pathology — Tyrosine/genetics
Identifiers		DOI: 10.4049/jimmunol.177.4.2285 PMID: 16887989
Full text		Article - Limited access to UNIGE Other version: http://www.jimmunol.org/cgi/reprint/177/4/2285.pdf
Citation (ISO format)		GENTON, Celine et al. The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity. In: The Journal of immunology, 2006, vol. 177, n° 4, p. 2285-2293. doi: 10.4049/jimmunol.177.4.2285 https://archive-ouverte.unige.ch/unige:11273