טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSeagal Jane
SubjectThe Role of Fas in Regulating Development and Selection of
Isotype-Switched B Cell Precursors and in the
Generation of an Autoimmune B Cell
Repertoire
DepartmentDepartment of Medicine
Supervisor Professor Doron Melamed


Abstract

In B-lymphocytes, IgM receptors drive development and construction of naive repertoire, whereas IgG receptors promote formation of the memory B cell compartment. This isotype switching process requires appropriate B cell activation and T cell help.  In the absence of T-cell help, activated B cells undergo Fas-mediated apoptosis, a mechanism contributing to the establishment of self-tolerance. Using Igm-deficient-mice (mMT), where development is blocked at proB stage, we show here an alternative developmental pathway utilized by isotype-switched B cell precursors. We find that isotype switching occurs spontaneously in B lymphopoiesis and is T-independent.  These IgG-driven B cells are negatively selected by Fas pathway, as blocking the Fas/FasL interaction rescues the development of isotype-switched B cells. In the absence of functional Fas (mMT/lpr mice), isotype- switched B cells acquire a marginal zone phenotype and give raise to high numbers of plasma cells producing elevated titers of serum IgG, a reminiscent of memory response.  Analysis of this IgG-driven repertoire revealed an oligo-monoclonal specificity and self-reactivity.  In contrast, mMT/lpr B cells grown in non-selective conditions utilize a wide repertoire, suggesting that the Fas pathway is an important regulator of this pathway. Additional studies revealed that the activation of autoimmune IgG-driven B cells depends on aβ T cells, whereas lack of gd T cells exacerbate autoimmunity in this mouse model. Our results suggest a novel developmental pathway utilized by isotype-switched B cell precursors that effectively circumvents peripheral tolerance requirements. This developmental pathway, however, is strictly controlled by Fas/FasL interaction to prevent B cell autoimmunity.