טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKeren Zohar
SubjectDepletion of B Cells Revives B Lymphopoiesis in Aging and
Modifies Autoantibody-Cytokine Network in
Rheumatoid Arthritis Patients
DepartmentDepartment of Medicine
Supervisor Professor Doron Melamed
Full Thesis textFull thesis text - English Version


Abstract

Age-associated changes in the B lineage include a reduction in B cell lymphopoiesis in the bone marrow and generation of a restricted B cell repertoire in the periphery. Consequentially, aged individuals fail to mount effective antibody responses to new infectious agents and to vaccination. The present study aims to define whether altering B cell homeostasis can revive B cell lymphopoiesis and rejuvenate the peripheral repertoire in aged mice. Our results reveal that in mice deficient of CD19 or invariant chain, where B cell maturation or survival are impaired, B lymphopoiesis in the BM maintains a young-like phenotype as reflected by precursor frequencies and by kinetics studies. Moreover, we found that the peripheral repertoire of these mice does not age. To test whether senescence of B lymphopoiesis can be reversed we have actively depleted B cells in aged mice. We found that multiple depletion cycles increased B lymphopoiesis in the BM as reflected by frequencies of precursor B cells and the rate of B lymphocyte return to the blood, and constructed a young-like peripheral repertoire. Finally, we show that aged mice that were treated for B cell depletion and had completely restored their peripheral B cell population developed a significantly increased antibody response to new antigenic challenge. Collectively, we propose that altering B cell homeostasis in aging revives B lymphopoiesis in the BM to rejuvenate the peripheral B cell repertoire and to increase immune competence to new antigens and to infections.

In a parallel study, we analyzed the effect of B cell depletion on serum cytokines in RA patients. We analyzed serum samples from RA patient before and after Rituximab (RTX) treatment for the level of 30 cytokines and other soluble factors. Unexpectedly, we found that levels of most of the serum cytokines did not significantly change up to 24 weeks after the initiation of RTX treatment. Instead, levels of IL-8 and TNF-alpha increased 8 weeks after administration of RTX and the depletion of B cells. We show here that anti-IL-8 autoantibodies are found in RA patients and that their level drops after RTX treatment. We further show that antibody-IL-8 complexes are abundant in synovial fluid and serum of RA patients and that their level drops after administration of RTX. Hence, our results suggest that RTX treatment modifies the regulatory network of cytokine-anti-cytokine autoantibodies.