The regulation of B cell responses in systemic autoimmunity

by Amanda Duhlin

Institution: Karolinska Institute
Year: 2017
Posted: 02/01/2018
Record ID: 2155099
Full text PDF: http://hdl.handle.net/10616/45622


Our immune system is a complex network made up of physical barriers and specializedproteins, cells and organs that all work together to prevent pathogens from causing disease inthe body. Once the immune system has successfully mounted an immune response uponintrusion of a pathogen it will mount an immediate and stronger response against anysubsequent exposure to it. This is known as immunological memory and is crucial forgenerating long-lasting protective immunity. The immune system has also developed tomaintain homeostasis and be tolerant to the presence of the bodys own structures, or socalled self-antigens. A loss of this tolerance can lead to the immune system attacking thebody itself, causing autoimmune disease. The pathogenesis of autoimmune disease involvesboth genetic and environmental factors. B cells and autoantibodies are major contributors toseveral autoimmune diseases such as systemic lupus erythematosus (SLE). The aim of this thesis was to investigate the regulation of B cell responses in systemicautoimmune disease. This was studied in mouse models of autoimmunity and atherosclerosisand in paper III also in SLE patient samples. Paper I was prompted by a study where transfer of spleen B cells from old atherosclerosisproneapolipoprotein E-deficient (ApoE-/-) mice to young ApoE-/- mice conferred protectionagainst plaque development. We characterized the B cell response in the spleen ofatherosclerotic ApoE-/- mice and found an ongoing B cell response in the form of germinalcenter B cells and plasma cells. Repeated injections of apoptotic cells, carrying the sameoxidation-specific epitopes as oxidized LDL, into young ApoE-/- mice led to the sameactivated phenotype, lowered cholesterol levels and protected against plaque development. In paper II the memory response to apoptotic cell-derived self-antigens was characterized.Upon primary immunization of apoptotic cells a transient autoantibody response against theself-antigens DNA and phosphorylcholine was induced and when the primary response hadwaned, a single boost injection of apoptotic cells led to a rapid induction of the sameautoantibodies. In a second recall response to apoptotic cells, mice presented with signs ofautoimmune pathology such as IgG-deposition in the kidneys, positive anti-nuclear stainingof antibodies from sera and altered architecture of the glomeruli indicating kidney damage. In paper III a role for the scavenger receptor CD36 on B cells was investigated in the context ofapoptotic cell-derived self-antigens. CD36 inhibited B cell activation in the response toapoptotic cells and associated with known negative regulators of autoimmunity; the tyrosinekinase Lyn and FcRIIB. Upon break of tolerance to the administered apoptotic cells and theactivation of autoreactive B cells, the level of CD36-expressing marginal zone B cells wasdramatically decreased and the same population of cells was found to be decreased in thecirculation of SLE patients