The regulation of B cell responses in systemic autoimmunity

Our immune system is a complex network made up of physical barriers and specialized proteins, cells and organs that all work together to prevent pathogens from causing disease in the body. Once the immune system has successfully mounted an immune response upon intrusion of a pathogen it will mount an immediate and stronger response against any subsequent exposure to it. This is known as immunological memory and is crucial for generating long-lasting protective immunity. The immune system has also developed to maintain homeostasis and be tolerant to the presence of the body’s own structures, or so called self-antigens. A loss of this tolerance can lead to the immune system attacking the body itself, causing autoimmune disease. The pathogenesis of autoimmune disease involves both genetic and environmental factors. B cells and autoantibodies are major contributors to several autoimmune diseases such as systemic lupus erythematosus (SLE). The aim of this thesis was to investigate the regulation of B cell responses in systemic autoimmune disease. This was studied in mouse models of autoimmunity and atherosclerosis and in paper III also in SLE patient samples. Paper I was prompted by a study where transfer of spleen B cells from old atherosclerosisprone apolipoprotein E-deficient (ApoE) mice to young ApoE mice conferred protection against plaque development. We characterized the B cell response in the spleen of atherosclerotic ApoE mice and found an ongoing B cell response in the form of germinal center B cells and plasma cells. Repeated injections of apoptotic cells, carrying the same oxidation-specific epitopes as oxidized LDL, into young ApoE mice led to the same activated 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 the self-antigens DNA and phosphorylcholine was induced and when the primary response had waned, a single boost injection of apoptotic cells led to a rapid induction of the same autoantibodies. In a second recall response to apoptotic cells, mice presented with signs of autoimmune pathology such as IgG-deposition in the kidneys, positive anti-nuclear staining of 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 of apoptotic cell-derived self-antigens. CD36 inhibited B cell activation in the response to apoptotic cells and associated with known negative regulators of autoimmunity; the tyrosine kinase Lyn and FcγRIIB. Upon break of tolerance to the administered apoptotic cells and the activation of autoreactive B cells, the level of CD36-expressing marginal zone B cells was dramatically decreased and the same population of cells was found to be decreased in the circulation of SLE patients compared to healthy individuals. In summary, the work presented in this thesis shows how B cell responses are regulated in different autoimmune contexts. A protective role for B cell responses in atherosclerosis was found, as well as a novel co-receptor involved in the response to self-antigens and the memory response to apoptotic-cell derived lupus-related self-antigens has been characterized in more detail than ever before. These findings are important for the understanding of B cell regulation in autoimmunity and can be implemented to inhibit harmful and promote protective responses in therapeutic approaches to combat autoimmune disease. LIST OF SCIENTIFIC PAPERS I. Grasset EK, Duhlin A*, Agardh HE*, Ovchinnikova O, Hägglöf T, Forsell MN, Paulsson-Berne G, Hansson GK, Ketelhuth DFJ, Karlsson MCI Sterile inflammation in the spleen during atherosclerosis provides oxidation-specific epitopes that induce a protective B-cell response Proc Natl Acad Sci U S A, 2015, 112(16), E2030-38 II. Duhlin A, Chen Y, Wermeling F, Sedimbi SK, Lindh E, Shinde R, Halaby MJ, Kaiser Y, Winqvist O, McGaha TL, Karlsson MC Selective memory to apoptotic cell-derived self-antigens with implications for systemic lupus erythematosus development J Immunol, 2016, 197(7), 2618-26 (Highlighted in Nat Rev Rheumatol 2016 Sep;12(10):559) III. Duhlin A*, Grasset EK*, He C, Amara K, Sippl N, Lindh E, Vargas L, Dahlberg CI, Westerberg LS, Smith ECI, Malmström V, Pierce SK, Karlsson MC Scavenger receptor CD36 on B cells senses modified self-antigens to prevent autoimmunity Manuscript