Innate mechanisms regulating peripheral B cell tolerance

Abstract: Our immune system protects us from invading pathogens such as bacteria, viruses, fungi and parasites. However, it can also cause disease by being improperly activated against our own tissues (autoimmune diseases) and harmless environmental factors (allergy). The immune system is built up by multiple, often overlapping, layers represented by cells and soluble factors working together to stop invading pathogens. The immune system is commonly described as being divided into a fast, more primitive, innate and a slower, more refined, adaptive part. Most often are both genetic and environmental factors affecting several parts of the immune system involved in autoimmune disease development. Thus, tolerance (related to tolerating our own tissues) is broken in patients with these diseases. The pathology associated with autoimmune disease is in general linked to the presence and activation of autoreactive B and T cells. The aim of the work presented in this thesis has been related to how certain innate mechanisms regulate autoreactive B cells. The two first papers [I, II] mainly address how increased levels of circulating apoptotic cells, evident in patients with the autoimmune disease SLE, activate autoreactive B cells. The two last papers [III, IV] relate, in a broad sense, to the splenic marginal zone (MZ) macrophage population and its function. Paper I identifies an important regulatory role for invariant natural killer T (iNKT) cells, controlling the activation of autoreactive B cells. This is dependent on a direct iNKT B cell interaction taking place before the autoreactive B cell enters a germinal center (GC). Of significance, the GC entry and subsequent autoantibody production in iNKT cell deficient mice can be limited by increasing iNKT cell levels, thus being relevant for SLE patients who have reduced levels of iNKT cells. Paper II identifies that splenic MZ macrophages with importance for tolerance bind apoptotic cells present in the circulation and that this binding involves the scavenger receptor MARCO. Furthermore, autoantibodies binding the MARCO receptor are found in SLE patients and before onset of disease in mice that develop spontaneous SLE-like disease. Paper III further addresses the role of the MARCO (macrophage) receptor and autoantibodies that bind it. The injection of an anti-MARCO antibody affected B cells and increased the production of disease-related autoantibodies following both in vivo and in vitro stimulation. The antibody-mediated MARCO engagement results in the release of soluble proinflammatory factors such as TNF-alpha. Paper IV identifies an important role for SIGN-R1, expressed on MARCO+ MZ macrophages, in the antiinflammatory affect mediated by IVIG treatment in a model of rheumatoid arthritis. In summary, these studies identify iNKT cells as a promising therapeutic target in SLE patients, MARCO as a novel autoantigen and describe a multifaceted role for the splenic MZ macrophage involved in removing apoptotic cells and (dependent on the type of stimuli) the ability to both activate and dampen the immune system. Furthermore, this thesis discusses the conflicting view of apoptotic cells as inducers of tolerance but also, during certain conditions, as activators of the immune system.