INNATE MECHANISMS REGULATING PERIPHERAL B CELL TOLERANCE

摘要: 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) harmless environmental factors (allergy). The is built up multiple, often overlapping, layers represented cells soluble working together to stop pathogens. commonly described divided into a fast, more primitive, innate slower, refined, adaptive part. Most are both genetic affecting several parts of the involved in autoimmune development. Thus, tolerance (related tolerating tissues) broken patients with these diseases. pathology associated general linked presence activation autoreactive B T cells. aim work presented this thesis has been related how certain mechanisms regulate two first papers [I, II] mainly address increased levels circulating apoptotic cells, evident SLE, activate last [III, IV] relate, broad sense, splenic marginal zone (MZ) macrophage population its function. Paper I identifies an important regulatory role for invariant natural killer (iNKT) controlling This dependent on direct iNKT–B cell interaction taking place before enters germinal center (GC). Of significance, GC entry subsequent autoantibody production iNKT deficient mice be limited increasing levels, thus relevant SLE who have reduced II that MZ macrophages importance bind present circulation binding involves scavenger receptor MARCO. Furthermore, autoantibodies MARCO found onset develop spontaneous SLE-like disease. III further addresses (macrophage) it. injection anti-MARCO antibody affected disease-related following vivo vitro stimulation. antibody-mediated engagement results release proinflammatory TNF-α. IV SIGN-R1, expressed MARCO+ macrophages, antiinflammatory affect mediated IVIG treatment model rheumatoid arthritis. In summary, studies identify promising therapeutic target patients, novel autoantigen describe multifaceted removing (dependent type stimuli) ability dampen system. discusses conflicting view inducers but also, during conditions, activators LIST OF PUBLICATIONS I. Wermeling F, Lind S. M, Domange Jordo E., Cardell S, Karlsson MCI. Invariant NKT limit CD1d positive J. Exp. Med. [Accepted publication March 2010] II. Chen Y, Pikkarainen T, Scheynius A, Winqvist O, Izui Ravetch JV, Tryggvason K, MC. Class A receptors predictive systemic lupus. 2007 Oct 1;204(10):2259-65. (Highlighted Nat. Clin. Pract. Rheumatology, 2008, 4:7) III. Prokopec Gronlund H triggers sterile inflammatory response implication activation. Manuscript IV. Anthony RM, MCI JV. Identification required anti-inflammatory activity IVIG. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19571-8. Additional publications not included thesis: Sakthivel P, Elmgren Hulthe J, Kakoulidou Kari Lefvert L. Circulating CTLA-4 markers 70 year old