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The Role of Igm and Complement in Antibody Responses

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The Role of Igm and Complement in Antibody Responses Trassla inte till saken genom att komma dragande med fakta Groucho Marx List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. Ia Rutemark C, Alicot E, Bergman A, Ma M, Getahun A, Ellmerich S, Carroll M, Heyman B. Requirement for complement in antibody responses is not explained by the classic pathway activator IgM. Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):E934-42. Epub 2011 Oct 10. Ib Rutemark C, Alicot E, Bergman A, Ma M, Getahun A, Ellmerich S, Carroll M, Heyman B. Requirement for complement in antibody responses is not explained by the classic pathway activator IgM. Author summary. Proc Natl Acad Sci U S A 2011 108(43): 17589-90 II Carlsson F, Getahun A, Rutemark C, Heyman B. Impaired antibody responses but normal proliferation of specific CD4+ T cells in mice lacking complement receptors 1 and 2. Scand J Immunol. 2009 Aug;70(2):77-84. III Rutemark C, Bergman A, Getahun A, Henningson-Johnson F, Hallgren J, Heyman B. B cells lacking complement receptors 1 and 2 are equally efficient producers of IgG in vivo as wildtype B cells. Manuscript. Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 Background ................................................................................................... 12 B cells ....................................................................................................... 12 Antibodies ................................................................................................ 12 T cells ....................................................................................................... 13 Antigen presentation and T cell activation ............................................... 13 Antibody feedback regulation .................................................................. 14 IgG-mediated suppression of antibody responses ............................... 14 Antibody-mediated enhancement of antibody responses .................... 15 IgM-mediated enhancement of antibody responses ............................. 15 The complement system in antibody responses ....................................... 18 Component 3 ........................................................................................ 18 Lectin pathway .................................................................................... 20 Alternative pathway ............................................................................. 20 Classical pathway ................................................................................ 21 Activators of C1q ................................................................................. 23 The C1q paradox in primary antibody responses ................................ 24 Complement Receptors 1 and 2 ........................................................... 25 Possible mechanisms for the importance of complement in antibody responses .............................................................................................. 27 Present investigation ..................................................................................... 29 Aims ......................................................................................................... 29 Paper Ia ................................................................................................ 29 Paper II ................................................................................................ 29 Paper III ............................................................................................... 29 Experimental setup ................................................................................... 30 Mice ..................................................................................................... 30 Immunizations and antigens ................................................................ 31 Adoptive transfer of T cells ................................................................. 31 Assays .................................................................................................. 31 Bone marrow chimeras ........................................................................ 31 Statistical analyses ............................................................................... 32 Results and discussion .............................................................................. 33 Requirement for complement in antibody responses is not explained by the classic pathway activator IgM (Paper Ia) ....................................... 33 Impaired antibody responses but normal proliferation of specific CD4+ T cells in mice lacking complement receptors 1 and 2 (Paper II) ....... 38 B cells lacking complement receptors 1 and 2 are equally efficient producers of IgG in vivo as wildtype B cells (Paper III) ..................... 40 Highlights of this thesis ................................................................................ 44 Acknowledgements ....................................................................................... 45 References ..................................................................................................... 47 Abbreviations APC antigen presenting cells BCIP/NBT 5-bromo-4-chloro-3-indolylphosphate p-toluidine salt and nitro blue tetrazololium HRBC horse red blood cells BCR B cell receptor Bf complement factor B BM bone marrow BSA bovine serum albumin CD cluster of differentiation CGG chicken gamma globulin CR1, 2 complement receptor 1, 2 CVF cobra venom factor CRP c-reactive protein DC dendritic cells DNP 2, 4-dinitrophenol ELISA enzyme-linked immunosorbent assay ELISPOT enzyme-linked immunospot assay Fc fragment crystallizable FDC follicular dendritic cells Fo B follicular B GC germinal center IC immune complex IgG, M… immunoglobulin G, M… IgM-IC antigen-specific IgM in complex with that antigen KLH keyhole limpet hemocyanin mAb monoclonal antibody MASP mannose-associated serine protease MAC membrane attack complex MBL mannose-binding lectin NP 4-hydroxy-3-nitrophenylacetyl MZ marginal zone OVA ovalbumin PBS phosphate buffered saline PFC plaque forming cell assay SAP serum amyloid P component SIGN-R1 specific intracellular adhesion molecule-grabbing noninteg- rin related gene 1 SCR short consensus repeats SRBC sheep red blood cells TCR T cell receptor TH T helper cell TD thymus-dependent TI thymus-independent TNP 2, 4, 6-trinitrophenol WT wildtype Introduction The immune system is our protection against foreign material such as viruses and bacteria, but also in clearing the body from dead cells and cancer cells. Assigned to the immune system are two global functions, recognition and response. In the recognition phase the ability to discriminate between self and non-self-structures, as well as the distinction between different foreign structures is paramount. Following optimal recognition comes then an ap- propriate and specific response. The immune system is often divided into innate immunity and adaptive immunity. The innate cells and molecules are encoded before an infection has occurred. Thus, this part is our very first line of defense, acting fast and with a broad spectrum of recognition. In contrast, the adaptive part is fairly slow to initiate and requires an intact innate defense to mount a full re- sponse. However, once this is fulfilled the adaptive system utilizes the torpe- does of the immune system, the antibodies, produced by B cells, but also cell-mediated defense caused by cytotoxic T cells. The antibodies are highly specific with the ability to discriminate targets that differ down to only one amino acid. However, antibodies recognizing self-antigens are one of the major causes for autoimmunity. Furthermore, the adaptive system also pos- sesses immunological memory, i e the same infection the second time around is responded to faster and with even higher affinity and specificity. Antibodies themselves have the ability to regulate the production of anti- bodies, a process called antibody feedback regulation. The outcome of this regulation can be either enhancement or suppression of the antibody re- sponse, depending on the antibody type or antigen involved. One of the connections between innate and adaptive immunity is the complement system, which is activated via different pathways upon recogni- tion of foreign surfaces. It consists of a group of soluble proteins and recep- tors that can, in very low concentrations, identify and incapacitate many pathogens. The complement system has shown various characteristics in engaging and enhancing the adaptive response, including antibody respons- es. In addition, complement deficiencies often lead to diseases such as auto- immunity. This thesis focuses on the factors that are activating complement and how complement further is affecting the antibody response. More specifically, the classical activation pathway and its most common activator, IgM, have been studied, along with the effect of the complement receptors 1 and 2. 11 Background B cells B lymphocytes (B cells) originate from the bone marrow (BM) and when they are let out into the circulation, each B cell carries a unique antigen- binding receptor on its surface. This receptor is an IgM antibody molecule bound to the B-cell membrane and is referred to as the B cell receptor (BCR). Mature B cells that meet the antigen recognized by the BCR, will start to proliferate and differentiate into antibody producing
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