Hypothesis 1: Chimerism induces a graft-versus-host reaction Host B lymphocyte B B B B Chimeric Th lymphocyte Chimeric CTL Stimulation No elimination or suppression of B cells Th Tc Factor ? Proliferation No elimination of antigen APC Host APC presents antigen responsible for SLE Production of SLE specific antibodies Requirements:Evidence: Presence of chimeric cells Chimeric cells are immunologically competent T cells Chimeric cells recognise host cells as foreign Lack of anti-host CTL development of chimeric cells Factor ? Chimeric cells found in blood of women with SLE Chimeric T cells found in kidneys with lupus nephritis 24 No direct evidence T regulatory cells Viruses and/or bacteria Genetics Sex hormones Immunologically competent chimeric T cells demonstrated in women with SSc 49, 50

Hypothesis 2a: Chimerism induces a host-versus-graft reaction- the direct response Requirements: Antigens on chimeric cell are foreign to host Inadequate immune response necessary for continuous B cell stimulation Chimeric cells present in affected organs Th Complement Relation between presence of chimerism and disease activity Limited disease Persistent, chronic disease Chimeric cell with antigen Existence of anti- paternal antibodies in mothers 52 Chimeric cells present in affected kidney, skin, lungs, heart, and intestines of woman with SLE 28 Abnormal T cell and complement function in patients with SLE 61 Host Tc cell MΦMΦ APC Host APC presents chimeric antigen to Th cell No direct evidence Chimeric cells present in kidneys of women with lupus nephritis 24 Female sex hormones suppress Tc cell function 78 Amount of chimerism in blood higher in women with lupus nephritis 27 Evidence: Host B cell B B B B Induces humoral immune response Proliferation Production of SLE specific antibodies Host Th cell Tc Inhibition of antigen elimination Macrophage Antigen elimination Induces innate immune response Induces cellular immune response

Primed Th cell Th APC Chimeric cell with (foreign) antigen Hypothesis 2b: Chimerism induces a host-versus-graft reaction- molecular mimicry Th B No helpHelp Proliferation APC Th Host APC presents chimeric antigen to naiveTh cell Priming of T cells Autoimmune response due to cross reactivity B B B Production of autoantibodies Stimulation Recognition of and reacting with epitope on autoantigen Requirements: Presence of autoreactive B cells or conditions to prime naive T cells Bidirectional HLA class II compatibility between sons with SLE and mothers 55 Fetal cells contain inherited maternal antigens (similar to the host) and inherited paternal antigens (foreign to the host) 30 Autoreactive B cells are present in women with SLE 79 Increased amount of fetal DNA and fetal cells in women during and after pregnancy 1, 10, 11, 15, 19 A strong relation between chimeric cells and disease activity is not necessarily present Chimerism in blood of women with SLE is not related to disease activity 27 Evidence: Chimeric cells expressing both self antigens and foreign antigens Autoreactive B cell recognizes epitope present both on foreign antigen and autoantigen Autoantigen Auto- antigen Autoreactive host B cell

Requirements: Presence of chimeric progenitor cells Chimeric cells must be able to differentiate into parenchymal cells Chimeric cells must migrate to injury sites Chimeric CD34+ progenitor cells present in mother after pregnancy 1 Chimeric cells present in bone marrow and rib sections of women with sons 17 Chimeric cells present in kidney, skin, lung, heart, and intestines of women with SLE 28 Chimeric cells are predominantly present in organs in which injury has occured Cytokeratin and heppar-1 positive chimeric cells found both in women with autoimmune disease and in women with other diseases 51 Fetus-derived chimeric cells travel to injured kidney and liver in mice 69, 70 Evidence: Chimeric cells present in bone marrow of host Organ damage Chimeric CD34+ progenitor cell Chimeric lymphocyte Bone marrow Chimeric erythrocyte Chimeric throphoblast cell Hypothesis 3: Chimeric cells repair injured tissue Differentiation fetus mother placenta Mobilizing chimeric cells Repair of injured tissue Parenchymal cell