Hypothesis 1: Chimerism induces a graft-versus-host reaction

1. Requirements: Evidence: Presence of chimeric cells Chimeric cells found in blood of women with SLE 25-27 APC Chimeric T cells found in kidneys with lupus nephritis 24 Chimeric cells are immunologically competent T cells Host B lymphocyte B Chimeric cells recognise host cells as foreign No direct evidence Lack of anti-host CTL development of chimeric cells B T regulatory cells B B Viruses and/or bacteria Factor ? Genetics Sex hormones Hypothesis 1: Chimerism induces a graft-versus-host reaction Host APC presents antigen responsible for SLE Factor ? No elimination of antigen Chimeric CTL Immunologically competent chimeric T cells demonstrated in women with SSc 49, 50 Tc Th Chimeric Th lymphocyte No elimination or suppression of B cells Stimulation Proliferation Production of SLE specific antibodies

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

3. Evidence: B Th Th Help No help B B B Hypothesis 2b: Chimerism induces a host-versus-graft reaction- molecular mimicry Requirements: Fetal cells contain inherited maternal antigens (similar to the host) and inherited paternal antigens (foreign to the host) 30 Chimeric cell with (foreign) antigen Chimeric cells expressing both self antigens and foreign antigens Autoreactive B cell recognizes epitope present both on foreign antigen and autoantigen Host APC presents chimeric antigen to naiveTh cell APC Bidirectional HLA class II compatibility between sons with SLE and mothers 55 Th Autoreactive host B cell Auto-antigen Priming of T cells Autoreactive B cells are present in women with SLE 79 Presence of autoreactive B cells or conditions to prime naive T cells Th Primed Th cell Increased amount of fetal DNA and fetal cells in women during and after pregnancy 1, 10, 11, 15, 19 Proliferation Recognition of and reacting with epitope on autoantigen Autoimmune response due to cross reactivity APC 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 Autoantigen Stimulation Th Production of autoantibodies

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