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How do plasma cells survive Claudia Berek Deutsches Rheuma Forschungs Zentrum, Berlin Institut der Leibniz Gemeinschaft Immune response Naive B cell Peripheral lymphoid organs Memory B cell T Germinal Bcenter IgM Pasma cell Plasma cells Long term protection Germinal center reaction U U Y U Y Y Memory B cell Y Y Y Plasma cells Antigen Proliferation Hypermutation Selection Differentiation Persistent serum antibody titer Induction selection homeostasis magnitude serum antibody splenic plasma cells days months and years short lived plasma cells Slifka and Ahmed 1998 Manz et al, 1997 Persistent serum antibody titer 16 years 20 years Amanna and Slifka 2010 Persistance of plasma cells in the bone marrow Induction selection homeostasis serum antibody magnitude bone marrow plasma cells splenic plasma cells days months and years short lived plasma cells Slifka and Ahmed 1998 Manz et al, 1997 Persistance of plasma cells in the bone marrow How is that achieved ? Memory B cells Plasma cells Immune response to small pocks Two arms of memory Memory B cell Memory plasma cell Mamani-Matsuda 2008 Long-term maintenance of plasma cells Induction selection homeostasis serum antibody magnitude bone marrow plasma cells splenic plasma cells days short lived plasma cells months and years long lived plasma cells Slifka and Ahmed 1998 Manz et al, 1997 Migration of plasma cells to the bone marrow Stromal cell Bone marrow CXCR4 CXCL12 Benner at el, 1981 Hauser et al, 2003 Chu et al, 2011 Mesenchymal stem cells Stromal reticular cells • long lived • don´t proliferate • radio resistant Stromal cells are the „house“ of lymphocytes They regulate the development, migration, activation of lymphocytes They are important in the selection of lymphocytes and in the maintenance of immunological memory Peripheral lymphoid organs network of Follicular Dendritic Cells Bone marrow bone marrow stromal cell B cells are embedded in a network of FDC Plasma cells are incontact with stromal cells Lymphocytes are attracted by the chemokine CXCL13 Plasma cells are attracted by the chemokine CXCL12 Tokoyoda et al , 2004 Stromal cell survival niche Plasma cell Stromal cell CXCR4 CXCL12 Tokoyoda et al, 2010 Radbruch et al, 2006 Plasma cell survival factors Ligand Receptors APRIL TACI, BCMA, PGL IL-6 IL-6R BAFF BAFF-R, TACI, BCMA IL-5 IL-5R TNF-α TNF-Rs IL-10 IL-10R Cassese et al, 2003 BAFF and APRIL belong to TNF superfamily Molecular basis of plasma cell survival Tumor necrosis super family BAFF-R BAFF B cell BCMA plasma cells TACI APRIL Proteo Glycans myeloid cell B cell plasma cell MacKay et al 2003 BAFF BAFF B cell APRIL plasma blast plasma cell BAFF -R BCMA O´Connor et al, 2004 Belnoue et al, 2008 Bone marrow survival niche APRIL IL-6 Plasma cell Stromal cell ? CXCR4 CXCL12 Support of plasma cells spleen: Basophils BM ? Gonzalez, 2010 Bone marrow: Megakaryocytes O Winter, 2010 lymph node: F4/80+ GR-1lo myeloid cells E Mohr 2009 Deutsches Rheuma Forschungs Zentrum, Berlin In the bone marrow F4/80 GR-1lo cells produce APRIL 8.89 % Gr-1 1 9.02% F4/80 I-APRIL Chu et al, 2011 Macrophages and eosinophils produce APRIL and Il-6 Eosinophils R1 33% R2 R2 17% eosinophil precursors SSC eosinophils CD11b R3 46% monocytes/macrophages R3 APRIL and IL-6 is found in the granules of Eos APRIL MBP IL-6 MBP MBP - Major Basic Protein Deutsches Rheuma Forschungs Zentrum, Berlin Eosinophils support plasma cell survival by secretion of APRIL and IL-6 90.6 9.4 52.1 47.6 44.1 55.9 83.4 16.6 % of Max _ Annexin-V TACI-Ig anti-IL-6 Plasma cell survival is dependent on Eosinophils 2° ip. 1° ip BALB/c Naive 6 weeks d0 2 months d 60 3 injections with Day 60 Siglec F specific antibody 1 week CD138hi plasma cells RatIgG2a α-Siglec-F BM 2.54 19.83 Spleen 6.31 % of Max 7.39 Annexin-V Deutsches Rheuma Forschungs Zentrum, Berlin The majority of plasma cells sit in the gut walls IgA DAPI Lamina propria IgA plasma cells Epithelial cells ~ 80% of all plasma cells Human 7 x 1010 The plasma cell survival niche APRIL IL-6 Plasma cell Stromal cell Eos CXCR4 CXCL12 How do plasma cells survive ? • Long-lived plasma cells are generated during the GC reaction (or from memory cells generated during the GC reaction) • Long-lived plasma cells need a specific micro-environment for their survival • Long-lived plasma cells require APRIL, IL-6 and other cytokines • Eosinophils are essential for plasma cell survival The plasma cell survival niche Stromal cells eosinophils plasma cell 30 µm section Van Trung Chu Nat Immunol 2011
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