How do plasma cells survive

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1 How do plasma cells survive Claudia Berek Deutsches Rheuma Forschungs Zentrum, Berlin Institut der Leibniz Gemeinschaft

2 Immune response Naive B cell Peripheral lymphoid organs Memory B cell Germinal T Bcenter IgM Pasma cell Plasma cells Long term protection

3 U Germinal center reaction U U Y Memory B cell Y Y Y Y Y Plasma cells Antigen Proliferation Hypermutation Selection Differentiation

4 Induction selection Persistent serum antibody titer homeostasis serum antibody magnitude splenic plasma cells days months and years short lived plasma cells Slifka and Ahmed 1998 Manz et al, 1997

5 Persistent serum antibody titer 16 years 20 years Amanna and Slifka 2010

6 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

7 Persistance of plasma cells in the bone marrow How is that achieved? Memory B cells Plasma cells

8 Immune response to small pocks Two arms of memory Memory B cell Memory plasma cell Mamani-Matsuda 2008

9 Long-term maintenance of plasma cells Induction selection homeostasis serum antibody magnitude bone marrow plasma cells splenic plasma cells days short lived plasma cells long lived plasma cells months and years Slifka and Ahmed 1998 Manz et al, 1997

10 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

11 Mesenchymal stem cells Stromal reticular cells long lived don t proliferate radio resistant

12 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

13 Peripheral lymphoid organs Bone marrow network of Follicular Dendritic Cells 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

14 Stromal cell survival niche Plasma cell Stromal cell CXCR4 CXCL12 Tokoyoda et al, 2010 Radbruch et al, 2006

15 Plasma cell survival factors Ligand APRIL IL-6 BAFF IL-5 TNF-α IL-10 Receptors TACI, BCMA, PGL IL-6R BAFF-R, TACI, BCMA IL-5R TNF-Rs IL-10R Cassese et al, 2003

16 BAFF and APRIL belong to TNF superfamily

17 Molecular basis of plasma cell survival Tumor necrosis super family BAFF BAFF-R B cell APRIL BCMA TACI plasma cells Proteo Glycans myeloid cell B cell plasma cell MacKay et al 2003

18 BAFF BAFF APRIL B cell plasma blast plasma cell BAFF -R BCMA O Connor et al, 2004 Belnoue et al, 2008

19 Bone marrow survival niche APRIL IL-6 Plasma cell? Stromal cell CXCR4 CXCL12

20 Support of plasma cells spleen: BM? Basophils Gonzalez, 2010 Bone marrow: Megakaryocytes O Winter, 2010 lymph node: F4/80 + GR-1 lo myeloid cells E Mohr 2009 Deutsches Rheuma Forschungs Zentrum, Berlin

21 In the bone marrow F4/80 GR-1 lo cells produce APRIL 9.02% 8.89 % Gr-1 F4/80 I-APRIL Chu et al, 2011

22 Macrophages and eosinophils produce APRIL and Il-6 Eosinophils R2 eosinophils R1 33% R2 17% eosinophil precursors SSC CD11b R3 46% monocytes/macrophages R3

23 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

24 Eosinophils support plasma cell survival by secretion of APRIL and IL-6 % of Max _ 16.6 Annexin-V TACI-Ig anti-il-6

25 Plasma cell survival is dependent on Eosinophils 1 ip 2 ip. BALB/c Naive 6 weeks d 0 2 months d 60 Day 60 1 week 3 injections with Siglec F specific antibody

26 CD138 hi plasma cells RatIgG2a α-siglec-f BM Spleen % of Max Annexin-V Deutsches Rheuma Forschungs Zentrum, Berlin

27 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 10 10

28 The plasma cell survival niche APRIL IL-6 Plasma cell Eos Stromal cell CXCR4 CXCL12

29 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

30 The plasma cell survival niche Stromal cells eosinophils plasma cell 30 µm section Van Trung Chu Nat Immunol 2011

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