How plasma cells develop. Deutsches Rheuma Forschungs Zentrum, Berlin Institut der Leibniz Gemeinschaft

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1 How plasma cells develop Deutsches Rheuma Forschungs Zentrum, Berlin Institut der Leibniz Gemeinschaft 1

2 Plasma cells develop from activated B cells Toll Like Receptor B Cell Receptor B cell B cell microbia antigen specific 2

3 plasma blast plasma cell Pre-Plasmablast Plasmablast Plasma cell IgG DAPI membrane Ig > secreted Ig mig <<< secreted Ig 3

4 Immune response Naive B cell Peripheral lymphoid organs Memory B cell Germinal center IgM Pasma cell Plasma cells T cell - independent T cell - dependent 4

5 Germinal center reaction clonal expansion Ig class switch affinity maturation establishment of the memory compartment 5

6 U Germinal center reaction U U Y Memory B cell Y Y Y Y Y Plasma cells Antigen Proliferation Hypermutation Selection Differentiation Dark zone Light zone 6

7 Affinity maturation A. Hypermutation B. Selection 1. follicular dendritic cell (FDC) 2. T -follicular helper cell (TFh) 7

8 Hypermutation highly specific mechanism nucleotide exchanges are introduced at a high rate of 10-3 / base pairs / generation accumulate specifically in the rearranged V- region genes active for a short time period 8

9 Selection Follicular dendritic cells T FDC support B cell B homeostasis affinity maturation Lymphoid follicle 9

10 Follicular dendritic cells: non hematopoietic cells antigen-antibody complexes bound to the surface present antigen to B cells 10

11 Suzuki K, Cyster J. JEM

12 Follicular dendritic cells: secrete the chemokine CXCL13 CCR7 T B CXCR5 12

13 T follicular helper cells Reticular cells CCL19 / CCL21 T cell zone Nutt and Tarlinton 13

14 Affinity selected differentiation IL-21 IL-21R T FH ICOS CD40L TCR ICOSL CD40 class II B GC CXCR5 antigen BAFF CXCR5 CXCL13 FDC CXCL13 14

15 development of plasma cells secreting antibodies of high affinity takes place in germinal centers 15

16 Transcription factors controlling the development of plasma cells B defines: Pax5 B cell state Blimp 1 B lymphocyte induced maturation protein 1 transcriptional repressor Plasma cell state regulate mutually exclusive transcriptional programs 16

17 Network of TF regulating the development of plasma cells maintain B cell phenotype: Pax5, Bach2 and Bcl6, promote plasma cell differentiation: Irf4, Blimp1 and Xbp1 B cell Plasma celle Germinal center B cell 17

18 UPR - unfolding protein response ER nucleus stress sensors: Ire1 induces splicing of Xbp1 ER stress Atf6 activation of ER chaperones folding enzymes Stress response expansion of the ER burden of unfolded protein increasing protein processing capacity enhanced secretion of Ig 18

19 XBP-1 is required for high Ig secretion XBP-1 deficient B cells Nutt SL JI 19

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

21 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,

22 Persistent serum antibdy titer How is that achieved? Memory B cells Plasma cells 22

23 Twoarmsofmemory Memory B cell Memory plasma cell Immune response to small pocks 23

24 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,

25 25

26 Development of long-lived plasma cells Naive B cell Peripheral lymphoid organs Germinal center Memory B cell IgM Pasma cell Long lived plasma cells 26

27 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,

28 Peripheral lymphoid organs Bone marrow Tokoyoda et al, 2004 network of Follicular Dendritic Cells bone marrow stromal cell Lymphocytes are attracted by the chemokine CXCL13 Plasma cells are attracted by the chemokine CXCL12 B cells are embedded in a network of FDC Plasma cells are in contact with stromal cells 28

29 Bone marrow survival niche APRIL IL-6 Plasma cell? Stromal cell CXCR4 CXCL12 29

30 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,

31 BAFF and APRIL belong to TNF superfamily 31

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

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

34 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,

35 Macrophages and eosinophils produce APRIL and Il-6 Eosinophils R2 eosinophils R1 33% R2 17% eosinophil precursors SSC CD11b R3 46% monocytes/macrophages R3 35

36 APRIL and IL-6 is found in the granules of Eos APRIL MBP IL-6 MBP MBP - Major Basic Protein Deutsches Rheuma Forschungs 36 Zentrum, Berlin

37 Eosinophils support plasma cell survival by secretion of APRIL and IL % of Max _ Annexin-V TACI-Ig anti-il-6 37

38 Development of mature long lived plasma cells 38

39 The plasma cell survival niche Stromal cells eosinophils plasma cell 30 µm section Chu Van Trung 39

40 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 40

41 CD138 hi plasma cells RatIgG2a α-siglec-f BM Spleen % of Max Annexin-V Deutsches Rheuma Forschungs 41 Zentrum, Berlin

42 How plasma cells develop plasma cells develop from antigen activated B cells their development is dependent on the TF BLIMP-1 the germinal center reaction is a pre-requisite for the generation of long-lived plasma cells eosinophils are required for the establishment and the maintenance of the plasma cell survival niche 42

43 Deutsches Rheuma Forschungs Zentrum, Berlin Institut der Leibniz Gemeinschaft 43