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INSTITUTE FOR IMMUNOBIOLOGY
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INSTITUTE FOR IMMUNOBIOLOGY

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  1. INSTITUTE FOR IMMUNOBIOLOGY B cell and B cell-mediated humoral immune response Department of Immunology Fudan University Wei Xu, Ph.D 021-54237749 wx2362@hotmail.com

  2. Adaptive immune response to pathogens

  3. Overview of the humoral immune response against bacterial B cells plasma cells

  4. B lymphocyte 5%~15% of peripheral lymphocytes 25% lymph node and 45% splenic lymphocytes secret antibodies (Ab) act as antigen-presenting cell (APC)

  5. B cells and humoral immune response • 1. Surface molecules of B cell • B cell subsets • B cell development • Function and significance

  6. 1. Surface molecules of B cell Surface receptor 1) B cell antigen receotor (BCR) 2) BCR coreceptor 3) Cytokine receptor(CKR) Surface functional molecules

  7. Surface receptor 1) B cell antigen receotor (BCR) BCR/mIgM Membrane Ig (mIg) Mature B cell: mIgM + mIgD BCR-Igα/Igβ complex

  8. BCR-Iga/Igb complex

  9. 2. BCR coreceptor CD19 B-specific surface marker signal transduction CD21CR2,receptor for C3d-bound Ag CD81 BCR-coreceptor ligation inducereversible palmitoylation of CD81 to stabilize the CD19/CD21/CD81 complex Help and strengthen the BCR-Ag-signaling JBC 2004;279:31973

  10. Coreceptor of BCR

  11. BCR-Iga/Igb coreceptor complex B cell epitope B cell activation

  12. TCR-CD3 BCR-Iga/b

  13. 3.Complement receptor, CR CR2(CD21):EB virus receptor

  14. 4.Cytokine receptor, CKR IL-1R、IL-2R、IL-4R、IL-5R、IL-6R、 IL-7R, IFN-γR regulate the activation, differentiation and function of B cells

  15. 1. Surface molecules of B cell Surface receptor 1) B cell antigen receotor (BCR) 2) BCR coreceptor 3) Cytokine receptor(CKR) Surface functional molecules

  16. Surface functional molecules • MHC-I、II molecules • co-stimulatory molecules • CD40: most important csm forB cell activation B cell CD40 CD40L T cell

  17. Two-signal activation model for T cells activation naive co-stimulatory molecules anergy none

  18. Two-signal activation model for B cells Signal 3 Signal 1 and signal 2 are not simultaneous But in two steps, signal 2 from Th cells

  19. B cells and humoral immune response • 1. Surface molecules of B cell • B cell subsets • B cell development • Function and significance

  20. 2、B cell subsets B1 Marginal zone B MZ B Follicular B FO B / B2 Innate immunity Generally mentioned B cell

  21. B1 cells in the peritoneal and pleural cavities and the gut lamina propria. unique phenotype: CD5, CD19 Progenitors: fetal liver generation and maintenance:Spleen produce ‘natural’ low-affinity IgM, in response to self-antigens and bacterial antigens at mucosal site: first line of defense Associated with chronic lymphocytic leukemia (CLL).

  22. Sjogren's Syndrome Cells are stained with anti-surface molecule-monoclonal Abs (fluorescent: FITC/green; PE/red ) women with dry eyes and mouth, chronic arthritis Destroyed exocrine glands T B2 FACS analysis B-1 cells are raised in autoimmune disorders and accumulate in chronic lymphocytic leukemia (CLL). CD5: T cell surface molecule CD19: B specific marker

  23. MZ B cells innate immune functions B-1cells (peritoneal cavity) marginal zone (MZ) B cells (spleen) frequent Ag encounter. Secreting essentially germline-encoded, polyreactive natural Abs, respond rapidly and vigorously to pathogens express Toll-like receptors (TLR), provide costimulation to GC B cells important link between the innate and adaptive immunity

  24. spleen

  25. GC B T

  26. Splenic B cells Follicular B, FO B major B population Marginal zone B, MZ B Against blood-borne pathogens, mounting Abs. Act as potent APC: lipid Ags

  27. MZ B cell and B cell lymphoma Infection-associated lymphomas derived from MZ B cells MZ lymphomas The list of microbial species :at least 5 Helicobacter pylori 幽门螺杆菌 gastric lymphoma Campylobacter jejuni 空肠弯曲杆菌 gastric lymphoma,small intestinal disease Borrelia burgdorferi 博氏螺旋体 cutaneous lymphoma Chlamydia psittaci 鹦鹉热衣原体 ocular lymphoma hepatitis C virus HCV spleen lymphoma Blood. 2006;107:3034-3044

  28. Histopathologic illustration of MALT/MZ lymphoma H pylori–gastric MALT lymphoma CD20 centrocyte-like MZ B C jejuni typical villous lymphocyte patient with HCV-associated splenic lymphoma H pylori (arrow) C jejuni–associated IPSID

  29. Systemic lupus erythematosus MZ B cell and SLE B-lymphocytes, innate immunity, and autoimmunity Muriel Viau, Moncef Zouali* Clinical Immunology 114 (2005) 17– 26

  30. The innate model of SLE pathogenesis: central role of TLR-activated MZ-B cells and pDCs. mDC derived BAFF promote survival and differentiation of auto B cells BAFF

  31. FO B Secret Ag-specific Abs Mediate humoral immunity Act as APC Present pep/MHC-Ⅱ CD4+Th Especially Soluble Ag

  32. B1 B2/FO B location mucosal sites spleen, LN Ig-producing way naturally Ag-inductive specificity poly-reactive highly specific Ag TI AgTD Ag (polysaccharide) Ig class Ig MIgG affinitylow high

  33. three major naive peripheral B-cell populations B cell High-affinity IgG Immunol Rev 2004; 197:206

  34. B cells and humoral immune response • 1. Surface molecules of B cell • B cell subsets • B cell development • Function and significance

  35. Lymphoid lineage Myeloid lineage

  36. 3. Development of B cells • Bone Marrow:Ag-independent • Peripheral (LN/spleen):Ag-dependent

  37. development of B cells Ag-independent MZ B FO B Newly formed B IgM+ IgD+ FB precursor Ag-dependent Nat Rev Immunol 2005; 5:230:

  38. Bone Marrow No antigen Peripheral lymphoid organ Ag-stimulation

  39. 1.pro B Ig H chain:D-J V-D-J rearrangement,Igα/Igβ surrogate Lchain 2 pre B L chain V-J rearrangement CD19、 CD20、MHC-II 3.immature B mIgM, negative selection 4.mature B mIgM+mIgD,leave

  40. Surrogate light chain, SLC SLC: Vpre-B/l5

  41. B lineage commitment Myeloid cell T HSC CD19 HSC (hematopoietic stem cell) LMPP(lymphoid/myeloid progenitor) ELP (earliest lymphocyte progenitor) ETP (early T-lineage progenitor) CLP (common lymphoid progenitor)

  42. B cells and humoral immune response • 1. Surface molecules of B cell • B cell subsets • B cell development • Function and significance

  43. Function of Antibodies 1. Neutralization toxin pathogen bind to them and block their functional domain

  44. Neutralization of viruses

  45. Function of Antibodies 2. activate complement pathway, lyze pathogens IgG /M -Ag

  46. 3. Opsonization- enhance MF Phagocytosis

  47. 4. Ab-dependent Cell-mediated cytotoxicity, ADCC enhance NK killing

  48. 5. Secreted IgA at the mucosal surface