Immunology 2011 Lecture 17 Lymphoid Tissue Architecture 13 October

Transcription

1 Immunology 2011 Lecture 17 Lymphoid Tissue Architecture 13 October

2 TODAY Lymphoid Tissue Architecture, Chap. 16

3 APC Antigen processing (dendritic cells, MΦ et al.) Antigen "presentation" Ag/Ab complexes Antigenspecific triggering B T ANTIGEN Proliferation Differentiation T H2 T H1 T-cell "help" Complement AFC LYMPHOID TISSUE ANTIBODY T-CELL FUNCTIONS TC T Inactivation of viruses Allergy T-cell killing: virus-infected cells, transplants Mixed Lymphocyte Reaction (MLR) Delayed type hypersensitivity, (DTH); e.g. tuberculin reaction Reg Killing of bacteria Inflammation Tolerance, suppression AUTOIMMUNITY AFFERENT CENTRAL EFFERENT THREE "LIMBS" OF THE IMMUNE RESPONSE

4 Lymphoid Tissues Central Thymus Bone Marrow Primary organs: Sources of competent cells RES reticuloendothelial system Peripheral Lymph Nodes Spleen Tonsils Appendix Peyer s Patches Secondary organs: Sites of immune responses

5 Lymphatics: Collect lymph and cells from tissues and deliver them to blood. migration, recirculation

6 THYMUS thoracic duct MIGRATION (pre-t cells) (T-cells) (B-cells) BONE MARROW bloodstream RECIRCULATION Lymph Node diffuse cortex, follicles efferent lymphatic LYMPHOCYTE MIGRATION, AND RECIRCULATION THROUGH LYMPH NODES Figure 16-3 Continuous regeneration Continuous movement

7 Small Lymphocyte

8 Medium/Large Lymphocyte activated, cycling.

9 Monocyte

10 PMN (polymorphonuclear neutrophil)

11 Basophil (& PMN)

12 Eosinophils Courtesy Dr. M. Samoszuk

13

14 Normal Mouse Lymph Node H&E

15 Secondary Follicle/Germinal Center MGP

16 Normal Mouse Lymph Node

17 ATxBM Mouse Lymph Node

18 Thymic Aplasia L.N.... Siberian Tiger

19 normal T-depleted Circulating Lymphocyte Depletion in Preparation for Renal Allotransplantation Fish et al., Surg. Gyn. Obs., 1969

20 Key Features of Immune Responsiveness Dendritic cells must be activated by microbial products to present Ag (Innate Recognition ) Ag-Presenting Cells Macrophages alveolar & peritoneal MΦ, Kupffer cells of liver B-Cells Dendritic cells - Langerhans cell of skin, et al.

21 Need fail-safe procedures for initiation

22 Two-Signal Principle helps reduce the risk of unauthorized attack.

23 Microbe- & tissue-derived triggers for DC activation LPS/TLR4 Flagellin/TLR5 Lipopeptides/TLR1,2,6 Mannans/MR NA (ss, ds, CpG)/TLR3,7,8,9 ATP/P2R Necrotic cells/clec9a etc Many pathways can activate dendritic cells, danger signal required for initation of adaptive immunity.

24 phagocytic, B7-, Class I & II low Dendritic cells activated by microbial products, induced to migrate to Lymph Node

25 non-phagocytic, B7+, Class I & II high to become effective antigen-presenting cells.

26 Key Features of Immune Responsiveness Dendritic cells must be activated by microbial products to present Ag (Innate Immunity ) T and B Cells differentiate & proliferate in response to antigen (Clonal Expansion, Memory) Recirculation promotes recruitment of antigen-specific cells to local site of reactivity Immune responsiveness and memory are systemic Germinal centers are sites of generation of memory B- cells - isotype switching and somatic mutation Immune responses to T-independent antigens do not generate germinal centers (no switching or memory)

27 Lymphocytes all look alike: Cell surface markers and labeling techniques are required to distinguish different populations.

28 Mouse Thymocytes: red-cd4; green-cd8 Lewis & Cahalan, Science, 1988

29 Normal Mouse Lymph Node: Anti-Ig Gutman & Weissman, 1972

30 Normal Mouse LN: Anti-T-cell Gutman & Weissman, 1972

31 Normal Mouse LN: Anti-T-cell Gutman & Weissman, 1972

32 Human L.N., αcd43, labels all except B-cells Courtesy Dr. R. Warneke

33 Human LN, αcd20, label only B-cells Courtesy Dr. R. Warneke

34 B-Cell Ag-dependent Differentiation small lymphocyte medium-large lymphocyte plasma cell mig resting activated terminally differentiated secreted Ig

35 Recirculation Migration to sites of inflammation (...& 3 lymphoid tissue Lymphocyte activation changes gene expression which modifies functional properties and migration/recirculation.

36 Lymphoid Tissues Central/ Primary * Thymus * Bone Marrow * Encapsulated * vs. non-encapsulated Peripheral/ Secondary Lymph Nodes Spleen Tonsils Appendix Peyer s Patches GALT: Gut-Associated Lymphoid Tissue Peyer s Patches, tonsils, appendix, adenoids MALT: Mucosa-associated Lymphoid Tissue BALT: Bronchus-Associated LALT: Larynx-Associated NALT: Nasal-Associated

37 Lymphoid Tissues Central/ Primary Thymus Bone Marrow Peripheral/ Secondary Lymph Nodes Spleen Tonsils Appendix Peyer s Patches Tertiary lymphoid tissues Organized, ectopic lymphoid aggregates which form at sites of chronic immune stimulation (e.g. in autoimmune or infectious diseases and at sites of graft rejection). May exhibit follicles, germinal centers, HEV s and other properties of conventional lymphoid tissue.

38 Tertiary Lymphoid Organ in a non-lymphoid Setting anti-cd20 (B-cells); Ab-Wue-1 (plasma cells) Follicle-like structure in synovial tissue of patient with rheumatoid arthritis. Berek & Kim (1997) Sem. Immunol. 9:261

39 Miller, Cahalan et al., 2003

40 Movement of T-Cells in an Intact Mouse Lymph Node Circled events show cells entering node via HEV (Color in right-hand panel represents depth-encoding)

41 Movement of T-Cells (green) and B-Cells (red) in an Intact Mouse Lymph Node Primary follicle Diffuse cortex

42 Mouse Lymph Node HEV Courtesy Dr. G. Levine

43 Small Lymphocyte Courtesy Dr. G. Levine

44 Small Lymphocyte