7/6/2009. The study of the immune system and of diseases that occur as a result of inappropriate or inadequate actions of the immune system.

Transcription

1 Diseases of Immunity 2009 CL Davis General Pathology Paul W. Snyder, DVM, PhD Purdue University Acknowledgements Pathologic Basis of Veterinary Disease, 4 th Ed Veterinary Immunology, An Introduction 8 th Ed Immunology, Kuby, 6 th Ed The Immune System, Parham, 2 nd Ed Immunobiology, Janeway, 5 th Ed 2 Immunology The study of the immune system and of diseases that occur as a result of inappropriate or inadequate actions of the immune system. 1

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3 pathogen The body s defense system Physical and chemical barriers - epidermis, mucosal epithelium - ph of the stomach - mucociliary apparatus - lysozyme Innate immunity Adaptive immunity 7 8 Innate (non-specific) immune system Cells Macrophages, dendritic cells, neutrophils, NK cells Recognition molecules Pathogen-Associated Molecular Patterns Toll-like like receptors Pattern Recognition Receptors Alarmins Released by damaged cells Defensins, cathelicidins, HMGB1 Effector functions Phagocytosis Complement system Inflammation Interactions 9 3

4 Neutrophils 10 Neutrophil migration 11 NK cells 5-15% of PBMC CD16 (FcR ) CD56 CD2 IL-12 stimulates NK cells to produce IFN T H

5 Receptors Activating C type lectin-like like (KLR) NK Cells Recognize viral and stress induced proteins Inhibitory Killer cell Immunoglobulin-like like receptors (KIR) FcγΙΙΙ receptor (CD16) ADCC FasL TLR 3 & 9 Species differences in MHC I specific receptors on NK cells KIR cattle, pigs, dogs, cats KLR mice, rats, horses Inhibitory vs activating differences 13 Function Cytotoxicity NK Cells Direct Indirect ADCC Perforin & granzyme, granulysin, fragmentin FasL (CD95) Cancer cells and virally infected cells 2 subsets in humans NK1 IFN ΝΚ2 IL13 14 NK Cells Regulation Activated by Type I interferons (α & β) ) during viral infections IL-12 from activated macrophages & DCs activate NK cells and enhances killing Activated NK cells produce IFN facilitating a T H 1 IL-2 & IL-15 activate NK cell proliferation IL-21 down regulates NK cells NK T cells Properties of CTL & NK cells Early T H 2 late T H 1 NK dendritic cells 15 5

6 Dendritic Cells Component of innate immunity Not a unique population but rather a large collection of subpopulations located in lymphoid and non-lymphoid tissues 2 Main DC subsets Conventional ( myeloid ) DC Plasmacytoid DC Anti-viral immunity TLR 7 & 9 Single stranded RNA (TLR7) and DNA viruses (TLR9) Type I IFN (α and β) 16 Dendritic cells DC-1 T H 1 > T H 2 DC-2 T H 1 < T H 2 Langerhans cell Dermal DC Interdigitating DC Plasmacytoid DC

7 Dendritic cells Important antigen presenting cells high expression of MHC II molecules efficient in processing and presentation of antigen Examples: Langerhans cells in the epidermis dermal dendritic cells interdigitating dendritic cells in the paracortex of the lymph node and in the thymus Follicular dendritic cells in lymphoid follicles not bone marrow derived do not process antigen Paul Langerhan 19 Antigen sampling by DC s Macropinocytosis sampling the extracellular fluid Receptor-mediated endocytosis, clathrin coated pits Fc receptors C receptors (CR3 and CR4) C-type lectin receptors (CLR s) Scavenger receptors Phagocytosis 20 Antigen sampling by DC s DC cell ability to capture antigen is attributed to: High endocytic capacity Anatomic location Skin Mucosal surfaces Spleen Unique strategy for sampling through epithelial barriers CX 3 CR1, receptor for fractalline a chemokine on the surface of intestinal epithelium 21 7

8 DC activation Sense danger signals PAMPs PRRs TLR s and CLR s Mature into different functional profiles dependent on the nature of the stimulus Intrinsic bias of DC subpopulations even though very plastic Main LN homing chemokine receptor CCR7 which recognizes CCL19 (interdigitating DC) and CCL21 (stromal cells) expressed in T cell areas 22 Maturation process DC activation expression of MHC-peptide complexes expression of CD40, CD80 & CD86 Cytokine synthesis Mature DC activate naïve T cells by delivering 3 signals: TCR MHC/peptide CD28 CD80/CD86 T cell differentiation IL12, IL18, IFNα TH1 Jagged family of NOTCH ligands TH2 23 DC & NK cell cross-talk NK cell role in process of DC maturation NK cells kill DC that do not acquire a mature phenotype Death receptor-mediated vs granule exocytosis NK cells stimulate maturation of DC s TNFα IFNγ 24 8

9 Follicular dendritic cells Stromal cells (not bone marrow-derived) Do not express MHC II Do not process antigen Display antigen in the form of immune complexes 25 Dendritic cell heterogeneity (mouse) CD4 -, CD8 + CD4 +, CD8 - CD4 -, CD8 - LC-type CD4 -, CD8 Spleen 23% 56% 20% Mes. LN 19% 4% 63% Skin- draining LN 17% 4% 37% 33%

10 Toll-like like receptors (TLR) Expressed on numerous cell types sentinel cells Macrophages, mast cells, DC s, mucosal epithelium, hematopoietic stem cells Constitutive and inducible forms Link innate and adaptive immunity TLR can partially substitute for T cell activation of B cells Patients with immunodeficiency disease can produce limited quantities of antibody MyD88 KO mice have impaired IgM, IgG1 & IgG2c, but not other isotypes Toll-like like receptors (TLR) TLR4 KO mice have impaired IgM responses Species differences in ligand specificity Genetic polymorphisms within a species 15 genes identified Innate autoimmunity HSP, fibrinogen, DNA RA and SLE 30 10

11 Toll-like receptors TIR = toll/il-1 receptor MyD88 an IL-1 receptor associated kinase -IRAK -universal activator of NK-κB Tumor necrosis receptor-associated factor 6 (TRAF6) MyD88 TRAF6 MAPK Pro-inflammatory mediators COX-2 PGE 2 NOS2 NO Caspase-1 protnfα TNFα proil-1β IL-1β pro-il-6 IL-6 31 Innate (non-specific) immune system Controls infections during the time (5-7 days) that is needed to engage the adaptive immune system Activates and directs the adaptive immune system, primarily through signals delivered by dendritic cells. 32 pathogens viruses bacteria parasites physical and chemical barrier infection tissue damage innate immune system dendritic cells neoplasms adaptive immune system 33 11

12 Adaptive immune system Cells T and B lymphocytes Recognition molecules TCR, BCR, MHC molecules Effector functions Immunoglobulin producing plasma cells Cytotoxic T cells Memory Interactions T H cells Recognition molecules of the adaptive immune system 36 12

13 B and T lymphocytes B lymphocyte T lymphocyte specificity immunoglobulin T cell receptor maturation function fetal liver thymus bone marrow ileal Peyer s patch bursa of Fabricius immunoglobulin secretion (plasma cells) regulation cytotoxicity 37 Hematopoiesis hemopoietic stem cell interleukin-3, GM-CSF IL-7 erythrocytes B T lymphocytes platelets macrophages granulocytes

14 40 Hematopoiesis Leukocytes programmed cell death 41 live cell neglect - lack of receptor stimulation or growth factors activation of TNF-receptor or Fas by ligand bcl-2 mitochondrial damage caspases breakdown of proteins apoptosis 42 14

15 T lymphocytes TCRαβ TCR δ CD4 + CD8 + T helper (T H ) cytotoxic T cell (CTL) 43 T lymphocytes TCRαβ TCR δ CD4 + MHC II CD8 + MHC I T helper (T H ) cytotoxic T cell (CTL) 44 Cytotoxic function of CD8 + T cells 45 15

16 Helper function of CD4 + T cells

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18 52 Exotoxins Vβ regions of TCR & MHC II 5-20% of T cells Cytokines TNF, IL-1 Toxic-shock syndrome Superantigens 53 Primary Lymphoid organs lymphocyte development development is independent of antigen involute in adult animals examples thymus bone marrow bursa of Fabricius ileal Peyer s patch Secondary initiation of the immune response development is dependent on antigen persist in adult animals examples lymph nodes spleen tonsils 54 18

19 Development of Immune System in the calf 55 Thymus medulla cortex Fig Lymph node 57 19

20 Lymphoid follicles 58 Germinal center Proliferation of B cells Somatic mutation and selection of high affinity B cells Isotype switching Memory cell induction

21 61 62 bursa of Fabricius 63 21

22 Spleen 64 Structure of spleen 65 Dog Storage spleen Thick capsule and many trabeculae Prominent smooth muscle Relatively poorly developed white pulp Dogs, cats, horses Rat Defense spleen Well developed lymphoid tissue Less smooth muscle Rats, mice, humans Intermediate spleen Cattle, swine 66 22

23 Peyer s patches Johannes Peyer Group I Ruminants, dogs & pigs Ileal PP Peyer s patches Primary lymphoid organ Developed at birth and involutes at sexual maturity Only B cells Jejunal PP which persist Group II Rabbits and rodents Randomly distributed between IL and JE Develop after birth and persist 69 23

24 Intraepithelial lymphocytes IEL CD3 CD3 + (90%) TCRαβ (30-50%) TCR δ (30-75%) CD4 + CD8- CD4 + CD8 + (5-8%) (5-8%) CD4 - CD8 + CD4 - CD8 + CD4 - CD8 - (20-40%) (30-60%) (5-10%) 70 24