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Diseases of Immunity 2011 CL Davis General Pathology Paul W. Snyder, DVM, PhD Purdue University Acknowledgements • • • • • Pathologic Basis of Veterinary Disease, 5th Ed Veterinary Immunology, An Introduction 8th Ed Immunology, Kuby, 6th Ed The Immune System, Parham, 3rd Ed Immunobiology, Janeway, 7th Ed Snyder 2010 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. Snyder 2010 4 Snyder 2010 5 Snyder 2010 6 The body’s defense system pathogen Physical and chemical barriers - epidermis, mucosal epithelium - pH of the stomach - mucociliary apparatus - lysozyme Innate immunity Adaptive immunity Snyder 2010 7 Snyder 2010 8 Innate Immunity – Cells • Phagocytic cells – Macrophages and neutrophils • Dendritic cells – sense “danger” – Not a unique population but rather a large collection of subpopulations • Mature into different functional profiles dependent on the nature of the stimulus – Activate naïve T lymphocytes - APCs • Signal 1 = TCR - MHC/antigen peptide • Signal 2 = CD28 - B7 • Cytokines – IL-12 → TH1 response, NK cell activation – IL-4, IL-5, IL-13 → TH2 response Neutrophils Snyder 2010 10 Neutrophil migration IL-8 (CXCL8) C5a LTB4 Snyder 2010 11 NK cells • 5- 15% of PBMC • CD16 (Fc III R) • CD56 • CD2 • IL-12 stimulates NK cells to produce IFN → TH1 Snyder 2010 12 NK Cells • Receptors • Activating • C type lectin-like (KLR) • • Inhibitory • • • • Killer cell Immunoglobulin-like receptors (KIR) FcgIII receptor (CD16) • • Recognize viral and stress induced proteins ADCC FasL TLR 3 & 9 Species differences in MHC I specific receptors on NK cells • • • KIR – cattle, pigs, dogs, cats KLR – mice, rats, horses 2010 Inhibitory vs activating Snyder differences 13 NK Cells • Function • Cytotoxicity • • • • • • Direct Indirect – ADCC Perforin & granzyme, granulysin, fragmentin FasL (CD95) Cancer cells and virally infected cells 2 subsets in humans • • NK1 → IFN g → macrophage activation NK2 → IL13 → inhibits macrophage activation Snyder 2010 14 NK Cells • Regulation • • • • • • Activated by Type I interferons ( & β) during viral infections IL-12 from activated macrophages & DCs activate NK cells and enhances killing Activated NK cells produce IFN g facilitating a TH1 IL-2 & IL-15 activate NK cell proliferation IL-21 down regulates NK cells NK T cells • Properties of CTL & NK cells • • Early TH 2 → late TH1 NK dendritic cells Snyder 2010 15 Dendritic Cells • Component of innate immunity • Not a unique population but rather a large collection of subpopulations located in lymphoid and nonlymphoid 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 ( and ) Snyder 2010 16 Dendritic cells Langerhans’ cell Interstitial DC Interdigitating DC Plasmacytoid DC Circulating DC Snyder 2010 17 Snyder 2010 18 Dendritic cells • Important antigen presenting cells – high expression of MHC II molecules Paul Langerhan – efficient in processing and presentation of antigen • Examples: – Langerhans cells in the epidermis – Interstitial (eg. 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 Snyder 2010 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 Snyder 2010 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 – CX3CR1, receptor for fractalline a chemokine on the surface of intestinal epithelium Snyder 2010 21 DC activation • Sense danger signals – PAMPsPRRs 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 Snyder 2010 22 DC activation • Maturation process – 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 » IL-12 → TH1 response, NK cell activation » IL-4, IL-5, IL-13 → TH2 response Snyder 2010 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 not granule exocytosis – NK cells stimulate maturation of DC’s • TNF • IFN – Specific action seems to be influenced by NK:DC ratios • High ratio = kill • Low ratio = stimulate maturation Snyder 2010 24 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 Attract B cells to lymphoid follicles via CXCL13 Produce cytokines that influence B cell maintenance Snyder 2010 25 Dendritic cell heterogeneity (mouse) CD4-, CD8+ CD4+, CD8- CD4-, CD8- Spleen 23% 56% 20% Mes. LN 19% 4% 63% Skindraining LN 17% 4% 37% Snyder 2010 LC-type CD4-, CD8lo 33% 26 Innate Lymphoid Cells (ILCs) • ILCs (non-T or B cells) develop in an Id2-dependent pathway, additional transcription factors drive additional subsets – NK cells → cytotoxic and non-cytotoxic subsets – Helper cells (IL-25 IL-33 induces) • ILC2 cells → IL-5 & IL-13 → anti-parasite responses – RORt cells (require IL-7) • Lymphoid tissue-inducer cells (LTi) → LN formation • ILC17 cells → IL-17A → neutrophils → extracellular bacteria • ILC22 cells → IL-22 → extracellular bacteria • Functions: – Responses to infectious organisms – Lymphoid tissue formation – Tissue remodeling following damage Innate Immunity – Polarized Responses • Similar to CD4+ TH subsets – ILC2 promote TH2 responses and inflammation at mucosal surfaces in conjunction with epithelial cells • ILCs can be polarized toward restricted cytokine profiles - plasticity • Exogenous signals drive the plasticity • Disease associations: – Allergic diseases – Inflammatory diseases like IBD – Autoimmune diseases Snyder 2010 29 Recognizing first responders RNA sensing Noninflammasome NLRs Regulation of adaptive immunity by innate immunity NLRP3 inflammasome a sensor for metabolic danger Snyder 2010 30 Innate Immunity -Components • Recognition molecules – Pattern Recognition Receptors (PRRs) • An ability to sense “danger” by cells other than T and B lymphocytes – Pathogen Associated Molecular Patterns (phagocytic) – Damage Associated Molecular Patterns (sensor) • PRRs – Toll-like receptor (TLR) family – Nucleotide oligomerization domain-like receptor (NLR) family – Retinoic acid-inducible gene I-like receptor (RLR) family Innate Immunity - Components • PRRs initiate signaling – Initiate cascades for cytokine synthesis through transcriptional regulation and posttranslational modifications – Type 1 IFNs (IFN-α and IFN-β) – IL-1 family cytokines (IL-1β and IL-18) • Inflammasomes – intracellular sensors – Cytosolic multi-protein complexes → activate caspase-1 → cleave pro-inflammatory cytokines into active forms Pattern Recognition Receptors • PRR’s are classified as secreted, transmembrane and cytosolic forms • Collectins and pentraxins are examples of secreted PRR – Bind microbial surfaces and activate complement • TLR’s and C-type lectins are examples of transmembrane PRR’s Snyder 2010 33 Pattern Recognition Receptors • Cytosolic PRR’s – Widely distributed, all nucleated cells – Examples are: • Retinoic-acid-inducible gene-1-like receptors (RLRs) • Nucleotide oligomerization domain-like receptor receptors (NLR’s) • PRR’s sense “danger” or “stranger” • Initiate adaptive immune responses and regulate cell death (apoptosis) Snyder 2010 34 Pattern Recognition Receptors • Cell-intrinsic recognition mechanisms – Involve Type I inferferons – Three members: • Retinoic acid inducible gene-1 (RIG-1) • Melanoma differentiation associated gene 5 (MDA-5) • Laboratory of genetics and physiology gene 2 (LPG-2) – Specifically detect RNA molecular patterns not normally present in the cytoplasm • Cell-extrinsic recognition mechanisms – Allows uninfected cells to participate in immune responses Snyder 2010 35 Pattern Recognition Receptors – Members of the NLR are central regulators of immunity and inflammation • Activate transcription factors like – Nuclear factor κB (NF- κB) – Interferon regulatory factor (IRF) – Nuclear factor of activated T cells (NFAT) • Some NLR members form multi-protein complexes referred to as inflammasomes that activate caspase-1 • Caspase-1 cleaves pro-inflammatory cytokines like IL10 and IL-8 • Other NLR members are involved in inflammasomeindependent innate immune responses Snyder 2010 36 NLR proteins signal through different multicomponent signalsomes Snyder 2010 37 Toll-like receptors (TLR) • Expressed on numerous cell types “sentinel cells” • • • • Constitutive and inducible forms Link innate and adaptive immunity TLR can partially substitute for T cell activation of B cells • • Macrophages, mast cells, DC’s, mucosal epithelium, hematopoietic stem cells… Patients with immunodeficiency disease can produce limited quantities of antibody MyD88 KO mice have impaired IgM, IgG1 & IgG2c, but not other isotypes Snyder 2010 38 Snyder 2010 39 Toll-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 Snyder 2010 40 Toll-like Receptors TIR = toll/IL-1 receptor MyD88 an IL-1 receptor associated kinase (IRAK) a universal activator of NK-kB Tumor necrosis receptor-associated factor 6 (TRAF6) Signal 1 - ↑ transcription Signal 2 – inflammasome activation of caspase-1 MyD88 TRAF6 MAPK Pro-inflammatory mediators COX-2 PGE2 NOS2 NO Caspase-1 pro-TNF TNF pro-IL-1 IL-1 pro-IL-6 IL-6 Innate Immunity - Functions • Phagocytosis – Phagocytic cells and opsonins (C3b, PAMPS) • Inflammation – Mediators (C3a, C5a, inflammatory cytokines) • Regulation – Cytokines polarize acquired immune responses • Interactions – Cross-regulation within innate immunity and to acquired immunity PAMPs DAMPs Inflammasomes LUNG Abestosis COPD Asthma Pro-IL-1 → IL-1 METABOLISM Type II Diabetes SKIN Allergy Inflammatory Conditions BRAIN Alzheimer’s Multiple Sclerosis JOINTS Rheumatoid Arthritis Gout HEART Hypertension CANCER Mesothelioma INTESTINE Inflammatory Bowel Disease 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. Snyder 2010 44 pathogens viruses bacteria parasites physical and chemical barrier infection tissue damage innate immune system dendritic cells neoplasms adaptive immune system Snyder 2010 45 Acquired Immune System • Lymphoid cells – T and B lymphocytes • Antigen recognition molecules – TCR, sIg (BCR), MHC molecules • Effector functions – B cells → Ig producing plasma cells – CD8+ Cytotoxic T cells – CD4+ T cells • Helper T cells (TH) • Regulatory T cells (Treg) • TH 17 • Interactions – Polarized responses • based on cytokine profiles Snyder 2010 47 Recognition molecules of the adaptive immune system Snyder 2010 48 B and T lymphocytes B lymphocyte T lymphocyte specificity immunoglobulin T cell receptor maturation fetal liver thymus bone marrow ileal Peyer’s patch bursa of Fabricius function immunoglobulin regulation secretion (plasma cytotoxicity cells) Snyder 2010 49 Hematopoiesis hemopoietic stem cell interleukin-3, GM-CSF IL-7 erythrocytes platelets macrophages granulocytes B T lymphocytes Snyder 2010 50 Snyder 2010 51 Snyder 2010 52 Hematopoiesis Leukocytes programmed cell death Snyder 2010 53 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 Snyder 2010 54 T lymphocytes TCR CD4+ T helper (TH) TCRd CD8+ cytotoxic T cell (CTL) Snyder 2010 55 T lymphocytes TCR CD4+ T helper (TH) TCRd MHC II CD8+ MHC I cytotoxic T cell (CTL) Snyder 2010 56 Cytotoxic function of CD8+ T cells Snyder 2010 57 Helper function of CD4+ T cells Snyder 2010 58 Snyder 2010 59 Snyder 2010 60 Snyder 2010 61 Snyder 2010 62 Snyder 2010 63 Snyder 2010 64 Superantigens • Exotoxins • V regions of TCR & MHC II • 5 - 20% of T cells • Cytokines – TNF, IL-1 • Toxic-shock syndrome Snyder 2010 65 Lymphoid Tissues • Primary lymphoid tissues • • • Generation of B and T lymphocytes Antigen-independent proliferation Include • • • Thymus Fetal liver, bone marrow Secondary (peripheral) lymphoid tissues • • • Initiation of antigen-specific immune response Antigen-dependent proliferation Include: • • • • Spleen (white pulp) Lymph nodes Peyer’s patches & lymphoid nodules NALT, tonsils, BALT Development of Immune System in the calf Snyder 2010 67 Thymus HSC (10-100 cells/day) Death by neglect >80% Negative Selection 5-10% Positive Selection <5% DN DP medulla cortex CD4 Snyder 2010 (< 5%, CD8 68 6 10 /day) Lymph node Snyder 2010 69 Lymphoid follicles Dark zone - B cell proliferation, somatic hypermutation Light zone – memory cells, plasma cell precursors, isotype switching Mantle – mature naïve B cells Snyder 2010 70 Germinal center • Proliferation of B cells • Somatic mutation and selection of high affinity B cells • Isotype switching • Memory cell induction Snyder 2010 71 Snyder 2010 72 Snyder 2010 73 Snyder 2010 74 Bursa of Fabricius Snyder 2010 75 Spleen Snyder 2010 76 Structure of spleen Snyder 2010 77 Dog Rat Snyder 2010 Storage spleen Thick capsule and many trabeculae Prominent smooth muscle Relatively poorly developed white pulp Dogs, cats, horses Defense spleen Well developed lymphoid tissue Less smooth muscle Rats, mice, humans Intermediate spleen Cattle, swine 78 Peyer’s patches Johannes Peyer Snyder 2010 79 Snyder 2010 80 Peyer’s patches • Group I • • Ruminants, dogs & pigs Ileal PP • • • • • 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 Snyder 2010 81 Intraepithelial lymphocytes IEL CD3 CD3+ (90%) TCR (30-50%) CD4+CD8+ CD4+CD8(5-8%) TCRd (30-75%) (5-8%) CD4-CD8+ (20-40%) CD4-CD8+ (30-60%) Snyder 2010 CD4-CD8(5-10%) 82