Understanding the Innate immune system
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A clear, concise summary of the Innate immune system.
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Understanding the Innate immune system
- 1. Innate Immunity University of Nairobi. Presenter: Dr. Isaac Mukuria Supervisor: Dr. Teresa Mwendwa 8-Sep-19 1
- 2. Innate Immunity Presenter: Dr. Isaac Mukuria Supervisor: Dr. Teresa Mwendwa 8-Sep-19 2
- 3. Objectives. • Definition. • Evolution of the immune system. • Components of the innate immune system • Complement system. • Inflammation and Septic shock. • Applied aspects. 8-Sep-19 3
- 4. Case scenarios • A 30yr old resident surgeon with recurrent bouts of fever, headache and photophobia. Involved in an RTA sustaining mild head injury 2/12 ago. Managed twice for bacterial meningitis on the basis of positive CSF analysis in the 2/12 span. Head CT scan done revealed an occult skull fracture. • A young girl with 20 burn wounds 15% TBSA that become septic and have to be debrided repeatedly. 8-Sep-19 4
- 5. Evolution of the immune system. Karim M. Yatim, and Fadi G. Lakkis CJASN 2015;10:1274- 1281 ©2015 by American Society of Nephrology 8-Sep-19 5
- 6. Historical perspective. • Edward Jenner: Father of immunology. -First successful vaccination-1796, small pox. • L. Pasteur: Cholera (in chicken) and rabies vaccines. • E. Behrig & S. Kitasato: antibodies (against Diptheria and Tetanus )in early 1890’s. • J. Bordet: 1899, Complement system. • E. Metchnikoff: Phagocytosis, called the cells Macrophages. • P. Ehrlich: Antiserum. 8-Sep-19 6
- 7. 8-Sep-19 7
- 8. ‘’The Elixir of Immortal Health’’ 8-Sep-19 8
- 9. Innate immunity • Non-specific defense mechanism. • Responds immediately or within minutes. • Classified into a) 1st line defense: anatomic ,chemical & microbiological barriers. b) 2nd line defense: antimicrobial proteins, phagocytes and other cells. 8-Sep-19 9
- 10. 8-Sep-19 10
- 12. 2nd line defense. • Sensor cells: macrophages, neutrophils and dendritic cells. • Sensor cells express Pattern Recognition Receptors(PRR’s) • PRR’s-discriminate between self and non-self. -Recognize Pathogen Associated Molecular Patterns(PAMP’s). • This activates innate immune cells. 8-Sep-19 12
- 13. Pattern Recognition Receptors[PRR’s] Classified on basis of their cellular localization and their function; a) Free receptors in serum e.g.. ficolins, histatins b) Membrane-bound phagocytic receptors. c) Membrane-bound signaling receptors. d) Cytoplasmic signaling receptors e.g. NOD like receptors. 8-Sep-19 13
- 14. 8-Sep-19 14
- 15. Pathogen Associated Molecular Patterns. • PAMP’s -are proteins that are part of many microorganisms but not of the host own body cells. They include; i. mannose-rich oligosaccharides, peptoglycans and lipopolysaccharides of bacterial cell wall. ii. unmethylated CpG DNA common to many pathogens 8-Sep-19 15
- 16. Phagocytic cells • Include macrophages, monocytes, granulocytes and dendritic cells. • Ingest pathogens via either phagocytosis, receptor-mediated endocytosis or macropinocytosis. • Have 3 surface receptor types; C-type lectin family receptors Scavenger receptors. Complement receptors. 8-Sep-19 16
- 17. Phagocytes. • Intra-membranous receptors- G-protein coupled receptors(GPCR’s). Stimulate killing of microbes. Directs responses to anaphylatoxins Example: Fmet-Leu-Phe(FMLF) receptor that signals production of reactive oxygen species. 8-Sep-19 17
- 19. Toll-Like Receptors. • Are single pass trans-membrane proteins. • Have a Leucin rich repeat(LRR) extracellular domain. • There are 10 expressed TLR genes hence limited specificity. • Activated by PAMP’s of pathogens extracellularly or in endocytic vesicles. 8-Sep-19 19
- 21. NOD-Like Receptors. • Intracellular sensors of bacterial infection and cell damage. • Recognize bacterial peptoglycans fragments. • Two types i. NOD 1- Senses ꝩ-glutamyl diaminopeptide ii. NOD 2- Senses muramyl dipeptide(MDP),found especially in the gut. 8-Sep-19 21
- 22. Other key receptors. • RIG-I-like receptors detect cytoplasmic viral RNA and activate MAVS. • NLRP react to infection/cell damage through an inflammasome to induce cell death and inflammation. • Cytosolic DNA sensors signal through STING to induce production of interferon I. 8-Sep-19 22
- 23. Innate Lymphoid cells. • Develop from the common lymphocyte progenitor like B & T cells. • Include Natural Killer(NK) cells. • Lack T & B-cell antigen receptor and co- receptor complex. • However, they express receptor for IL-7. 8-Sep-19 23
- 24. 8-Sep-19 24
- 26. Complement system. • Composed of > 30 plasma proteins synthesized especially in the liver. • Three pathways so far; Classical pathway- antibody triggered pathway. Alternative pathway- activated by presence of pathogen alone. Lectin pathway- activated by lectin-type proteins. 8-Sep-19 26
- 29. Inflammation. • Induced by cytokines, chemokines, prostaglandin, leukotrienes and platelet activator factor. • Roles ; Delivery of additional effector molecules & cells Induce local blood clotting. Promote repair of injured tissues. 8-Sep-19 29
- 30. Inflammation. • Vascular changes; 1) Increased diameter, blood flow hence heat& redness. 2) Endothelial cells express cell adhesion molecules. 3) Increased vascular permeability hence swelling & pain 4) Clotting in micro-vessels. 8-Sep-19 30
- 32. Septic Shock. • Due to uncontrolled systemic bacterial infection. • Lipopolysaccharides induce an overwhelming secretion of cytokines particularly TNFɑ. • TNFɑ cause increased vascular permeability, vasodilation leading to hypotension. • TNFɑ also induces blood clotting in microvasculature resulting in DIC and multiorgan failure. 8-Sep-19 32
- 34. Surgical significance. • Mechanical barriers. Susceptibility of burn patients to infections. Recurrent meningitis in patients with occult skull fractures • Disturbance of drainage and necrotic or poorly vascularized tissue- inaccessible by immune cells Recurrent UTI in patients with enlarged prostate, posterior urethral valves. Chronic leg ulcers/diabetic foot- require serial debridement. 8-Sep-19 34
- 35. • Secretions Recurrent enteric infections post vagotomy. • Normal micro-biota. Irrational use of antibiotic and antiseptic solutions resulting in staphylococcal enteritis. 8-Sep-19 35
- 36. References. • Janeway’s immunobiology by Kenneth Murphy, Casey Weaver 9th edition. • Ganong’s Review of medical physiology 25th edition. • Roitt’s Essentials of Immunology 12th edition. • Karim M. Yatim, Fadi G. Lakkis Abrief journey through the immune system https://cjasn.asnjournals.org/content/10/7/12 74 8-Sep-19 36
Editor's Notes
- Evolution of the immune system. Adaptive immunity as we know it in humans did not evolve until the emergence of the first jawed vertebrates (fish) around 450 million years (my) ago. Evolution of adaptive immunity was heralded by the appearance of lymphocytes, the major histocompatibility complex (MHC), immunoglobulin (Ig) molecules, T-cell receptor for antigen (TCR), and recombinase activating genes (RAG) responsible for the diversity in these recognition molecules. Our more ancient ancestors, such as the sponges (−700 my), relied on basic defense systems without the benefit of lymphocytes, antigen receptors with fine molecular specificity, or any noteworthy immunologic memory. An approximate timeline for evolution of innate immune components (antimicrobial peptides, phagocytosis, complement, and Toll-like receptors) is also shown.
- Variolation- inhalation/transfer into superficial skin wounds of material from small pox pustules as protection against the disease in 1400’s. WHO announced eradication of small pox in 1979. Metchnikoff & Ehrlich shared the Nobel prize in 1908.
- ‘microbiome/commensal microorganisms; archaea, bacteria & fungi……..not harmful Pathogens- cause damage. Unlike adaptive immunity where cells have a vast repertoire of specificity. Anatomic & chemical barriers- avoidance, resistance(via effector mechanisms) and tolerance Complement system acts if barriers are breached.
- Common myeloid progenitor(CMP)- MQ, Granulocytes(neutr,eosino,basophils), Mast, Dendritic cells ‘’granulocytes’ ---densely staining granules in cytoplasm. Common Lymphoid progenitor(CLP)- NK cells & Innate Lymphoid/lymphocytes cells
- Antimicrobial enzymes- Lysozymes: break down peptoglycans component of bacterial cell wall. - Secretory Phospholipase A2 :hydrolyzes phospholipids in bacterial cell membrane. Antimicrobial peptides- Defensins(lyse bacterial, fungi &viral cell membrane). - Cathelicidins - Histatins – prod by parotid, sublingual n submandibular glands; histidine-rich; act against fungi-C. neoformans, C.albicans. - Lectins, Reg III(produced by paneth cells for pore formation) Lamellar bodies- lipid rich organelles that contain b-defensins(produced by epidermal keratinocytes in skin & type2 pneumocytes in lungs)-forms a water tight lipid sheet on epidermis & lung surfactant. Inherited disease cystic fibrosis: mucus becomes abnormally thick and dehydrated & unable to flow due to defects in a gene, CFTR, encoding a chloride channel in the epithelium. Such individuals frequently develop lung infections caused by bacteria that colonize the epithelial surface but do not cross it
- Toll-like receptors(TLR’s) -detect PAMP’s derived from extracellular or vesicular bacteria NOD-like receptors(NLR’s) -sense intracellular bacterial invasion
- MAMPs- microbial Associated molecular patterns….current terminology to cover both pathogenic & non-pathogenic microbes.
- Monocytes- 90% are ‘classical monocytes’ that express CD14, a co-receptor for PRR. They function during infxn by entering tissues and differentiating into activated inflammatory monocytes or macrophages. -10% are ‘patrolling monocytes’ roll along endothelium rather than circulate freely in blood. They express CD14 & CD16. Dendritic cells-reside in lymphoid organs and in peripheral tissues. -main role- antigen presentation, other role-phagocytic. -2 functional types : -conventional/classical dendritic cells[cDCs], main fxn-antigen presentation, other roles- phagocytic, secrete cytokines -plasmacytoid dendritic cells[pDCs]-secrete cytokines, mainly interferon type 1/antiviral interferon
- G-protein-coupled receptors for C5a (which can be produced by activation of the complement system’s innate pathogen-recognition ability) and for the bacterial peptide fMLF synergize with phagocytic receptors in activating the NADPH oxidase in phagosomes to generate antimicrobial reactive oxygen intermediates. NADPH Oxidase reaction results in respiratory burst(transient increase in oxygen consumption by the cell), creating superoxide anion within the lumen of phagolysosome which is converted to H2O2 superoxide dismutase(SOD). SOD enzyme is defective due genetic mutation in a familial form of Amyotropic Lateral Sclerosis{dx of neurones for voluntary ms control} H2O2 kills the microbe and can be broken down to hydroxyl radical (OH), Hypochlorite (OCl) and hypobromite (OBr) which are fatal to pathogens. Pus formation- follows death of neutrophils due to their short life span. Chronic granulomatous disease- due to deficiency of NADPH oxidase in phagocytes hence inability to kill ingested pathogens.
- Recurrent Herpes simplex Encephalitis- due to mutation of ectodomain of TLR-3. TLR-4 recognizes Lipopolysaccharide[LPS] of gram negative bacteria using an accessory protein MD-2 LPS causes septic shock. TLR activate NFkB, AP-I & IRF transcription factors to induce expression of inflammatory cytokines TNF-α, IL-1β, and IL-6, and antiviral cytokines including type I interferons.
- NOD- Nucleotide binding Oligomerization Domain. Loss of function mutation of NOD 2 is seen in Crohn’s Disease. Gain of function mutation of NOD 2 is seen in early onset Sarcoidosis, Blau syndrome…characterised by spontaneous inflammation in tissues e.g. liver, eyes, joints and skin.
- RIG (Retinoic acid Inducible gene I) MAVS(Mitochondrial antiviral signaling protein) activates Type I interferon production and pro-inflammatory cytokines. NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. They cause pyroptosis/fiery death of microbes via Capase I activation. Gout – urate crystals activate NLRP -3 inflammasome that induces inflammatory cytokines associated with symptoms of gout. Mutations in NLRP3 in humans are associated with hereditary periodic fever syndromes, such as familial cold inflammatory syndrome and Muckle–Wells syndrome. STING- Stimulator of interferon genes.
- -Enhaces the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promotes inflammation, and attacks the pathogen's cell membrane. -classical pathway so called as it’s the first to be discovered. -lectin-type proteins recognize and bind to carbohydrates on pathogen surfaces. -Activation by proteins is inherent i.e a complement protein detects a pathogen, activates a complement zymogens sequentially amplifying the signal resulting in activation of 3 effector pathways: inflammation, phagocytosis and membrane attack.
- Nomenclature -1st proteins to be discovered belong to classical pathway hence letter C. named in order of discovery i.e C1, C2, C3, C4….. Cleavage produces a small ’a’ and a large fragment ‘b’ in a proteins except C2 where C2a is the larger fragment and C1 which has three distinct subcomponents[one molecule of C1q and two molecules each of C1r and C1s respectively]. Alternative pathway C3 convertase –unique as its C3bBb unlike the C4bC2a (C3 convertase) of the classical and lectin pathways. Alternative pathway is activated in 2 ways; By C3b from either classical or lectin pathways. Hydrolysis of thioester bond in C3 to form C3(H2O)
- Several structural families of adhesion molecules have a role in leukocyte migration, homing, and cell–cell interactions: the selectins(p & E), the integrins(LFA-1), and proteins of the immunoglobulin superfamily(ICAM-1). Multi-step process: Rolling adhesion, Tight binding, Diapedesis & Migration. Cell adhesion molecules promote binding of circulating leucocytes thence extravasation to tissues via diapedesis.
- Systemic infection with Gram-negative bacteria (sepsis). Macrophages activated in the liver and spleen secrete TNF-alpha into the bloodstream. Systemic edema causing decreased blood volume, hypoproteinemia, and neutropenia, followed by neutrophilia. Decreased blood volume causes collapse of vessels. Disseminated intravascular coagulation leading to wasting and multiple organ failure. Death.
- Acute phase responses contribute to host defense mechanism: Elevation of body temperature by Endogenous pyrogens (TNFα, IL-1β and IL-6) Increase in acute phase proteins e.g. C-reactive protein, manose binding lectin and Surfactant proteins. These proteins increase in concentration in response to early álarm’ inflammatory mediators such as IL-1 following infection or tissue damage.