Immunology n Dr Mohed Shaker Helpful Hints n

Immunology n Dr. Mohed Shaker

Helpful Hints n n n n Readings in text are beneficial I expect you to read the relevant chapters in Nester. Understanding the concepts is not optional Think, rather than memorize Test questions are based on concepts Ask questions Don’t wait until the last minute to study Check the website

Lecture 1 Immunology Introduction & Innate immunity

Why Does a Dentist Need to Understand Immunology? n Many of the oral diseases have an immune component n n n Periodontal disease Caries Sjögren’s Syndrome Current and future therapeutics affect the immune system and oral health Systemic and Oral diseases are interrelated Cooperation with other health care professional requires a common language

What is immunity? n n “Protection” from infection, tumors, etc. Innate immunity is always available Adaptive immunity distinguishes “self” from “non-self” and involves immune system “education” Responses that may result in host tissue damage

Two types of immunity n Innate immunity (not antigen-specific) n n n Anatomical barriers Mechanical Biochemical n n n Non-specific (eg. Low p. H in stomach) Receptor-driven (eg. PAMP-recognition) Adaptive immunity (antigen-specific) n n Receptor-driven Pre-existing clones programmed to make a specific immune response (humoral/cellular)

Antigen n n A substance (antigen) that is capable of reacting with the products of a specific immune response, e. g. , antibody or specific sensitized Tlymphocytes. A “self” component may be considered an antigen even though one does not generally make immune responses against those components.

Characteristics of Adaptive Immunity n Immune response is highly specific for the antigen that triggered it. n n Receptors on surface of immune cells have same specificity as the antibody/effector activity that will be generated Exposure to antigen creates an immunologic “memory. ” n n Due to clonal expansion and creation of a large pool of cells committed to that antigen Subsequent exposure to the same antigen results in a rapid and vigorous response

Components of the immune system

platelets Cells eosinophil involved neutrophil in immunity basophil megakaryocyte T Lymphocyte Pluripotent hematopoietic stem cell B Lymphocyte common myeloid progenitor common lymphoid progenitor mast cell plasma cell Natural Killer cell monocyte macrophage

Blood Where is that stuff? Serum or Plasma Leukocytes, Platelets and RBC Serum Proteins Mononuclear Cells • Immunoglobulins • Complement • Clotting factors • Many others • Lymphocytes (T cells, B cells & NK cells) • Monocytes Polymorphonuclear leukocytes (or Granulocytes) • Neutrophils • Eosinophils • Basophils

Lymphoid Organs n Primary or central lymphoid organs bone marrow and thymus n where lymphocytes are generated n n Secondary or peripheral lymphoid organs n where adaptive immune responses are initiated

Distribution of Lymphoid Tissues

Response to Initial Infection

Stages of Response to Infection

Course of Typical Acute Infection

Innate Host Defense Mechanisms n Anatomic Factors n Mechanical Factors n Biochemical Factors

Skin n n Stratified and cornified epithelium provides a mechanical barrier Indigenous microbiota competes with pathogens Acid p. H inhibits growth of disease producing bacteria Bactericidal long chain fatty acids in sebaceous gland secretions

Respiratory Tract n Upper Respiratory Tract n n n Lower Respiratory Tract n n Nasal hairs induce turbulence Mucous secretions trap particles Mucous stream to the base of tongue where material is swallowed Nasal secretions contain antimicrobial substances Upper respiratory tract contains large resident flora Particles trapped on mucous membranes of bronchi and bronchioles Beating action of cilia causes mucociliary stream to flow up into the pharynx where it is swallowed 90% of particles removed this way. Only smallest particles (<10µ in diameter) reach alveoli Alveoli n Alveolar macrophage rapidly phagocytize small particles

Alimentary Tract n General defense mechanisms n n n Stomach n n Generally sterile due to low p. H Small Intestine n n n Mucous secretions Integrity of of mucosal epithelium Peristaltic motions of the gut propel contents downward Secretory antibody and phagocytic cells Upper portion contains few bacteria As distal end of ilieum is reached flora increases Colon n n Enormous numbers of microorganisms 50 -60% of fecal dry weight is bacteria

Genitourinary Tract n Male n n n n No bacteria above urethrovesicular junction Frequent flushing action of urine Bactericidal substances from prostatic fluid p. H of urine Bladder mucosal cells may be phagocytic Urinary s. Ig. A Female (Vagina) n n Large microbial population (lactobacilli) Microorganisms produce low p. H due to breakdown of glycogen produced by mucosal cells

Eye Flushing action of tears which drain through the lacrimal duct and deposit bacteria in nasopharynx n Tears contain a high concentration of lysozyme (effective against gram positive microorganisms n

Receptors n Almost all of biology occurs because recognition Enzymatic action n Interactions between cells (cooperation/activation) n Communication between cells n n Innate and adaptive immunity requires it

Innate Immune Recognition n n All multi-cellular organisms are able to recognize and eliminate pathogens Despite their extreme heterogeneity, pathogens share highly conserved molecules, called “pathogen-associated molecular patterns” (PAMPs) Host cells do not share PAMPs with pathogens PAMPs are recognized by innate immune recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs)

Typical PAMPs n n Lipopolysaccharides Peptidoglycans Certain nucleotide sequences unique to bacteria Other bacterial components

Endogenous Signals Induced by PAMPs Mediate inflammatory cytokines n Antigen-presenting cells recognize PAMPs n Same APC processes pathogens into specific pathogen-derived antigens and presents them with MHC encoded receptors to T-cells n T-cell responds only when presented with both signals n n Different Effector Cytokines in Response to Different Pathogens (Th 1 vs. Th 2)

Antimicrobial Peptides/Defensins n n Four hundred peptides described to date Defensins (3 - 5 -k. D, four families in eukaryotes) n n n a-defensins (neutrophils and intestinal Paneth cells) b-defensins (epithelial cells) Insect defensins Plant defensins Defensins appear to act by binding to outer membrane of bacteria, resulting in increased membrane permeability. May also play a role in inflammation and wound repair

Complement System n Three pathways now known Classical n Alternative n Lectin or MBL pathway (binding to mannosecontaining carbohydrates) n n Host cells have complement regulatory proteins on their surface that protect them from spontaneous activation of C 3 molecules

Inflammatory Mediators in Innate Immunity n Cytokines secreted by phagocytes in response to infection include: n IL-1 n n n IL-6 n n n Induces expression of b 2 integrin adhesion molecules on neutrophils, leading to neutrophil migration to infection site IL-12 n n Induces B-cell terminal maturation into Ig-producing plasma cells IL-8 n n activates vascular endothelium and lymphocytes Increases adhesiveness of leukocytes Activates NK cells and induces Th 1 -cell differentiation IL-18 TNF-a n Activates vascular endothelium and increases vascular permeability, leading to accumulation of Ig and complement in infected tissues

Other Mediators and Molecules n Phagocytes n n Toxic oxygen radicals Peroxides Nitric oxide (NO) Lipid mediators of inflammation n n Complement component C 5 a n n Stimulates mast cells to release histamine, serotonin and LTB 4 IL-1, IL-6 and TNF-a n n n Prostaglandins LTB 4 Platelet activating factor Induce acute-phase response in liver Induce fever IL-1 and IL-18 signaling pathways activate NF-k. B, important in innate immunity

Immune Cells and Innate Immunity n Phagocytes n n Neutrophils Moncyte/macrophage Eosinophils (to a lesser extent) NK cells (large granular lymphocytes) n n Antibody-dependent cell-mediated cytotoxicity (ADCC) Have two major functions n n n Act against intracellular pathogens n Herpesviruses Leishmania n Listeria monocytogenes Act against protozoa n Toxoplasma n Trypanasoma n n Lysis of target cells Production of cytokines (IFN-g and TNF-a)

Immune Cells and Innate Immunity (cont’d) n g/d T cells n Two types of T cell receptors n n n One composed of a and b chains (basic T cell antigen receptor) One composed of g and d chains (minor population of T cells) Two groups of g/d T cells n n One group found in lymphoid tissues One group located in paracellular space between epithelial cells n n n Recognizes unprocessed target antigen in absence of APC help B-1 cells (minor fraction of B cells, do not require T-cell help) Mast cells n n n Located in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glands Capable of phagocytosis Process and present antigen using MHC class I or II receptors LPS can directly induce release of mast cell mediators Complement (C 3 a and C 5 a) induce mast cells to release mediators n n Chemotaxis, complement activation, inflammation TNF-a secreted by mast cells results in neutrophil influx into infected site

Summary of Innate Immunity n n External and mechanical barriers Receptors for pathogen motifs Soluble antimicrobial proteins Pattern of cytokines produced influences adaptive response