* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Slide 1
Survey
Document related concepts
Monoclonal antibody wikipedia , lookup
Complement system wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Adaptive immune system wikipedia , lookup
Transcript
Immunology Part I: Innate Host Resistance Lecture #17 Bio3124 Immunity and immunology immunity ability of host to resist a particular disease or infection immune system composed of widely distributed immune cells, tissues, and organs recognizes foreign substances or microbes and acts to neutralize or destroy them Antigens: considered foreign to the host Microorganisms: Bacteria, viruses, fungi, etc. Cells and Tissues: Cancer, blood products, organ transplants Operates through immune cells Cells of the Immune System Leukocytes (WBC) Function in innate and adaptive branches of immunity Hematopoietic stem cells Myeloid Mast PMN Monoblast Lymphoid B and T cells NK cells Relative numbers of WBC Total and differential WBC counts changes in disease conditions Monocytes and macrophages phagocytic cells make up monocyte-macrophage system monocytes mononuclear phagocytic leukocytes ~8 hours, mature into macrophages macrophages reside in specific tissues variety of surface receptors named according to tissue they reside in Plymorphonuclear leukocytes (PMNs) Basophils: 2-3 lobbed nucleus, stain bluish-black with basic dyes nonphagocytic release histamine, prostaglandins, serotonin, and leukotrienes play important role in development of allergies and hypersensitivities Eosinophils: 2-lobbed nucleus, stain red with acidic dyes defend against protozoan and helminth parasites release cationic proteins and reactive oxygen metabolites may play a role in allergic reactions Neutrophils 3-5 lobbed nucleus, stain at neutral pH highly phagocytic circulate in blood then migrate to sites of tissue damage kill ingested microbes with lytic enzymes and reactive oxygen metabolites contained in primary and secondary granules Dendritic and Mast Cells Dendritic cells: present in small numbers in blood, skin, and mucous membranes of nose, lungs, and intestines contact, phagocytose and process antigens display foreign antigens on their surfaces (antigen presentation) Mast cells: differentiate in blood and connective tissue contain granules containing histamine and other pharmacologically active chemicals play important role in development of allergies and hypersensitivities DC Lymphocytes B cells (B lymphocytes) mature in bone marrow circulate in blood settle in lymphoid organs mature ->plasma cells -> produce antibodies T cells (T lymphocytes) mature in thymus can remain in thymus, circulate in blood, or reside in lymphoid tissue like B cells, require antigen binding to surface receptors for activation and continuation of replication cytokines, chemicals that have effects on other cells, are produced and secreted by activated T cells Cell mediated immunity (CMI) Natural Killer (NK) Cells small population of large non-phagocytic granular lymphocytes kill malignant cells and cells infected with pathogens (viruses) two ways of recognizing target cells bind to antibodies coating infected cells (antibody-dependent cell- Pore forming agents mediated cytotoxicity (ADCC) recognizes cells that have lost their class I major histocompatibility (MHC-1) antigen due to presence of virus or cancer Primary and secondary Lymphoid Organs Primary: immune cell production and maturation; move to secondary sites thymus site of T cell maturation bone marrow site of B cell maturation in mammals Secondary: places lymphocytes may encounter and bind antigens; Proliferate, differentiation to effector cells; eg. Spleen filter blood, phagocytes and dendritic cells capture microbes, present antigens to T and B cells Lymph nodes: filter lymph, microbes sampled by phagocytes, B cells differentiate to plasma cells and memory cells Secondary Lymphoid Tissue lymphoid tissues throughout the body interface btw innate and adaptive host immunity areas of antigen sampling and processing associated with specific tissues skin-associated lymphoid tissue (SALT) mucous-associated lymphoid tissue (MALT) gut-associated lymphoid tissue (GALT) Types of immune responses nonspecific immune response (innate) also called nonspecific resistance, innate immunity, and natural immunity acts as a first line of defense offers resistance to any microbe or foreign material lacks immunological memory specific immune response (adaptive) also called acquired immunity, adaptive immunity and specific immunity resistance to a particular foreign agent has “memory” effectiveness increases on repeated exposure to agent the two types of responses usually work together Innate Immune Response Innate immune response is the first line of host defense 4 innate barriers Anatomical (physical) barriers Skin mucous membranes Physiologic barriers pH Temperature Chemical barriers – Chemical mediators: gastric juice, lysosyme, antimicrobial peptides – complement Phagocytic barrier Macrophage/neutrophil mediated phagocytosis Inflammatory barrier Skin strong mechanical barrier to microbial invasion keratin produced by keratinocytes in outer layer inhospitable environment for microbes organisms removed by shedding of outer skin cells pH is slightly acidic (pH5-6) high NaCl concentration subject to periodic drying Skin commensal microbial flora out competes pathogens Skin: epidermis microbes enter epidermis Encounter specialized skin- associated lymphoid tissue (SALT) Langerhans cell phagocytic cells that can internalize antigens differentiates to dendritic cell– move to lymph nodespresents antigen to and activates T cells intraepidermal lymphocyte function as T cells Have limited antigen receptors-specialized for common skin pathogens Mucous membranes protective covering in intestine, lungs, eye etc., resists penetration and traps microbes antimicrobial secretions Lysozyme: hydrolyzes bond connecting sugars in peptidoglycan Lactoferrin: secreted by activated macrophages and PMNs sequesters iron Lactoperoxidase: produces superoxide radicals contain mucosal-associated lymphoid tissue (MALT) Mucosal-Associated Lymphoid Tissue (MALT) specialized immune barrier gut-associated lymphoid tissue (GALT) bronchial-associated lymphoid tissue (BALT) urogenital system MALT: M cells pass antigen to a pocket under the cellmacrophages, other immune cells eliminate Ag Physiologic barriers 1. pH: eg. gastric juice, skin, urine etc., inhibitory effect on bacterial growth 2. Fever: oral temperature (37°C) rectal temperature (37.5°C) most common cause of fever is viral or bacterial infection or bacterial toxins endogenous pyrogen, a cytokine produced in response to pathogen, triggers fever e.g., interleukins IL-1, IL-6, tissue necrosis factor TNF produced by macrophages in response to pathogenic microbes after release, pyrogens hypothalamus and induce production of prostaglandins which reset hypothalamus to a higher temperature Fever and the Host Defense Augmentation of host immune defenses: stimulation of leukocytes to destroy pathogen enhances specific immune system activity promote microbiostasis (growth inhibition) by decreasing available iron to microbes- hypoferremia is the redistribution of iron by fever making it less available to bacteria In contrast hyperferremia – increased iron availability- during menstruation enhances virulence of N.gonorrhea Physiologic Barriers 3. Chemical barriers Defensins: cationic peptides, highly conserved, damage bacterial plasma membranes rich in arginine and cystein found in neutrophils, intestinal Paneth cells and intestinal and respiratory epithelial cells Specific for bacterial membranes Alter cross membrane voltage, make pores and leak ions The Complement System composed of >30 serum proteins produced in liver Activated as a cascade augments (or “complements”) the antibacterial activity of adaptive system major roles: defending against bacterial infections bridging innate and adaptive immunity Role in innate response results in lysis of bacteria mediates inflammation Opsonization: attracts and activates phagocytic cells Complement: alternative pathway Series of proteins Activate each other via proteolytic cleavage C3 normally made and degraded quickly Stabilized by Gramˉ LPS Inserts into bacterial outer membrane Reacts with other components Factor B, Factor D, Properdin Cleaves C5 to C5b Complement C5b protein binds C6, C7 Forms pre-pore complex in target cell membrane C8, C9 proteins attach Forms membrane attack complex Lyses target membrane Phagocytic barrier Phagocytosis: non-specific mechanism monocytes, tissue macrophages, dendritic cells and neutrophils recognize; ingest and kill microbes pathogen recognition involves two mechanisms: Opsonic recognition mechanism Opsonins: complement factors or antibodies Non-opsonic mechanism common pathogen components are non- specifically recognized & activate phagocytes Opsonization process in which microbes are coated by serum components in preparation for recognition/ingestion by phagocytic cells molecules that carry out above are called opsonins some complement proteins are opsonins bind to microbial cells, coating them for phagocyte recognition Opsonin-Independent phagosytosis involves nonspecific and specific receptors on phagocytic cells four main forms: recognition by lectincarbohydrate interactions recognition by protein-protein interactions (eg. RGD motif and receptor) recognition by hydrophobic interactions detection of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs, e.g., toll-like receptors) Back to Phagocytosis… microbes or components internalized as part of a phagosome respiratory burst reactions occur toxic oxygen products kill invading microbes Animation: phagocytosis and antigen presentation Inflammation nonspecific innate response to tissue injury can be caused by pathogen or physical trauma acute inflammation is the immediate response of body to injury or cell death the release of inflammatory mediators from injured tissues initiates a cascade of events which result in the signs of inflammation cardinal signs redness (rubor) warmth (calor) pain (dolor) swelling (tumor) altered function (functio laesa) Acute Inflammatory Response involves chemical mediators Chemokines: released by injured cells Selectins: cell adhesion molecules on activated capillary endothelial cells Integrins: adhesion receptors on neutrophils various processes occur Margination, diapedesis, extravasion More About Acute Inflammation… events which result in elimination of invading pathogens capillary dilation and increased blood flow bring more antimicrobial factors and leukocytes that kill pathogens temperature rise stimulates inflammatory response fibrin clot may restrict pathogen movement phagocytes accumulate in inflamed area and destroy pathogens bone marrow is stimulated by various chemicals to release neutrophils and increase rate of granulocyte production Animation: Acute inflammation