Non-Specific Immunity PDF

Non-Specific Immunity NOREFRINA SHAFINAZ MD NOR I. Fundamentals of Host defense Barriers to Pathogen invasion Natural Host Resistance Infection Site and Tissue Specificity Physical and Chemical Barriers to Infection Barriers to Pathogen invasion  1. First Line Defense A. Physical barriers 1....

Non-Specific Immunity NOREFRINA SHAFINAZ MD NOR I. Fundamentals of Host defense Barriers to Pathogen invasion Natural Host Resistance Infection Site and Tissue Specificity Physical and Chemical Barriers to Infection Barriers to Pathogen invasion  1. First Line Defense A. Physical barriers 1. Skin – (cutaneous membrane = dermis+epidermis) epidermis: -top layer = dead cells, keratin filled, cells tightly linked -dry, unfavorable, constantly shed -impermeable unless damaged or moist  2. Mucous membranes -thick, moist epithelium -less protective than keratinized -has goblet cells for mucus production 3. Ciliary escalator -ciliated epithelium of respiratory tract -cilia beat in wave motion: clear microbes in mucus out of respiratory tract  4. Lacrimal apparatus (lacrimal gland & lacrimal canals) -constant tears over eye -washes microbes off -Tears - Lysozyme - enzyme, fatty acid 5. Salivary glands -produce amylase 6. Vomiting & diarrhea -rapid contractions of gastrointestinal tract to rapidly flush out microbes and toxins B. Chemical factors 1. Mucus: Nose, nasopharyngeal -glycoproteins + water -thick, inhibits colonization 2. sebum -oily, from sebaceous glands -fatty acids & lactic acids make skin pH 3-5 -acid pH inhibits microbe growth 3. perspiration -water + salts -water flushes microbes off skin -salt accumulates inhibiting microbe growth 4. lysozyme -enzyme in most body secretions -breaks down peptidoglycan cell walls 5. gastric juice -HCl + enzymes + mucus -pH 1-3 destroys most bacteria and toxins 6). Normal Microbiota -microbial antagonism: -compete for nutrients or space -alter environment (pH, oxygen) -produce toxins (e.g. bacteriocins) These beneficial microbes also aid in digestion and absorption of our food. Staphylococcus epidermidis is a normal resident of the skin and Escherichia coli is a normal resident of the intestinal tract Microorganism Not all microbes are pathogen. Degree of virulent is different: healthy human not easily infected by microbes which was weak in virulence. For individual Few mechanisms in human body which defense against microorganisms from entering or kill the II cells and organs of the immune system  Immunity Structure 1. Cells in the blood 2. Organ in immunity systems 3. Reticulum-endothelium systems 4. Lymphatic system  Innate immunity: 1. First lines of defense – skin, mucous membrane and secretions, Type of normal microbiota 2. Second lines of defense- Defenses Natural Killer cells (NK), phagocytes, inflammation, fever, antimicrobial substances  Definition: Immunity is mechanisms to build individual Immunity immunity to recognize foreign substances and also to neutralize, to destroy and to metabolize those substances without bring any harm to the human itself.  1. Nonspecific defense: also known as innate, or natural immunity. Defense present at birth. Rapid respond to protect against diseases. Types of Does not involved against specific recognition of microbe immunity Does not have memory concept React as early warning systems The body adequately protected by its innate defenses—against any type of invading agents. First line defense. Types of immunity Innate defenses 2. Specific defence (adaptive): specific cells (Lymphocyte) recognize foreign substances (ANTIGEN, or IMMUNOGEN) and react by destroy them by producing specific protein (ANTIBODY) which destroy the antigen or to be recognize and be destroy by other cells; also known as ACQUIRED IMMUNITY or ADAPTIVE IMMUNITY. Slow to respond but have memory respond Second line defenses. Two groups: Passive: placenta antibody cell activation - Active: cured from disease - Antitoxin injection - vaccination 1. BLOOD Cellular substances: Granulocytes Neutrophils Eosinophils Basophils monocytes – macrophage lymphocytes Liquids dissolve Antibody Other substances Water Nutrient  Cellular defenses 1. Cellular defenses - Second line defense -mechanisms using specific cells in the blood and other tissues in the body -Blood consists of plasma 60% (liquid) and formed elements 40% (cells and cell fragments): formed elements: erithrocytes (red bc), platelets and leukocyte (white bc). All derived from Pluripotent Stem cells – bone marrow. Platelets, short live, fragments of large cells— MEGAKARTOCYTES – blood clotting. Leukocytes divided into 2: granulocytes and agranulocytes  1: Granulocytes Cytoplasms --granular cytoplasm, irregular shaped, lobed nucleus. Derived from Myeliod stem cells in bone marrow Granulocyte: basophils, mast cells, eosinophils, and neutrophils- different by shape of nuclei and staining reaction with specific dye. Basophils release histamine which starts the inflammation reaction Mast cells in the connective tissues and along blood vessels also release histamine and related to allergy reaction.  Eosinophils occurs in large numbers during allergy reaction and worm infection. It also detoxify foreign substances and help turn off inflammatory reactions. Neutrophils (polymorphonuclear leukocyte PMNLs) guard the skin and mucous membrane against infection. These cells are phagocytic and respond quickly when tissue injury. Dendritic cells (DC)—long membrane extension resemble dendrites of nerve cells. They are phagocytes—involve in initiating adaptive defense systems. Abundant in epidermis, mucous membrane, thymus, lymph nodes. 2. Agranulocytes No granular cytoplasm and round nuclei. Consists of monocytes and lymphocytes. Monocyte from stem cell myeloid. Limphocyte from stem cell lymphoid. For specific host defense (adaptive). Circulate in the blood, large numbers in lymph nodes, spleen, thymus and tonsils. Granulocyte Granulocyte Granulosit: Neutrophil sel mast Chemoattractant Chemokines? Sitokin kecil - protein isyarat yang boleh mendorong Chemotaxis CXC chemokines (i.e CXCL8 (IL-8)+CXCR1/R2 induce migration of neutrophil + degranulation Mengenal motif Positive” ELR” asid glutamik leucine arginine  3. Phagocytes Phagocytes cells that eat or engulf other substances. Patrols, circulate, destroy dead cells and remove cellular debris. Guard the skin and mucous membrane against invasion. The first cells attacks microbes and other foreign materials at portal of entry. Neutrophils- circulate in the body Migrate quickly at site of infection– inactivating bacteria and small particles. Die 1or 2 days Phagocytosis Process 4 steps: 1. Find 2. Adhere 3. Ingest 4. Digest mo 1. Chemotaxis Phagocytes in the tissues recognize the invading mo. Macrophage and dendritic cells can distinguish between gram negative, gram positive and between bacteria vs pathogens. Infectious agent and damage tissues also release chemical substances to which monocytes and macrophage are attracted. Basophil and mast cells ->histamine Phagocyte at the infection sites - cytokines—activation of cells involved in inflammation response. Chemokines– attract additional phagocytes to the site of infection. Phagocytes go to site of infection by chemotaxis– movement of cells towards chemical stimulant.  2. Adherence and ingestion Infectious agents attach to the plasma membrane of phagocytic cells. The ability of the phagocyte cell membrane to bind to specific molecule on the surface of microbe—adherence. Antiphagocytic capsule – Streptococcus pneumoniae and Haemophilus influenzae make adherence difficult to phagocytes. Streptococcus pyogenes contains M protein which interfere with adherence. Host produce antibodies or protein complement systems – phagocytes easier to bind to microbes. Pseudopodia surround the microbe—fuse– microbe in vacuole----phagosome.  3. Digestion Mechanisms for digestion of ingested microbes. 1. LYSOSOMES — contains digestive enzymes and small proteins DEFENSINS– fuse with phagosome membrane--PHAGOLYSOSOME. Breaking pathogens into small molecules (amino acid, sugar, fatty acids) can be used as building blocks for metabolic and energy by phagocytes. 2. Phagocytic cells use oxygen to form H2O2, NO, superoxide ion and hypochlorite ions– damaging plasma membrane.  Indigestible material left over in phagolysosome– RESIDUAL BODY. Phagocyte transport to plasma membrane—excreted. Some microbes develop mechanisms to prevent destruction within phagolysosome. Some can multiply within phagocytes. III. Phagocyte Response Mechanisms Phagocytosis and Phagocyte inhibition Pathogen Recognition and Phagocyte signal transduction pathogen-associated molecular patterns (PAMPs) pattern recognition receptors (PRRs),  Monocytes migrate from bone marrow into the blood– to tissues– cellular changes– mature into macrophage. Macrophage (big eaters)- destroy not only mo but large particles (debris from neutrophils). Macrophages perform 3 important functions : 1) phagocytosis (professional eaters); 2) release chemical messengers to alert other immune cells; and 3)present information about the foreign microbes (antigens) to the T cells, Arrive late at site of infection but in large nos.  2 types of macrophage Fixed macrophages: FIXED OR WANDERING at one location in the tissues - Fixed macrophage- remain stationary in tissues. Wandering- circulate in the blood Both live for months---years. Also involve in specific host defense. Macrophages that migrate into specific tissues are named for their location in the body.  LYMPHATIC CIRCULATION The process of draining excess fluids from the spaces between cells starts with lymphatic capillaries. It collect excess fluids and plasma proteins leak from the blood into the spaces between cells. Once in the lymphatic capillaries– the fluid– LYMPH. lymphatic capillaries  lymphatic vessels  lymphatic nodes  return to the blood via right and left lymphatic duct. The flow depend on skeletal muscle contractions. Microbial Invasion? Tissue Damage and Chemokine Release Resident macrophages, which are found in all of the body’s organ systems, are stimulated by the presence of invading pathogens to secrete chemokines that establish a gradient of chemoattractants Neutrophils and other phagocytes that encounter pathogens in damaged areas must be able to recognize, capture, and destroy pathogens to clear infections and restore body tissues to a healthy state  IV other innate Host defenses Inflammation is a non-specific response to tissue injury or infection that limits the spread of pathogens, removes damaged cells or tissues, destroys pathogens, and stimulates tissue repair Also response towards mechanical injury (cuts), heat (burns), uv (sunburn), chemicals (Phenol, acid, alkaline) and allergy. Inflammation is characterized by redness (erythema), swelling (edema), pain, and heat, usually localized at the site of infection. The mediators of inflammation are a group of cell activator and chemoattractant molecules, including cytokines and chemokines. Various cells, including those damaged by injury, produce these activators. The most important chemokines and cytokines are called proinflammatory because of their inflammation-inducing capacity, and they are produced in high concentrations by phagocytes and lymphocytes during pathogen challenge. Both innate and adaptive immune responses to infection can cause inflammation Signs of Inflammation INFLAMMATION 1. Cell damage/cut, basophil and mast cells ---histamine and leukotrienes--- diffuse into capillaries---walls vessels dilates (VASOLIDATION). Process; chemotaxis 2. Histamine causes vasodilation or expansion of the blood vessels. This causes redness (rubor) and increased heat (color) in the affected region. Leukotrienes make the blood vessel walls more permeable or leaky. INFLAMMATION 3. Neutrophils & macrophages crawl out of the blood vessels by diapedesis. This causes swelling (tumor or EDEMA) in the affected tissue. Neutrophils and macrophages remove microbes or damaged tissue by phagocytosis (eating) and pus is formed 4. Blood delivers clotting factors, nutrients and other substances to injured area— removed waste and excess fluids. INFLAMMATION If cut– platetets and clotting factors such as fibrin forming blood clot. Pain associated with tissue injury due to release of bradykinin, a small peptide at the injured site Inflammed tissue also stimulate leukocytosis– no of leukocytes increase in blood. An hour after inflammatory process--- phagocytes arrived— leukocytes pass out by squeezing between endothelial cells lining the vessel wall– process DIAPEDESIS –neutrophil congregate in tissue fluid. INFLAMMATION 5. Macrophage release cytokines – chemokines attracts other phagocytes and tumor necrosis factor alpha (TNF-α) (cytokines)--- add more vasodilation and edema. PUS-The accumulation of dead phagocytes, injured or damage cells, remains of ingested mo, other tissues debris---form white or yellow fluid– PUS. Pus continuous to form until the infection under control. Streptococcus pyogenes produce pus – leukocidin destroy the phagocytes. Virus do not cause pus formation. ABSCESS- Accumulation of pus in a cavity hollowed out by tissue e.g: Pimples, boils. FEVER Fever a systemic increase in body temperature. Hypothalamus normally set Normal body at 37°C (98.6F) Fever 37.8C (100.5F)—oral or 38.4C (101.5F) rectal. If > 43C— death. Fever can be cause by many pathogens, certain immunological process (vaccination), tissue injury, - triggered by microbial substance (e.g. LPS) or cytokines from activated phagocytes which reset thermostat in hypothalamus FEVER ENDOGENOUS PYROGENES: Certain cytokines released during an inflammatory response induce fever, a condition of elevated body temperature. For example, the proinflammatory cytokines IL-1, IL-6, and TNF-a are endogenous pyrogens. These substances stimulate the hypothalamus, the temperature-controlling center of the brain, to produce prostaglandins, chemical signals that raise body temperature and cause fever. These same cytokines released in small amounts at local sites of infection induce localized heating, which increases blood flow and promotes healing. The release of endogenous FEVER EXOGENOUS PYROGENES: Gram-negative endotoxin cause phagocytes to release interleukin–1 (IL–1) )—circulate in blood hypothalamus activate neuron secrete POSTAGLANDINS which reset the hypothalamus thermostat at higher Temperature (T), body T rise within 20 min. Body increases rate of metabolism and shivering which raise temperature.  ADVANTAGES – Increase transferrins – Increase IL–1 activity – At high T, some microbial enzyme or toxin, – slow down microbial reaction-faster rate of body inactivated - Inc level of metabolism, not kill defense mechanism attack immune response by inc rate of chemical FEVER -enhances activity of -accelerates defense antiviral & antibacterial mechanisms & repair enzymes DISADVANTAGES – Tachycardia – Acidosis – Dehydration MOLECULE DEFENSES innate defenses against Viruses Interferon ----small, soluble protein, responsible for viral interference –interfered with virion replication in other cells. In human, 3 groups of interferon, alpha, beta and gamma, Produce after infection of virus ( α and β) ds RNA endotoxin, parasite MOLECULE DEFENSES innate defenses against Viruses 1. IFNβ: -produced by virus infected cells -trigger neighboring uninfected cells to produce AVPs (antiviral proteins) -AVPs block viral replication in the cell AVP s specifically effective against RNA virus.  MOLECULE DEFENSES innate defenses against Viruses 2. IFNα: -produced by leukocytes -trigger AVP production in body cells -activates defense cells (e.g. NK cells) to kill virus infected cells 3. IFNγ: -produced by lymphocytes and NK cells -activate defense cells for phagocytosis (e.g. macrophages & neutrophils) - also block virus replication by AVP synthesis. Other innate Natural killer cells (NK cells) are cytotoxic lymphocytes that are distinct from T cells and B cells defenses against NK cell engages an infected or otherwise diseased cell, granules in the cytoplasm of the NK cell migrate to the con- tact site and release their contents. These granules Viruses? contain perforin and proteases called granzymes. Perforin binds the membrane of the target cell and forms a pore through which granzymes enter the target cell Most cells in the body contain a suite of surface proteins called the major histocompatibility complex (MHC)  COMPLEMENT SYSTEM The complement system is a group of sequentially interacting proteins, many with enzymatic activity, that functions to boost the efficiency of both innate and adaptive immune responses for the destruction of pathogens. Complement proteins are produced in the liver and found throughout the body, and their activities can be triggered by innate or adaptive mecha- nisms. The major outcomes of activating the complement system are enhanced phagocytosis, inflammation, and lysis of invading cells.  1. Classical Pathway The classical pathway of complement activation is initiated when complement proteins, attracted by bound antibodies, attach to patho- gen surfaces. The antibodies are said to fix (bind) the ever-present complement proteins, and thus, classical complement activation depends upon the adaptive immune response. Antibodies bound to the surface of the microbe Ab binds with Ag involves complement protein (C1, C4, C2) to activate next protein 2. Alternative pathway The alternative pathway is a nonspecific complement activation mechanism that uses many of the classical complement pathway components, as well as several unique serum proteins. Together they induce opsonization and activate the C5–9 MAC. The first step in alternative pathway activation is the binding of C3b to LPS on the bacterial cell surface Activated by contact between complement protein (Factor B, factor D, factor P) and lipid- polysaccharides at pathogen surface. Activated earlier compared to classical. C3 a key protein in the systems. MAC- Lysis The C5b−7 complex recruits C8 and C9, forming a large C5b–9 unit called the membrane attack complex (MAC). The MAC forms a pore through the cytoplasmic membrane of the pathogenic cell, allowing extracellular fluids to rush in and lyse the cell Dozens to hundreds of MACs may perforate a single bacterial cell at the point of lysis. 3. Lectin Pathway The mannose-binding lectin (MBL) pathway depends on the activity of a serum MBL protein. MBL is a soluble PRR that binds to mannose- containing polysaccharides found only on bacterial cell surfaces Macrophoge ingest bacteria, viruses, and other foreign matter by phagocytosis stimulate the liver produce LECTINS, proteins that bind to CHO. Mannose-binding lectin, bind to mannose (on bacterial cell wall). Complement Fixation? Three antimicrobial results of complement fixation: 1. Opsonization=phagocytosis ---opsonin (an Ab) and C3b to be recognize by phagocytes. 2. Membrane attack complex (MAC)= Cytolysis immune, complement protein, C-C9 produce lesion on membrane pathogen to cause cell lysis. 3. inflammation=phagocytosis, C3a +C5a trigger histamine release fpm mast cells  SUMMARY Note Ref and further reading Brock Biology of Microorganisms FIFTEENTH EDITION (2019), PEARSON SUMMARY SUMMARY INNATE and ADAPTIVE IMMUNITY