Innate Immunity Lecture PDF

Innate Immunity DR NANCY LAMBRIANIDES NEUROIMMUNOLOGY DEPARTMENT THE CYPRUS INSTITUTE OF NEUROLOGY AND GENETICS The enemy Bacteria (e.g. skin - Staph aureus, food poisoning - Salmonella) Viruses (e.g. influenza) Fungi Protozoa Mycoplasma Route which pathogens enter the host Breaks in the...

Innate Immunity DR NANCY LAMBRIANIDES NEUROIMMUNOLOGY DEPARTMENT THE CYPRUS INSTITUTE OF NEUROLOGY AND GENETICS The enemy Bacteria (e.g. skin - Staph aureus, food poisoning - Salmonella) Viruses (e.g. influenza) Fungi Protozoa Mycoplasma Route which pathogens enter the host Breaks in the skin Respiratory tract (mouth, nose) Gastrointestinal tract Mucous membranes Transplacental (from mother to fetus) Urogenital (sexual) What is immunity? All mechanisms used by the body to protect itself against all foreign things Two types of Immunity: Innate (non-specific immunity) Adaptive (specific) immunity  Innate Immunity Adaptive Immunity First line of defense Second line of defense Third line of defense - Intact skin - Phagocytes, such as - Specialized - Mucous membranes neutrophils, lymphocytes: T cells and their secretions eosinophils and and B cells - Normal microbiota macrophages - Antibodies - Inflammation - Fever - Antimicrobial substances Innate immunity Rapid response (immediate) and first line of defense All elements which we are born with Always present Creates time for the specific immunity to occur Not selective, non-specific (has no memory) Innate immunity Consists of 4 types of defensive barriers: 1. Anatomic 2. Physiologic 3. Phagocytic 4. Inflammatory Innate immunity Consists of 4 types of defensive barriers: 1. Anatomic 2. Physiologic 3. Phagocytic 4. Inflammatory First line of defense Keep microbes out!  Anatomic barriers - Skin Breaks resulting from scratches and wounds Penetrating insect bites Barrier delays the entry of microbes Top layer of the skin contains dead cells which are tightly linked It is dry and unfavourable to microbes Acidic environment (pH 3-5) retards entry of 1. microbes 2. Impermeable unless damaged or moist  Skin: protective barrier against infection The skin consists of two distinct layers: -a thinner outer layer, the epidermis -a thicker layer—the dermis. The dermis, contains sebaceous glands, which produce an oily secretion called sebum. Sebum consists of lactic acid and fatty acids, which maintain the pH of the skin between 3-5; this pH inhibits the growth of most microorganisms.  Anatomic barriers - Mucous Membranes - Normal flora compete with microbes for attachment sites and nutrients - Consists of thick, moist epithelium - They line passageways of digestive, respiratory, urinary and reproductive tract - Has goblet cells for mucous production - Mucous coating and movement of cilia trap and remove foreign particles from internal surfaces of the body  Other anatomic barriers Lacrimal glands - production of tears to wash microbes off Salivary glands - washing of teeth & mouth to reduce colonization Gastrointestinal tract - vomiting and diarrhea to rapidly flush out microbes and toxins Antimicrobial HCl in Lysozyme in tears Peptides in sweat stomach /saliva Innate immunity Consists of 4 types of defensive barriers: 1. Anatomic 2. Physiologic 3. Phagocytic 4. Inflammatory Physiologic barriers Temperature -Normal body temperature inhibits growth of some pathogens -Fever inhibits growth of some pathogens. Low pH -Acidity of stomach contents kills most ingested microorganisms. Chemical mediators / humoral components -Lysozyme, present in most body secretions, cleaves and breaks down bacterial cell wall. -Interferon induces antiviral state in uninfected cells. -Complement lyses microorganisms or facilitates phagocytosis. -Toll-like receptors recognize microbial molecules, signal cells to secrete cytokines. -Collectins disrupt cell wall of pathogen. -Blood coagulation system - increase vascular permeability Innate immunity Consists of 4 types of defensive barriers: 1. Anatomic 2. Physiologic 3. Phagocytic 4. Inflammatory Second line of defense If microbes enter, attack and defend! Phagocytic barriers- Cellular components Various specialized cells internalize and break down foreign macromolecules The major phagocytic cells are known as macrophages and granulocytes These are white blood cells (or leukocytes) When activated most leukocytes will produce cytokines that function to trigger, enhance and coordinate various defense mechanisms. Leukocytes are divided into cells that contain cytoplasmic granules (granulocytes: neutrophils, basophils and eosinophils) and those that do not (lymphocytes and monocytes).  Components of Blood Cellular components come into play when the external defenses are breached Complement proteins Coagulation proteins Cytokines WBCs Leukocytes Never Neutrophils Let Lymphocytes Monkeys Monocytes Eat Eosinophils Bananas Basophils Physiology of leukocytes  Monocytes/Macrophages Monocytes (~5% of WBCs) Monocytes become macrophages when they move from the bloodstream to the tissues Monocytes move to the tissues when infection occurs Over a period of 8hrs they enlarge and produce granules within themselves, becoming Lung Bone macrophages. The granules are filled with enzymes and other substances that help kill and digest bacteria Macrophages (“Big eaters”) stay in the tissues, Liver Brain Main function is phagocytosis and intracellular intestine killing  Neutrophils 8536d_ch02_024-056 8/5/02 4:02 PM Page 42 mac79 Mac 79:45_BW:Goldsby et Have multi-lobed nuclei and two types of cytoplasmic granules Short-lived cells with a lifespan of 6-7 hours 42 in bloodP A R T I Introduction and 1-4 days in tissue sites (a) Neutrophil Neutro oxygen-ind Highly mobile and phagocytic Glycogen substances macrophag exhibit a la Dominate during the initial stages of infection Secondary sequently a granule diates and Multilobed addition, n nucleus Primary azurophilic macrophag granule Their main activity is phagocytosis and EOSINOPH Phagosome intracellular killing Eosinophi can migra (b) Eosinophil phagocytic neutrophil fense again Crystalloid granule creted con  can migrate (b) Eosinophil phagocytic r neutrophils, fense agains Crystalloid granule creted conte parasite mem Basophils BASOPHILS Basophils ar releasing ph toplasmic gr tain allergic (c) Basophil MAST CELLS They are not phagocytic Mast-cell pr by hematopo Glycogen ated cells; th and enter th Have granules which contain ety of tissues histamine organs, and tourinary, a Granule these cells h contain hist stances. Mas Participate in immediate type portant role hypersensitivity reactions initiated by FIGURE 2-10 Drawings showing typical morphology of granulo- cytes. Note differences in the shape of the nucleus and in the num- allergens ber and shape of cytoplasmic granules. DENDRITIC The dendrit ered with lo components, components of the blood-clotting system, and sev- drites of ner eral cytokines secreted by activated TH cells and macrophages. because the Like macrophages, neutrophils are active phagocytic cells. damage thei Phagocytosis by neutrophils is similar to that described for techniques t macrophages, except that the lytic enzymes and bactericidal facilitated is substances in neutrophils are contained within primary and many types  42 PART I Introduction (a) Neutrophil Ne Eosinophils Glycogen oxyge substa macro exhib Secondary seque Slightly phagocytic granule diates Multilobed additi nucleus Primary azurophilic macro Only a very small numbers of these cells are granule EOSIN normally present in the circulation, most are Phagosome Eosin found in tissues can m (b) Eosinophil phago neutr fense Produce toxins to fight multicellular parasite Crystalloid creted infections granule parasi BASO Primarily involved in the killing of worm Basop parasites releas toplas tain a (c) Basophil MAST Mast- Dendritic cells Characterized by long finger-like processes, like the dendrites of nerve cells Reside in tissues in an immature form Functions Phagocytic Act as antigen presenting cells (APC) Link the innate immune response and the adaptive immune response MHC class I & MHC class II They have slightly different structures Both have an elongated cleft in the extracellular surface of the molecule in which a single peptide is trapped MHC class I expressed on most cells of the body MHC class II expressed mostly by antigen- presenting cells (ie dendritic cells) MHC class I presenting peptides to T cells is recognized by the CD8 molecule that is also expressed on the surface of the T cells MHC class II presenting peptides to T cells is recognized by the CD4 molecule that is also expressed on the surface of the T cell NK cells: Innate, adaptive or both? Natural killer (NK) cells can directly kill tumor or virus infected cells through two primary mechanisms: 1. Perforin-granzyme pathway 2. Fas-Fas L pathway They are similar in appearance and function to cytotoxic T lymphocytes, but lack the receptor T cells are using to identify virus-infected cells (the T cell receptor). They also secrete both inflammatory and immunosuppressive cytokines. Although NK cells are part of the innate immune system, they can also be directed to target structures by antibodies, in a mechanism termed antibody- dependent cellular cytotoxicity (ADCC). NK cells differentiate/choose the cells to kill? Uninfected cell / Normal cell Microbe infected cell / cancer cell Some cell surface proteins are missing How does the killer kill? Kills both host cells and microbes Release of granules with perforins and proteases Second line of defense If microbes enter, attack and defend! Innate immunity Consists of 4 types of defensive barriers: 1. Anatomic 2. Physiologic 3. Phagocytic 4. Inflammatory Inflammatory barriers Your body’s response to tissue damage or microbial invasion What happens? Tissue damage and infection induce leakage of vascular fluid, containing serum proteins with antibacterial activity, and influx of phagocytic cells into the affected area. Inflammatory barriers - bring phagocytes to the injured area to: - isolate, destroy and inactivate the invader - remove debris - prepare subsequent healing Inflammation Local manifestations: redness, heat, swelling, pain, loss of function Vascular responses: - blood vessel dilation - Increased vascular permeability and leakage - White blood cell adherence to the inner walls of the vessels and migration through the vessels What are the goals: - Limit and control the inflammatory process - Prevent and limit infection and further damage - Initiate adaptive immune response - Initiate healing Inflammatory response  Cellular mediators of inflammation Macrophages stimulated via innate immune receptors - Pattern recognition receptors - Pathogen associated molecular patterns - Toll-like receptors - Complement receptors - make pro-inflammatory mediators which include cytokines Cytokines are soluble protein mediators secreted by immune cells (mostly) that act on other cells to regulate their activity; many are called interleukins (IL-1, IL-2, etc.) however their names are not at all intuitive A few examples: interleukins, TNFα (tumor necrosis factor-α), IFNγ (interferon-γ), GM-CSF (granulocyte/macrophage-colony stimulating factor), TGF-β (transforming growth factor-β) Not everything about Inflammation is good The good and bad about inflammation Acute /short-term -Good chronic /long-term - Bad  Chronic inflammation and tissue damage Chronic inflammation Reduced tissue function Tissue damage Activation of Killing of host cells immune cells Acute Vs. Chronic Inflammation Cytokines Small proteins – secreted by cells of the immune system Affect the behaviour of other cells Signalling molecules Key players in innate and acquired immunity Examples of cytokines Interferon Interleukins Tumour necrosis factor (TNF)  Interferons (IFN) Signalling proteins produced by by virus infected monocytes and lymphocytes with the aim of slowing or inhibiting virus replication in neighboring cells Secreted proteins – Key anti-viral proteins “Interfere” with virus replication Warn the neighbouring cells that a virus is around... If we did not have IFNs – most of us may die of influenza virus infection How do interferons inhibit viruses? Cell surface receptors, Toll-like receptors – look out for microbes  Toll-like receptors – What are they? The innate immune system responds to common molecules shared by a vast majority of pathogens, called pathogen associated molecular patterns, or PAMPs These are recognized by the toll-like receptors, or TLRs Transmembrane proteins expressed by cells of the innate immune system, which recognize invading microbes The TLR family includes eleven proteins (TLR1-TLR11) They activate signaling pathways that launch immune and inflammatory responses to destroy the invader TLRs – bind to microbes/components of microbes Which microbial components are recognised by TLRs What happens when a TLR bind to a microbe? They activate signaling une Secretion of imm pathways that launch immune d ce nse Cytokines / an o and inflammatory responses Enh resp Interferon to destroy the invader Phagocytosis TLR of infected Inflammation binding to cell microbe g of l Apoptosis in l Kill ted ce of infected c infe cell systemic exposure of mammals to relatively small quantities of purified LPS leads to an acute inflammatory response (see be- low). The mechanism for this response is via a TLR on macrophages that recognizes LPS and elicits a variety of mole- Phagocytosis, The Pac-Man of the immune cules in the inflammatory response upon exposure. When the TLR is exposed to the LPS upon local invasion by a Gram-neg- ative bacterium, the contained response results in elimination system of the bacterial challenge. (b) Cells That Ingest and Destroy Pathogens Make Up a Phagocytic Barrier to Infection 1 A specific form of endocytosis involving the Bacterium becomes attached to membrane evaginations internalisation Another of defense important innate bacteria mechanism is the inges- called pseudopodia tion of extracellular particulate material by phagocytosis. A cell’s isplasma Phagocytosis one typemembrane of endocytosis,expands the generalaround term for 2 the uptake by a cell of material from its environment. In the particulate material to form large vesicles phagocytosis, a cell’s plasma membrane expands around the Bacterium is ingested, forming phagosome calledmaterial, particulate phagosomeswhich may include whole pathogenic microorganisms, to form large vesicles called phagosomes 3 Phagosome (Figure moves to isthe 1-3). Most phagocytosis cell’s interior conducted and by specialized Phagosome fuses with cells,fuses such with a lysosome as blood monocytes, neutrophils, and tissue lysosome macrophages (see Chapter 2). Most cell types are capable of The other digested forms contents of endocytosis, are such as eliminated by receptor-mediated endo- 4 Lysosomal enzymes digest exocytosis cytosis, in which extracellular molecules are internalized after captured material binding by specific cellular receptors, and pinocytosis, the process by which cells take up fluid from the surrounding 5 medium along with any molecules contained in it. Digestion products are released from cell Phagocytosis is conducted by monocytes, neutrophilsRepresents Inflammation and macrophages a Complex Sequence of Events That Stimulates Immune Responses Tissue damage caused by a wound or by an invading patho- of inflammation” as rubor (redness), tumor (swelling), genic microorganism induces a complex sequence of events calor (heat), and dolor (pain). In the second century AD, an- The complement system Activated by invading organisms The biochemical cascade consists of a series of 11 soluble plasma proteins produced by the liver that work to "complement" the work of antibodies in destroying bacteria Complement proteins circulate in the blood in an inactive form Each of the complement proteins performs its specialized job in turn, acting on the molecule next in line Functions of the complement system 1. Activation of inflammation 2. The opsonisation of pathogens and cells for clearance/destruction 3. The direct killing of target cells/microbes by lysis Overview of initiation mechanisms and outcomes of complement Diseases associated with complement deficiencies The four main tasks of the immune system The immune system must fulfil four main tasks: Immunological Immune effector Immune Immunological recognition functions regulation memory Presence of Contain the Ability of the Having been infection must be infection and if immune system detected possible to self-regulate exposed once to eliminate it infectious agent, completely a person will Provided by cells Failure of such of the immune regulation make a faster system known as Complement contributes to and stronger white blood cells system of blood conditions such response against proteins, as allergy and any subsequent antibodies autoimmune exposure to it produced by disease lymphocytes, and the destructive function of white blood cells Summary Innate responses are good, but they have limitations -Non-specific -Short-term There has to be a “smart system” to compensate: - Adaptive immunity