Innate - Adaptive Immunity.pdf

Innate & Adaptive Immunity Dana M. Tofiq MBChB, FAAAAI Assistant Professor of Allergy & Immunology Learning objectives By the end of this session, students should be able to: Define innate immunity and adaptive immunity Understand components involved in innate and adaptive immunity IMMUNITY The...

Innate & Adaptive Immunity Dana M. Tofiq MBChB, FAAAAI Assistant Professor of Allergy & Immunology Learning objectives By the end of this session, students should be able to: Define innate immunity and adaptive immunity Understand components involved in innate and adaptive immunity IMMUNITY The term 'immunity' (Latin word ‘immunitas’, means freedom from disease) is defined as the resistance offered by the host against microorganism(s) or any foreign substance(s). Immunity can be broadly classified into two types: o Innate immunity: present right from the birth o Adaptive / Acquired: acquired during the course of the life Differences between innate and adaptive immunity Innate immunity Adaptive / Acquired immunity Resistance to infection that an individual possesses from birth Resistance to infection that an individual acquires during his lifetime Immune response occurs in minutes Immune response occurs in days Prior exposure to the antigen is not required Develops following the antigenic exposure Diversity is limited, acts through a restricted set More varied and specialized responses of reactions Differences between innate and adaptive immunity Innate immunity Adaptive / Acquired immunity Immunological memory responses are absent Immunological memory responses are present Respond to microbial antigens that are not Respond to specific microbial antigens specific to some microbe, rather shared by many microbes (called microbes-associated molecular patterns) Host cell receptors (pattern recognition receptors) Host cell receptors are specific- e.g. T cell receptors and B cell are non- specific – e.g. Toll-like receptor immunoglobulin receptors Differences between innate and adaptive immunity Innate immunity Components of innate immunity Anatomical barriers such as skin and mucosa Physiological barriers (e.g. body temperature) Phagocytes (neutrophils, macrophages & monocytes) Natural killer (NK) cells Other Classes of lymphocytes -γδ T cells , NK-T cells, B-1 cells and marginal-zone B cells Mast cells Dendritic cells Complement pathways- alternative & lectin pathways Fever and inflammatory responses Normal resident flora Cytokines- TNF-α, certain interleukins (IL-1, IL-6, IL-8, IL-12, IL-16, IL18), IFN-α, β and TGF-β Acute phase reactant proteins (APRs) Adaptive / Acquired immunity Components of adaptive immunity T cell B cell Classical complement pathway Antigen presenting cells Cytokines (IL-2, IL-4, IL-5, IFN-γ) Types of acquired immunity It can be classified in two ways: Active and passive immunity Artificial and natural immunity INNATE IMMUNITY Innate immunity is the inborn resistance against infections that an individual possesses right from the birth, due to her/his genetic constitution or makeup. Features of innate immunity Acts in minutes Prior microbial exposure is not required Diversity is limited Non-specific No memory Factors influencing innate immunity 1. Age: Certain infections are common in a particular Age. For example, congenital infections like rubella is common in fetal life, chicken pox and measles occur in children, whereas urinary tract infection is common in adults. 2. Hormone: Certain hormonal disorders like (e.g. diabetes mellitus) or patients on hormone therapy (e.g. corticosteroids) are at increased risk of developing various infections 3. Nutrition: Malnutrition suppresses the host immunity, thereby predisposes to various infections MECHANISMS OF INNATE IMMUNITY Receptor interaction o Following the exposure of microorganisms, several mediators of innate immunity are recruited to the site of infection. o The first step that takes place is attachment, which involves binding of the surface molecules of microorganisms to the receptors of cells of innate immunity. MECHANISMS OF INNATE IMMUNITY Microbial surface moleculeso Repeating patterns of conserved molecules which are common to most microbial surfaces; called as Microbes-associated molecular patterns (MAMPs). o Examples - peptidoglycan, lipopolysaccharides (LPS), teichoic acid and lipoproteins present on bacterial surface. MECHANISMS OF INNATE IMMUNITY Pattern recognition receptors (PRRs)o Molecules present on the surface of host cells (e.g. phagocytes) that recognize MAMPs. o Conserved regions, encoded by germ line genes. o Toll like receptors (TLRs) - classical examples of pattern recognition receptors. MECHANISMS OF INNATE IMMUNITY Pattern recognition receptors (PRRs)o TLRs binds to MAMPs signals are generated activate transcription factors stimulate expression of genes encoding cytokines & enzymes antimicrobial activity. o Most important transcription factors activated by TLR signals are: Nuclear factor B (NF- B) - promotes production of cytokines. Interferon regulatory factors (IRFs) - stimulate expression of the antiviral interferons α & β. Toll like receptors So named because they are similar to Toll receptors present in the fruit fly- Drosophila, where it is the main receptor for induction of innate immunity. There are 13 types of Toll like receptors (TLR 1 to 13). Important ones areo TLR-2 binds to bacterial peptidoglycan o TLR-3 binds to dsRNA of viruses o TLR-4 binds to LPS of Gram negative bacteria o TLR-5 binds to flagella of bacteria o TLR-7 & 8 bind to ssRNA of viruses o TLR-9 binds to bacterial DNA Components of innate immunity 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Anatomical and physiological barriers Phagocytes Natural killer (NK) cells and other classes of lymphocytes Mast cells Dendritic cells Complement pathways Inflammatory response Normal resident flora Cytokines Acute phase reactant proteins (APRs) Anatomical and physiological barriers Anatomical Barrier Function Skin Barrier Mechanically prevents entry of microbes Produces sebum containing antimicrobial peptides and fatty acids Killing of microbes by intraepithelial lymphocytes Mucosal Barrier 1. Mucous membrane Prevents entry of microbes mechanically and by producing mucous which entraps microbes 2.Cilia Cilia present in the lower respiratory tract propel the microbes outside 3.Normal flora Intestinal & respiratory mucosa are lined by normal flora Anatomical and physiological barriers Physiological Barrier Function 1.Temperature Normal body temperature inhibits the growth of some microbes 2.Low pH Gastric acidity inhibits most of the microbes 3.Secretory products of mucosa Saliva Enzymes in saliva damage the cell wall and cell membrane of bacteria Tears Contains lysozyme, that destroys the peptidoglycan layer in bacterial cell wall Gastric juice HCl kills microbes by its low pH Trypsin Hydrolyse bacterial protein Bile salts Interfere with bacterial cell membrane Fatty acids Denature the bacterial proteins Spermine Present in semen, inhibits growth of Gram positive bacteria Lactoferrin Binds to iron, thus interferes with acquisition of iron by bacteria Phagocytes Phagocytes - neutrophils, macrophages including monocytes are the main component of innate immunity. Rapidly recruited to the infection site. Phagocytosis involves three sequential steps: o Engulfment of microbes and subsequent hosting in phagosome. o Fusion of lysosome with phagosome to form phagolysosome o Microbial killing Natural killer (NK) cells and other classes of lymphocytes NK cells: o Class of lymphocytes that kill virus infected cells and tumor cells. Natural killer (NK) cells and other classes of lymphocytes γδ T cells (also called as intraepithelial lymphocytes) -present in epithelial lining of skin and mucosa NK-T cells - present in epithelium and lymphoid organs B-1 cells - found mostly in the peritoneal cavity and mucosal tissues Marginal-zone B cells - present at the edges of lymphoid follicles of spleen Mast cells They are present in the epithelial lining of the respiratory and other mucosa. Activated by microbial products binding to toll like receptors or by IgE antibody dependent mechanism. They release abundant cytoplasmic granules rich in histamine, prostaglandins & cytokines that initiate inflammation and proteolytic enzymes that can kill bacteria. Dendritic cells Respond to microbes by producing numerous cytokines that initiate inflammation. Serve as vehicle in transporting the antigen(s) from the skin and mucosal site to lymph nodes where they present the antigen(s) to T cells - bridge between innate and adaptive immunity. Complement pathways Alternative and lectin pathways are the chief mediators of innate immunity. Alternative complement pathway is activated in response to bacterial endotoxin. Lectin pathway (mannose-binding lectin pathway, mannanbinding lectin pathway) is stimulated by mannose carbohydrate residues on bacterial surface. Complement pathways – Biological function Lysis of the target microbes (by forming pores on the microbial surfaces) Stimulate inflammation (by secreting inflammatory mediators) Stimulate adaptive immunity: Complements are another bridge between innate and adaptive immunity. Inflammatory response Inflammation is defined as the biological response of vascular tissues to harmful stimuli, such as microorganisms or other foreign substances. Inflammatory response Vasodilation due to release of vasoactive substances from the damaged tissues Leakage of plasma proteins through blood vessels Inflammatory response Recruitment of phagocytes (e.g. neutrophils) to the site of inflammation. Phagocytes undergo the following steps o Margination (adherence to the endothelium). o Rolling on endothelium o Extravasation (moves out of the blood vessels) o Chemotactic migration to the inflammation site Inflammatory response Engulfment of microbes and dead material by the phagocytes Destruction of the microbes Inflammation is not always protective in nature hypersensitivity reactions (injurious consequences) Normal resident flora Normal resident flora lining intestinal, respiratory and genital tract exert several antimicrobial activities. Compete with the pathogens for nutrition . Produce antibacterial substances. Cytokines In response to the microbial antigens, dendritic cells, macrophages, and other cells secrete several cytokines that mediate many of the cellular reactions of innate immunity such as: o Tumor necrosis factor-α (TNF-α) o Interleukin-1 (IL-1), IL-6, IL-8, IL-12 & IL-16 o Interferons (IFN-α, β) and o Transforming growth factor (TGF-β) Acute phase reactant proteins (APRs) Proteins synthesized by liver at steady concentration, but their synthesis either increases or decreases exponentially during acute inflammatory conditions. APRs can also be synthesized by various other cells such as endothelial cells, fibroblasts, monocytes and adipocytes. Positive APRs Proteins whose levels increase during acute inflammation. Examples include: o C- Reactive Protein (opsonin on microbes) o Ferritin (Binding iron, inhibiting microbe iron uptake) o Complement Factors: (opsonization, chemotaxis, lysis, clumping of target cells) o Coagulation Factors: fibrinogen, prothrombin, factor VIII, von Willebrand factor (trapping invading microbes in blood clots, some cause chemotaxis) o Mannan-binding lectin o Alpha 2-macroglobulin o Haptoglobin o Ceruloplasmin o Serum Amyloid A o Hepcidin o Plasminogen activator inhibitor-1 Negative APRs Proteins whose levels are decreased during acute inflammation, thus creating a negative feedback that stimulates the liver to produce positive APRs. Examples of negative APRs include: o Albumin o Transferrin o Antithrombin o Transthyretin o Retinol-binding protein o Transcortin Adaptive / Acquired Immunity Adaptive immunity is defined as the resistance against the infecting foreign substance that an individual adapts or acquires during the course of her/ his life. PROPERTIES OF ADAPTIVE IMMUNITY Mediators- T cells & B cells are the chief mediators of adaptive immunity. Others includeo Classical complement pathway o Antigen presenting cells o Cytokines (IL-2, IL-4, IL-5) Response occurs in days - It requires the activation of T and B cells against the microbial antigens. Requires prior microbial exposure- Adaptive immunity develops only after the exposure to the microbes. PROPERTIES OF ADAPTIVE IMMUNITY Specific- Adaptive immunity is highly specific; directed against specific antigens that are unique to the microbes. Memory present- A proportion of T and B cells become memory cells following primary contact of the microbe, which play an important role when the microbe is encountered subsequently. Diversity is wide- Adaptive immunity though takes time to develop, is active against a wide range of repertoire of antigens. PROPERTIES OF ADAPTIVE IMMUNITY Host cell receptors of adaptive immunity are specific for particular microbial antigeno Examples include-T cell receptors and B cell immunoglobulin receptors o Encoded by genes produced by somatic recombination of gene segments Types of Adaptive Immunity Active and passive immunity Artificial and natural immunity Active Immunity The host’s immune system is actively involved in response to the antigenic stimulus; leading to the production of immunologically active T cells, B cells and production of specific antibodies. ACTIVE IMMUNITY Active immunity is the resistance developed by an individual towards an antigenic stimulus. Active immunity may be induced naturally or artificially: o Natural active immunity occurs following an exposure to a microbial infection (e.g. measles virus infection) o Artificial active immunity develops following an exposure to an immunogen by vaccination (e.g. measles vaccine). ACTIVE IMMUNITY Long-lasting- Active immunity usually lasts for longer periods but the duration varies depending on the type of pathogen. o Last lifelong- e.g. following certain viral infections such as chicken pox, measles, small pox, mumps and rubella. o Last short- e.g. following influenza infection. o Premunition or concomitant immunity – Immunity may last as long as the microbe is present. Once the disease is cured, the patient becomes susceptible to the microbe again (Spirochaetes and Plasmodium). o Active immunity may not be protective at all- e.g. for Haemophilus ducreyi, the patient may develop genital lesions following reinfection even while the original infection is active. Immune response Immune responses in active immunity are different for the microbial exposure that occurs for the first time (called primary immune response) and subsequent time (called secondary immune response). Primary immune response When the antigenic exposure occurs for the first time, the following events take placeo Latent or lag period - Active immunity develops only after a latent period following the antigenic exposure, which corresponds to the time required for the host's immune apparatus to become active. o Effector cells- Majority of activated T and B cells against the antigenic stimulus become effector T and B cells Effector T cells such as helper T cells and cytotoxic T cells Effector B cells include plasma cells Primary immune response o Memory cells- A minor proportion of stimulated T and B cells become memory cells, which are the key cells for secondary immune response. o Antibody surge Activated B cells produce antibodies (mainly IgM type). Antibodies appear in the serum in slow & sluggish manner; reach peak, maintain the level for a while and then fall down. Finally, a low titer of baseline antibodies may be maintained in the serum. Secondary immune response When the same antigenic exposure occurs subsequently, the events which take place are as follows: o Latent period: Is either absent or of short duration. This is because memory cells become active soon after the antigenic exposure. o Negative phase: At the onset of secondary immune response, there may be a negative phase during which the antibody level may become lower than it was before the antigenic stimulus. o Antibody surge: Secondary antibody response is prompt, powerful, long-lasting and mainly of IgG type. Hence, it is said that, the booster doses of vaccines are more effective than the first dose. PASSIVE IMMUNITY Passive immunity is defined as the resistance that is transferred passively to a host in a 'ready-made' form without active participation of the host’s immune system. Passive immunity can also be induced naturally or artificially. o Natural passive immunity involves the IgG antibody transfer from mother to fetus across the placenta. o Artificial passive immunity develops following ready-made transfer of commercially prepared immunoglobulin (e.g. Rabies immunoglobulin) Role of passive immunity Immunodeficient individuals (as host’s immune apparatus is not effective) Post-exposure prophylaxis; when an immediate effect is warranted. Passive immunity develops faster; there is no lag phase or negative phase. There is no immunological memory as the memory cells are not involved. Booster doses are not effective Differences between active and passive immunity Active immunity Passive immunity Produced actively by host immune system Immunoglobulins received passively Induced byInfection (natural) Vaccination (artificial) Acquired byMother to fetus IgG transfer (natural) Ready-made antibody transfer (artificial) Long-lasting Lasts for short time Lag period present No Lag period Memory present No Memory Booster doses-useful Subsequent doses-Less effective Negative phase may occur No Negative phase Not useful in immunodeficient individuals Useful in immunodeficient individuals Differences between primary and secondary immune response Primary immune response Immune response against primary antigenic challenge Slow, sluggish (appear late) and short lived Secondary immune response Immune response against subsequent antigenic challenge Prompt, powerful & prolonged (long-lasting) Lag period is longer (4-7 days) Lag period is absent or short (1-3 days) No negative phase Antibody produced in low titer & is of IgM type. Antibodies are more specific but less avid Antibody producing cells- Naive B cells Negative phase may occur Antibody produced in high titer & is of IgG type Antibodies are less specific but more avid Both T dependent and T independent antigens are processed Only T dependent antigens are processed Antibody producing cells- Memory B cells BRIDGES BETWEEN INNATE AND ADAPTIVE IMMUNITY Macrophages and dendritic cells: o Belong to innate immune system but as antigen presenting cells, they present the antigenic peptides to T cells. o Cytokines secreted from macrophages (interleukin-1) are also involved in T cell activation. ADCC (antibody dependent cell mediated cytotoxicity): o Type of cell mediated immune response (CMI), which involves both innate and adaptive components. o Cells of innate immunity such as NK cell, eosinophils, and neutrophils destroy (by cytotoxic effect) the target cells coated with specific antibodies. BRIDGES BETWEEN INNATE AND ADAPTIVE IMMUNITY Complements (classical pathway) o Part of both innate and adaptive immunity. o Destroy the target cells which are coated with specific antibodies. o Alternate and mannose binding pathways do not take help of antibodies. Cytokines o Secreted from cells of innate immunity can activate cells of adaptive immunity and vice versa. o E.g. IL-1 secreted from macrophage activates helper T cells and interferon-γ secreted by helper T cell can activate macrophage. BRIDGES BETWEEN INNATE AND ADAPTIVE IMMUNITY Rare classes of lymphocytes such as γδ T cells , NK-T cells, B-1 cells and Marginal-zone B cells. o These cells have many characteristics that place them in the border of innate & adaptive immunity. o Function in the early defense against microbes as part of innate immunity. o Although their receptors are encoded by somatic recombination of genes (similar to that of classical T and B cells), but these receptors have limited diversity. o They develop a memory phenotype in contrast to the property of innate immunity. Local (Mucosal) Immunity Immune response that is active at the mucosal surfaces such as intestinal or respiratory or genitourinary mucosa. Mediated by a type of IgA antibody called secretory IgA. Local immunity can only be induced by natural infection or by live vaccination (but not by killed vaccines). Herd immunity Herd immunity is defined as the overall immunity of a community (or herd) towards a pathogen. Elements that contribute to create strong herd immunity are: o Occurrence of clinical and subclinical cases in the herd o On-going immunization programme o Herd structure i.e. type of population involved o Type of pathogen- Herd immunity may not be strong in a community against all the pathogens. Herd immunity Herd immunity develops following effective vaccination against some diseases like: o Diphtheria and Pertussis vaccine o Measles, Mumps and Rubella (MMR) vaccine o Polio (Oral polio vaccine) o Smallpox vaccine Thank You