Infections and Immune Response PDF

INFECTIONS & IMMUNE RESPONSE Dr. Hasni Mahayidin Department of Pathology Faculty of Medicine and Health Sciences UPM Learning Outcomes: Definitions an invasion of the body by harmful/pathogenic microorganisms Disease: a condition that impairs normal body functioning and is typically manifested by distinguishing signs and symptoms a condition of being able to resist a particular disease ( a bodily response to an antigen that occurs when lymphocytes identify the antigenic molecule as foreign and induce the formation of antibodies and lymphocytes capable of reacting with it and rendering it harmless Vaccination: the act of receiving vaccine Immunisation: the act of making someone or something immune Normal immune response… Eliminate abnormal cells à tumour / cancer Defend against pathogens à infections - Virus - Bacteria - Fungi - Parasites (e.g. helminth, protozoa) Rejection of non-self cells / tissues / organs Entry routes of pathogens Physical and chemical barriers against pathogens: Recognition of pathogens by immune system To fight infections, the immune system must be able to identify pathogens. Pathogens have molecules called antigens on their surface. Antigens provide a unique signature for the pathogen that enables immune system cells to recognize different pathogens and distinguish pathogens from the body's own cells and tissues. PAMPs and PRRs Pattern Recognition Receptors (PRRs) are a class of receptors that can directly recognise the specific molecular structures on the surface of pathogens. The PRRs are divided into four families: Toll-like receptors (TLR) Nucleotide-binding oligomerization domain-like receptors (NLR) C-type lectin receptors (CLR) RIG-1 like receptors (RLR) These receptors recognise conserved molecular structures of pathogens. These motifs called pathogen-associated molecular patterns (PAMPs). PAMPs could be proteins, nucleic acids or glycans. PAMPs Upon recognition of PAMP (pathogen) by PRR (innate immune cells) --> Trigger pro- inflammatory and antimicrobial responses e.g. production of pro- inflammatory cytokines Mucosal Immune System Mucosal tissues are major barriers to the entry of pathogens into the body (gastrointestinal, respiratory and urogenital systems) Secretory IgA (sIgA) in mucous and other secretions can bind to the pathogen, and in the cases of many viruses and bacteria, neutralise them Neutralisation is the process of coating a pathogen with antibodies, making it physically impossible for the pathogen to bind to receptors and enter host cells Neutralising antibodies are the basis for the disease protection offered by vaccines Vaccinations for diseases that commonly enter the body via mucous membranes, such as influenza, are usually formulated to enhance IgA production. Gut mucosa - Mucosal barrier integrity physically stops pathogens from entering the body - The mucosal barrier is formed due to the tight junctions between the epithelial cells of the mucosa and the presence of the mucous on the cell surface - In the gut, lymphoid tissue is dispersed in gut-associated lymphoid tissue (GALT) and Peyer’s patches - Secretory IgA (sIgA) is the dominant antibody class in mucosal secretions - sIgA protects against the adhesion of pathogens and their penetration into the intestinal barrier. Immune Response to Viruses Interferons, natural killer (NK) cells, and phagocytes prevent the spread of viruses in the early stages of infection. Specific antibodies and complement proteins participate in viral neutralisation and can limit the spread and reinfection. Adaptive immunity is crucial for protecting the body against viruses, including CD8+ T cells, which kill infected cells, and CD4+ T cells, which serve as the dominant effector cell population in response to many virus infections. Immune Response to Viruses When a virus infects a person (host), it invades the cells of its host in order to survive and replicate (intracellular pathogen) Intracellular peptides (including viral peptide) is displayed by MHC class I on cell surface Cytotoxic CD8 T cell will recognise viral peptide with its T cell receptor (TCR) Each cytotoxic T cell has TCRs that can specifically recognise a particular antigenic peptide bound to an MHC molecule The T cell releases to kill the infected cell and, therefore, prevent survival of the invading virus Immune Response to Viruses Viruses are highly adaptable and have developed ways to avoid detection by T cells. Some viruses stop MHC molecules from getting to the cell surface to display viral peptides. If this happens, the T cell doesn’t know there’s a virus inside the infected cell. However, another immune cell (NK cell) specialises in killing cells that have a reduced number of MHC class I molecules on their surface When the NK cell finds a cell displaying fewer than normal MHC molecules it releases toxic substances, in a similar way to cytotoxic T cells, which kill the virally- infected cell. Immune Response to Viruses: How cytotoxic cells kill virus-infected cells Cytotoxic factors are stored inside compartments called granules, in both cytotoxic T cells and NK cells. One of these mediators is perforin, a protein that can make pores in cell membranes. Enzymes called granzymes are also stored in the granules. Granzymes enter target cells through the holes made by perforin. Once inside the target cell, granzymes initiate a process known as programmed cell death (apoptosis), causing the target/infected cell to die. Another released cytotoxic factor is granulysin, which directly attacks the outer membrane of the target cell, destroying it by lysis. Cytotoxic cells also newly synthesise and release other proteins, called cytokines, after making contact with infected cells. Cytokines e.g. interferon-ɣ and tumour necrosis factor-⍺ transfer a signal from the T cell to the infected, or other neighbouring cells, to enhance the killing mechanisms. Immune Response to Viruses Virally infected cells produce and release small proteins called , which play a role in immune protection against viruses. Interferons prevent replication of viruses, by directly interfering with their ability to replicate within an infected cell. They also act as signalling molecules that warn nearby cells of a viral presence – this signal makes neighbouring cells increase the numbers of MHC class I molecules surface expression. Immune Response to Viruses Antibodies are proteins that specifically recognise invading pathogens and bind (stick) to them. This binding serves many purposes in the eradication of the virus: Immune Response to Viruses Immune Response to Bacteria Neutralising antibodies are produced if the bacterial pathogenicity is due to a toxin. Opsonising antibodies are produced as they are essential in destroying extracellular bacteria. The complement system is activated especially by gram-negative bacterial lipid layers. Phagocytes kill most bacteria by using positive chemotaxis, attachment, uptake, and, finally, engulfing the bacteria. CD8+ T cells can kill cells infected by bacteria. Immune Response to Bacteria Complement proteins assist in bacterial killing via three pathways, the classical complement pathway, the alternative complement pathway or the lectin pathway. Complement pathway Activation from bacterial infection Classical pathway Binding of antibodies to the surface of the target bacteria. Complement C1 molecule binds to the Fc region of the antibody, and initiates a cascade leading to formation of a membrane attack complex (MAC) on bacterial surface à causing bacterial lysis. Alternative pathway Does not require antibody. In this pathway, complement C3 directly bind to bacteria and activate downstream components in the complement cascade à formation of MAC à lysis of the bacteria. Lectin pathway Mannan-binding lectin (MBL) binds to proteins containing mannose residues that are found in some types of bacteria (such as Salmonella spp.). Once bound, MBL forms a complex with an enzyme that participates in forming MAC. Effector functions from complement activation: 1) Formation of membrane attack complex (MAC) à lysis of bacteria 2) Formation of opsonin (C3b, C4b) à binds on bacteria à enhance phagocytosis of bacteria 3) Formation of anaphylatoxins (C5a, C3a) à recruitment & activation of WBCs (neutrophils) Immune Response to Bacteria Complement and antibodies bind to the surface of bacteria by a process called opsonisation. Activated phagocytes engulf and destroy opsonised bacteria by a process called phagocytosis. Opsonisation allows killing of Gram-positive bacteria (e.g. Staphylococcus spp.) that are resistant to killing by MAC. Phagocytosis bacteria are killed by various processes that occur inside the cell, and broken into small fragments by enzymes. Phagocytes present the fragments on their surface via MHC class II molecules. Immune Response to Bacteria Circulating recognise the bacterial fragments via T cell receptor (TCR) and begin to produce proteins called. Two major groups of helper T cells are known as and cells. These cell types differ in the types of cytokine they secrete. Th1 cells predominantly produce , which promotes. Th2 cells produce mostly ( ), which promotes by activating. B cells can differentiate into plasma cells and secrete antibodies. Immune Response to Bacteria Some bacteria engulfed during phagocytosis avoid the killing mechanisms of the phagocyte to survive inside cells. Macrophages are a common targets for intracellular bacteria (e.g. Salmonella spp., M. tuberculosis) that live inside cell compartments. These bacteria cannot be detected by complement or antibody but, instead, are eliminated using a cell-mediated response. Infected macrophages present bacterial peptides on their cell surface using MHC class II molecules. This mechanism is called antigen presentation. A helper T cell surveys MHC class II molecules with its T cell receptor (TCR). If a bacterial peptide is presented, the Th1 cell releases IFN-ɣ. IFN-ɣ stimulates killing mechanisms, (such as production of lysozyme) inside the infected macrophage to digest and destroy the invading bacterium. IFN-ɣ also increases antigen presentation by cells, making the bacterium more visible to the immune system and more prone to attack. Immune Response to Fungi The innate immunity to fungi includes defensins and phagocytes. CD4+ T-helper cells are responsible for the adaptive immune response against fungi. Dendritic cells secrete interleukin-12 (IL-12) after ingesting fungi, and IL-12 activates the synthesis of interferon-ɣ, which activates cell-mediated immunity. Recognition of fungi by innate immune system Most fungi are detected and destroyed by phagocytes (e.g. dendritic cells and macrophages) through the recognition of fungal PAMP by pattern-recognition receptors (PRRs). Killing of fungi can occur intracellularly through phagocytosis, or extracellularly through release of antimicrobial peptides (e.g. defensins) and reactive oxygen species (ROS). Complements deposited on fungal surfaces can mediate fungal killing directly (via MAC formation) and at the same time activate other immune cells (via chemo attractants C3a and C5a) and opsonisation and phagocytosis (via opnosins C3b and C4b). Adaptive immune response in fungi infection DCs are also involved in the processing and presentation or cross-presentation of fungal antigens to CD4+ and CD8+ T cells respectively, as well as the secretion of cytokines to shape T cell responses. Th1, Th17 and CD8+ T cells can protect against fungal infection, while Th2 cells are considered detrimental during antifungal defence. Production of antibodies (B cell activation) also contribute to anti-fungal immunity. Effector functions in clearing fungi infection Immune Response to Parasites Parasitic infection stimulates various mechanisms of immunity due to their complex life cycle. Both CD4+ and CD8+ cells protect against parasites. Macrophages, eosinophils, neutrophils, and platelets can kill protozoa and worms by releasing reactive oxygen radicals and nitric oxide. Increased eosinophil number and the stimulation of IgE by Th2 CD4+ T cells are necessary to kill intestinal worms. Inflammatory responses also combat parasitic infections. Immune response to protozoan parasites: For protozoa, IL-12 is produced by phagocytic cells and induces the production of IFN-γ by NK cells and T cells. This early production of IFN-γ may help control infection by immediately activating macrophages. In addition, IL-12 and IFN-γ favour the development of parasite-specific Th1 cells, in addition to inducing the production of high levels of IFN-γ by already differentiated Th1 cells. Immune response to helminth: Helminth antigens do not induce the production of IL-12; instead, IL-4 is produced. IL-4, in turn, activates TH2 cells to produce IL-10; IL-10 further inhibits the production of IL-12 via a negative-feedback mechanism In addition to other cytokines involved in a proinflammatory response. Infection with helminths result in high levels of IgE and eosinophils induced by TH2 cytokines. Vaccination The principle of vaccination relies on the immune system ability to remember past infections i.e. immunological memory Vaccines contain killed pathogens, or extracts from pathogens, or modified strains of pathogens that are no longer harmful (unable to cause disease). For example, the MMR vaccine contains weakened (the technical term is ‘attenuated’) variants of the three viruses that cause measles, mumps and rubella. Giving MMR vaccine stimulate the immune system to produce antibody and immunological memory against viruses causes measles, mumps and rubella. Principle of vaccination Principle of Vaccination Principle of Vaccination The antigens used in vaccine (weakened organism or its inactive parts) will not cause disease in the person receiving the vaccine. Vaccination will stimulate primary immune response à result in formation of immune memory cells (memory B cells, memory T helper cells, memory T cytotoxic cells). Memory cells remain circulating in the blood for a long time and allow for a rapid secondary immune response. Subsequent exposure to the specific organism, result in secondary immune response (recognition of the same antigen by memory cells). Secondary immune response is very quick, meaning that the infection can be eliminated before the number of pathogen increases and cause disease. THE END [email protected]

Infections and Immune Response PDF

Document Details

Tags

Related

Summary

Full Transcript