Lecture 2.2 - The Innate Immune System PDF

Factors determining the outcome of host-pathogen relationship: Key definitions: ◦Immune system - cells and organs that contribute to immune defences against infectious and non-infectious conditions (self vs non-self) ◦Infectious disease - when the pathogen succeeds in evading and/or ove...

Factors determining the outcome of host-pathogen relationship: Key definitions: ◦Immune system - cells and organs that contribute to immune defences against infectious and non-infectious conditions (self vs non-self) ◦Infectious disease - when the pathogen succeeds in evading and/or overwhelming the host’s immune defences Roles of the immune system: The immune response: The innate barriers: Innate barriers - microbiota (commensals): ◦The skin: ‣ Staphylococcus aureus ‣ Staphylococcus epidermis ‣ Streptococcus pyogenes ‣ Candida albicans  ◦The nasopharynx: ‣ Streptococcus pneumoniae ‣ Neisseria meningitidis ‣ Haemophilus species ◦All can become pathogenic Clinical problems start when: ◦Normal flora is displaced from its normal location to sterile location. ◦Breaching the skin integrity: ‣ Skin loss (burns) ‣ IV lines ‣ Surgery ‣ Skin diseases ‣ Injection drug users ‣ Tattooing/body piercing ◦Fecal-oral route ‣ Foodborne infection ◦Fecal-perineal-urethral route ‣ Urinary tract infection (women) ◦Poor dental hygiene/dental work ‣ Dental extraction ‣ Gingivitis ‣ Brushing/flossing - common cause of harmless bacteraemia ◦Serious infections in high risk patients ‣ Asplenic (and hyposplenic) patients ‣ Patients with damaged or prosthetic valves ‣ Patients with previous infective endocarditis ‣ -> Prevention and advice to patients (NICE) ◦Normal flora overgrown and becomes pathogenic when host becomes immune-compromised ‣ Diabetes ‣ AIDS (not an infection) ‣ Malignant diseases ‣ Chemotherapy (Muscositis) ◦When normal flora in mucosal surfaces is depleted by antibiotic therapy: ‣ Intestine -> severe colitis (Clostridium difficile) ‣ Vagina -> thrush (Candida albicans) The immune response:  Initial immune response: ◦The initial immune response occurs if the pathogen overcomes the innate barriers and enters the body. ‣ Macrophages have pattern recognition receptors (PRRs) on their surface which recognise the pathogen associated molecular patterns (PAMPs) on an invading pathogen and phagocytosed them. ‣ Macrophages release cytokines which recruit other cells to the site of infection, for example monocytes (precursors of macrophages) and neutrophils ‣ Cytokines also have other functions including causing inflammation Cytokines cause inflammation which results in: ◦Vasodilation ◦Vascular permeability ◦Mast cell degranulation ◦Clotting system Microbes: PRRs and PAMPs: Interaction between microbial PAMPs and their PRRs in innate cells: Action of macrophage, monocyte, neutrophils and other cell-derived cytokines such as TNF alpha, IL-1, IL-6 and IL-8: ◦Systemic actions: ‣ Liver: C reactive protein (CRP) acts as opsonin (IL_6) Mannose binding lectin (MBL -> complement activation) ‣ Blood vessels:  Neutrophil recruitment (IL-8) ‣ Hypothalamus: Increased body temperature (IL-1) ◦Local inflammatory actions: ‣ Blood vessels Vasodilation Vascular permeability ◦NOTE: TNF alpha reactive which is also released from these cells can do all of the above. Initial immune response: ◦Dendritic cells phagocytose and travel in the blood or the lymphatic system to present the antigen from the pathogen to the T and B cells which initiates the specific adaptive immune response. ◦The presence of the pathogen leads to the activation of the complement system via the lectin pathway or the alternative pathway. The complement system: ◦Complement pathways ◦20 serum proteins ◦Most important C1-C9 ◦3 activating pathways ‣ Classical pathway Initiated by antibody-antigen Reaction (membrane attack complex) ‣ Alternative pathway Initiated by cell surface microbial Constituents (endotoxins on E.coli) ‣ Mannose binding lectin pathway Initiated when MBL binds to mannose-containing residues of proteins found on many microbes (Salmonella spp.) Candida albicans Main phagocytes:  Other key cells of innate immunity: Microbes: Examples of opsonins: ◦Complement proteins: ‣ C3 ‣ C4 ◦Antibodies ‣ IgG ‣ IgM ◦Acute phase proteins ‣ C-reactive protein (CRP) ‣ Mannose-binding lectin (MBL) ◦-> Essential in clearing encapsulated bacteria: ‣ Neisseria meningitidis ‣ Streptococcus pneumoniae ‣ Haemophilus influenza b Clearance of opsonised pathogen: ◦Complement can “punch holes” in the cell membrane of the pathogen leading to death. ◦Phagocytes such as macrophages and neutrophils have Fc receptors on their surface which bind to the Fc region of an antibody which has formed a complex with an antigen. ‣ This leads to internalisation of the pathogen which has been coated in antibody ‣ The macrophage produces reactive oxygen species to destroy the pathogen  Phagocytosis: killing of pathogens: Phagocyte intracellular killing mechanisms: ◦Oxygen-dependent pathway (respiratory burst) ‣ Toxic O2 products for the pathogens: Hydrogen peroxide, Hydroxyl radical, Nitric oxide, Singlet oxygen, Hypohalite ◦Oxygen-independent pathways: ‣ Lysozyme ‣ Lactoferrin or transferrin ‣ Cationic proteins (cathepsin) ‣ Proteolytic and hydrolytic enzymes ‣ NETs (neutrophil extracellular traps) NETosis: ◦The process by which neutrophils externally trap pathogens ‣ Release of decondensed chromatin and granule contents into the extracellular space ◦Can be used as a mechanism of neutrophil cell death ◦Commonly used to deal with pathogenic insult Summary of the innate immune response: The innate immune response: Clinical problems start when phagocytosis is reduced: ◦Decrease spleen function ‣ Asplenic patients (no spleen) ‣ Hyposplenic patients (reduced spleen function) ◦Decrease neutrophil number (