Advanced immunology - Lecture notes 1-5 PDF

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Notes taken from Janeway textbook...

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To defend against the great variety of microbes, the immune system has numerous molecular and cellular functions, effector mechanisms, suited to resist different categories of pathogens. Immunological tolerance refers to mechanisms that prevent an immune response from being mounted against the host’s own tissues. Anatomic and chemical barriers are the initial defences against infection. Mucosal surfaces produce a variety of antimicrobial proteins that act as natural antibiotics to prevent microbes from entering the body. Complement contributes to both innate and adaptive immune responses by acting in conjunction with antibodies and targeting foreign organisms in the absence of a specific antibody.

By innate recognition receptors. Sensor cells function to amplify the immune response.

Macrophages can ingest microbes and produce toxic chemical mediators, such as degradative enzymes or reactive oxygen intermediates, to kill them. Macrophages are phagocytic - engulf and kill. Phagocytosis can also be triggered by activation of complement - recognised by phagocytes via complement receptors. Macrophages orchestrate immune responses - induce inflammation, produce inflammatory mediators that activate other immune cells and recruit them into an immune response. Dendritic cells may produce cytokine mediators, including many cytokines that activate target tissues, such as epithelial or other immune cells, to resist or kill invading microbes more efficiently. Dendritic cells continually ingest large amounts of the extracellular fluid and its contents by a process known as macropinocytosis. Process and presents antigens to T cells. Mast cells, eosinophils, basophils release granules containing histamine and proteases, defence against parasitic worms. Innate response is faster but adaptive response is more efficient. Adjuvants are needed to activate innate receptors on various types of sensor cells to help activate T cells in the absence of an infection.

TLRs detect PAMPs derived from extracellular bacteria or bacteria taken into vesicular pathways by phagocytosis. NLRs detect intracellular bacterial invasion.

Inflammation increases the flow of lymph, carrying microbes and cells bearing their antigens to nearby lymphoid tissues, where the adaptive immune response is initiated. After the adaptive response has been generated, inflammation also recruits these effector components to the site of infection. Endothelial cells produce cytokines in response to infection. These alter the adhesive properties of endothelial cells and cause circulating leukocytes to stick to the endothelial cells and migrate between them into the site of infection. Naive lymphocytes not yet activated by antigen. Effector lymphocytes activated and differentiated into fully functional lymphocytes. B cells differentiate into plasma cells and secrete antibodies. TCR are related to BCR but it’s quite distinct in structure and recognition properties. BCR can recognise proteins, glycoproteins and polysaccharides of pathogens. TCR recognise a peptide (protein) epitope derived from a partially degraded protein, bound to MHC. Cytotoxic T cells kill infected cells (virus/intracellular pathogen) bearing the antigen. Helper T cells provide signals (specific cytokines) that activate the functions of other cells, such as B-cell production of antibody and macrophage killing of engulfed pathogens. Regulatory T cells suppress the activity of other lymphocytes and help to limit the possible damage of immune responses. Clonal selection hypothesis Each lymphocyte bears a single type of receptor with a unique specificity. (BCR) Interaction between a foreign molecule and a lymphocyte receptor capable of binding that molecule with high affinity leads to lymphocyte activation. The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical specificity to those of the parental cell. BUT affinity maturation.

Lymphocytes bearing receptors specific for ubiquitous self-molecules are deleted at an early stage in lymphoid cell development and are therefore absent from the repertoire of mature lymphocytes - immunogenic tolerance (clonal deletion). Opsonisation of pathogens by complement facilitates their uptake by phagocytic APC that express complement receptors, this enhances presentation of pathogen antigen to T cells. B cells express receptors for complement proteins that enhance their responses to complement-coated antigens. Key activated complement components are rapidly inactivated unless they bind to the pathogen surface on which their activation was initiated. (Thioester bond cleaved by reaction with water, irreversibly inactivated, stops it from diffusing away from the site of infection and binding to healthy self-cells) C1r and C1s interact noncovalently and form tetramers that fold into the arms of C1q, with at least part of the C1r:C1s complex being external to C1q. C1q binds to lipoteichoic acid (bacterial cell wall), C-reactive protein and Fc regions of antibodies. Membrane-attached protein, DAF/CD55, competes with Factor B for binding to C3b on cell surface and can displace Bb on convertase already formed. Convertase formation can also be prevented by cleaving C3b to iC3b (inactive), by Factor I in conjunction with MCP/CD46. S. aureus has Spa protein binds to the Fc regions of Ig and interferes with the recruitment and activation of C1. SAK cleaves Ig bound to the pathogen membrane preventing complement activation and avoiding phagocytosis. Complement activation: LP - Initiated by MBL/ficolins, associated MASPs trigger cleavage of complement CP - C1q (recognition), associated C1r and C1s (ser proteases) cleave complement AP - spontaneous hydrolysis and activation of C3...