Fundamentals of Immunology PDF

als of Immunolog y WHAT IS IMMUNOLOGY? Protection against infectious diseases caused by microorganisms ◦ Bacteria ◦ Viruses ◦ Protozoa and Fungi ◦ Parasites Protection against cancer Pathogen transmission THE IMMUNE SYSTEM https://doi.org/10.1016/B978-0-12-805417-8.000...

als of Immunolog y WHAT IS IMMUNOLOGY? Protection against infectious diseases caused by microorganisms ◦ Bacteria ◦ Viruses ◦ Protozoa and Fungi ◦ Parasites Protection against cancer Pathogen transmission THE IMMUNE SYSTEM https://doi.org/10.1016/B978-0-12-805417-8.000 -9  BARRIERS PHYSICAL ◦ Skin SECRETIONS ◦ contain molecules that can neutralise bacteria ◦ Saliva ◦ Tears MUCOSAL TISSUE ◦ Lungs, airways and gut – coated with mucus ◦ Trap potential pathogens ◦ Mobile ciliate hair transports ‘contaminants’ out TISSUE RESIDENT IMMUNE CELLS ◦ Skin, mucosal surfaces and airways contain immune cells that fight pathogens Organisation of the immune system Comprised of tissues and cells throughout the body Primary lymphoid tissue Bone marrow: Pluripotent hematopoietic stem cells – source of most cells in the immune system Thymus: T cells produced in the bone marrow must travel to the thymus to complete their maturation Secondary lymphoid tissue Lymph node Spleen  Primary lymphoid tissue - Thymus The Thymus is an encapsulated lymphoid organ where T cell maturation and differentiation occurs. Its cortex is rich with immature T cells, while its medulla contains sparse mature T cells  IMMUNE TISSUES Secondary lymphoid tissue ◦ lymph nodes, ◦ spleen, ◦ mucosa-associated lymphoid tissue ◦ Sites important for adaptive immune response and contain lymphocytes ◦ Lymphatic system – systems of vessels draining fluids from body tissues ◦ Lymph nodes – monitor lymph for signs of infection ◦ Mucosa-associated lymphoid tissues important for Anatomy of Immunology. Primary and secondary lymphoid mucosal immune response in gut and airways tissues. ◦ Spleen serves as ‘ lymph node’ for the blood  Secondary lymphoid tissue - Lymph node A Lymph node is an encapsulated, trabeculated lymphoid organ that has many afferent and one or more efferent branches. It functions as a filter, as storage and activation centre for B and T lymphoid cells, and a centre for antibody production Secondary lymphoid tissue - Lymph node 3 main components of the lymph node: ◦ Follicle: site of B cell storage and proliferation ◦ Medulla: composed of medullary cords and sinuses acting as a filter ◦ Paracortex: location of T cells Secondary lymphoid tissue - Spleen Anatomic structures ◦ Sinusoids: are composed of elongated channels with fenestrated membrane and adjacent macrophages, functioning as filters ◦ Periarterial lymphatic sheath (PALS): white pulp  houses T cells. ◦ Follicle: white pulp houses B cells ◦ The spleen contains two major units: white pulp and red pulp. ◦ The white pulp is composed of lymphatic tissue and contains mainly white blood cells involved in the initiation of the adaptive immune response. ◦ White pulp throughout the spleen is surrounded by red pulp. The red pulp is composed of splenic cords and a large volume of venous sinuses. IMMUNE CELLS  Immune system overview Innate immunity: the physical and biochemical barriers both inside and outside the body, as well as immune cells that have specific functions and responses ◦ No memory ◦ Does not involve antibodies ◦ Does involve complement system Acquired/adaptive immunity: the specific response to infectious agents (e.g. pathogens) that depends on the antigen presentation, recognition and the antigen- antibody response ◦ Has memory ◦ Involves antibodies  Overview: Innate Immune System Non-specific immune response that will indiscriminately attack invaders regardless of their nature (virus, bacteria, parasite…) Has no memory, which means that repeated exposures to the same pathogen will produce the same response as the first exposure. First line of defence Most pathogens enter the body via the respiratory system, gut or genitourinary tract. The skin is an effective physical barrier Other defences include: Mucus  trap and remove particles and small organisms Cilia lining the trachea and main bronchi  catch and remove pathogens Reflexes  Coughing, sneezing and elevation of body temperature serves to remove and destroy pathogens  Innate immunity – cell types 2 primary cell types involved in the innate immune response: Natural killer (NK) cells Professional phagocytes Recognize virally infected and malignant changes on the Phagocytic cells act to engulf debris, infectious particles and surface of cells as well as antibody-coated (opsonised) bacteria and destroy and remove it from the body. cells. Neutrophils are efficient phagocytes. NK cell binding to a target cell leads to release of cytolytic and cytotoxic granules that kill target cells by apoptosis Macrophages are recruited to site of infection.  INNATE IMMUNITY - CELLS Cellular and humoral (blood-borne) components Mast cells and basophils ◦ Secrete histamines – inflammatory mediators ◦ Mast cells are tissue resident ◦ Basophils are found in the blood ◦ Key role in allergic response (hypersensitivity type I) Mast cell Basophil Phagocytes – Neutrophils and Macrophages ◦ Respond to signs of infection (i.e. inflammation) in the tissue ◦ Recognition of microorganisms by pathogen-associated molecular patterns (PAMPs) on the microbial surface ◦ Recognition by innate receptors – pattern recognition receptors (PRRs), e.g. Toll-like receptors (TLRs) ◦ Neutralisation and phagocytosis Neutrophil Macrophage Phagocytes in the body Functions of Phagocytes ◦ Enter an infected site from circulation ◦ Bind, engulf and kill a wide variety of microbial agents ◦ Produce immunomodulatory substances, e.g. cytokines, chemokines, which regulate the immune response ◦ Act as first line of defense against infection  Cell surface proteins of immune cells Immune cells have cell surface proteins: Macrophages: MHC II, B7, CD40, CD14 These cell surface proteins have distinct functions, supporting cell interaction and communication. Examples are: Macrophages (APC) express MHC II MHC II in complex with antigenic peptide bind T cell TCR  The non-cellular (humoral) innate immune response The humoral innate immune response is a defence mechanism that attacks pathogens in a rapid, non-specific manner Type What is it? Actions Complement Plasma proteins Destroy cell membranes (lytic pore). Attract phagocytes & stimulate activity of other immune cells.(anaphylatoxins C3a, C5a). Promote phagocytosis (Opsonins, C3b/iC3b, C4b). Fever Elevation of body Release of pyrogens increase body temperature via temperature cyclooxygenase-2 (COX-2) Inflammation Mast cells release pro- Blood vessels dilate, allowing influx of immune cells and inflammatory cytokines & fluid (plasma). Symptoms are pain, swelling, redness and chemokines heat  Complement The complement system consists of a number of small proteins in the blood that interact with the immune system to play a role in humoral immunity and inflammation Complement is activated via 3 pathways: Classical pathway –requires antibodies, typically IgG and IgM, bound to antigens Alternative pathway – requires presence of antigen, such as endotoxin, or a foreign surface, such as a bacterial surface Lectin pathway – requires presence of bacterial carbohydrates  Adaptive immune system humoral and cell-mediated immunity Two categories: ◦ Cell-mediated: relies on direct contact between immune cells and the pathogen ◦ Humoral: an antibody-mediated response that relies on proteins (antibodies) to convey signals between cells of the immune system Specific immune response Immune memory ◦ Repeated exposure to the same pathogen will Pathogen produce an enhanced response to that same pathogen the next time it is encountered.  T cells and Bcells T cell B cell Important functions in acquired immunity: T cells: provide cell-mediated activation of B cells B cells: make antibodies and other immune cells (T helper or CD4+ T cells) IgM, IgG, IgD, IgE, IgA or direct cell killing (cytotoxic or CD8+ T cells)  ADAPTIVE IMMUNITY - RECEPTORS T CELLS carry T cells receptors (TCRs) B CELLS carry B cell receptors (BCRs) ◦ Variable structures allow high degree of specificity T cells interact with another set of receptors – the MHC ◦ Major histocompatibility complex (MHC), play an important role in Cytotoxic T cell (CD8+) adaptive immunity ◦ MHC class I receptors are displayed on all nucleated body cells ◦ MHC class II receptors are only expressed on antigen-presenting cells (APCs) ◦ Both MHC class I and II interact with TCRs Helper T cell (CD4+) CELLULAR VS HUMORAL ADAPTIVE RESPONSE Cellular adaptive response – effected by cytotoxic T cells (CD8+) ◦ Targets infected body cells (e.g. viruses) ◦ Targets malignant cells (e.g. cancer) Humoral adaptive response – effected by B cells (antibodies) ◦ Targets pathogens or antigens that are free in the blood stream or on mucosal surfaces ◦ T helper cells (CD4+) are important ‘gatekeepers’ ◦ Once activated helper T cells can shape the subsequent immune response by secreting effector molecules (e.g. cytokines) ◦ Controlling the activation of other cell types T cell (left); Antigen presenting cell (right)  Cell surface proteins of immune cells Immune cells have cell surface proteins: T helper cells: CD4, TCR, CD3, CD28, CD40L Cytotoxic T cells: CD8, TCR, CD3 These cell surface proteins have distinct functions, supporting cell interaction and communication. Examples are: T cell TCR binds and interacts with MHC class I or II T helper cells binds and interacts with a B cell via CD40L on its surface and CD40 on the B cell  MHC I and II An important part of acquired immunity is the major histocompatibility complex or MHC MHC I and MHC II have distinct functions The major histocompatibility complex (MHC) is a protein complex encoded by human leukocyte antigen (HLA) genes MHC I is encoded by HLA-A, HLA-B, and HLA-C. It is expressed on nucleated cells. MHC II is encoded by HLA-DR, HLA-DP, and HLA-DQ. It is expressed on antigen presenting cells (APCs).  T cell differentiation T cells play an important role in cell-mediated acquired immunity T cell precursor cells from the bone marrow travel to the thymus where they differentiate into CD8+ and CD4+ cells. These cells then travel to the lymph node were they further differentiate: CD8+ cells: differentiate into cytotoxic T cells CD4+ cells: differentiate into helper T (Th) cells T helper cell subsets Th1 – guide adaptive response towards a cellular profile (Cytotoxic T cells, intracellular pathogens) Th2 – guide adaptive response towards a humoral profile (B cells, extracellular pathogens) Th17 – recently identified, response againist extracellular bacteria and fungi, IL-17 T regs - control the immune response to self and foreign particles (antigens)  Humoral acquired immunity- B cells The role of B cells in acquired immunity ◦ The primary and secondary antibody response ◦ The body produces B cells that express a wide variety of surface receptors (BCRs) of IgD or IgM class that recognize a wide array of antigens  Adaptive immune system Humoral adaptive immune response relies on the recognition of antigens by antibodies Antigen: a substance that can elicit the production of a specific antibody and can specifically bound by that antibody Antibody: proteins that are classified as immunoglobulins, are produced by plasma cells (B cell derived), and are defined functionally according to their class IgM, IgG, IgE, IgD, IgA  Antibodies Antibody structure: ◦ The Fab fragment binds to antigens with the variable components of the L and H chains recognizing distinct antigens. ◦ The Fc fragment determines the antibody class ◦ The Fc fragment of IgG and IgM fixes complement. Antibody function: Opsonisation – the antibody promotes phagocytosis (via Fc receptors on phagocytes recognizing antibody- antigen complexes and binding antibody via its Fc fragment). Neutralisation – the antibody inhibits the antigen (e.g. bacterial adherence by binding and blocking a surface protein on bacteria required for adhering to cell surfaces). Complement activation – antibody-antigen complexes bind C1q within the C1 complex and trigger the classical pathway of complement. Classical pathway activation creates opsonins C4b and also C3b and amplification via the alternative pathway.  Primary and secondary antibody response Primary response: ◦ B cells proliferate into plasma cells, secrete antibodies, create memory B cells ◦ IgM Secondary response: ◦ Antigen-specific memory, B cells secrete antibodies, isotype switching ◦ IgG ◦ Higher affinity, higher titre (serum concentration)  CYTOKINES CYTOKINES are immune mediators ◦ The downstream effects of a particular cytokine occurs through its high-affinity binding of its receptor expressed on the surface of a target cell. ◦ Stimulate or inhibit the differentiation, proliferation and activity of immune cells ◦ Cytokine mode of action, with specific examples: Receptor engagement triggers intracellular signalling cascades leading to altered gene expression in the target cell, which lead to a biological effect. Resources Reading material: Roitt’s Immunology (online access available on Learning Central) https://www.immunology.org/public-information/bitesized-immunology