Humoral Immunity PDF

FUNDAMENTALS OF IMMUNOLOGY HUMORAL IMMUNITY DR NUR AYUNIE ZULKEPLI Centre for Medical Lab. Technology Studies Faculty of Health Sciences UiTM Puncak Alam LECTURE OBJECTIVES 1. Describe the compo...

FUNDAMENTALS OF IMMUNOLOGY HUMORAL IMMUNITY DR NUR AYUNIE ZULKEPLI Centre for Medical Lab. Technology Studies Faculty of Health Sciences UiTM Puncak Alam LECTURE OBJECTIVES 1. Describe the components of humoral immunity 2. Explain the relationship of B lymphocytes, plasma cells, memory cells. 3. Describe the major steps involve in the activation, proliferation, and differentiation of B-cells in antibody – mediated immunity. 4. Differentiate between the 5 classes of Ab.  Overview of Immune System IMMUNE SYSTEM Innate immunity Adaptive immunity Immediate response to wide Slow and delayed response to array of substances specific antigen External defenses T-lymphocytes B-lymphocytes Skin and mucosal Internal defenses (cell-mediated (humoral immunity) Membranes & barriers immunity) Cells Chemicals Physiologic responses Plasma cells (e.g., macrophages, (e.g., interferon, (e.g., inflammation, (synthesize and NK cells) complement) fever) release antibodies) Mechanism Of Adaptive Immune Response CELL MEDIATED IMMUNITY HUMORAL IMMUNITY  INTRODUCTION Mediated by antibodies which are produced by activated B cells. o Antibodies recognize the microbial antigen, neutralize the infectivity, and target the microbes to other effector system for degradation.  The developmental process that result in production of plasma cells and memory B cells can be divided into three broad stages: 1. Generation of mature, immunocompetent B cells (maturation), 2. Activation of mature B cells when they interact with antigen, 3. Proliferation & differentiation of activated B cells into plasma cells & memory B cells.  1. B CELLS B = bone marrow Majority accumulate at specific sites known as the germinal center which include the white pulp of the spleen and the cortex of the lymph node Humoral immunity involves the activation of B cells into plasma cells Plasma cells produce antibodies Released to blood and lymphatic fluid to exert its biological functions 8  B-CELL RECEPTORS (BCRS) Antigen-specific receptor Two identical heavy chains and two identical light chains connected by disulfide bonds into a basic “Y” shape Two antigen-binding sites = binding of specific pathogen epitopes to initiate the activation process. They can interact with epitopes on free antigens or with epitopes displayed on the surface of intact pathogens. BCRs do not require antigen presentation with MHC 9  2. ACTIVATION OF B CELLS Activation of B cells occurs through different mechanisms depending on the molecular class of the antigen. 1. T Cell-independent Activation of B cells - direct binding to polysaccharides, lipopolysaccharides, and other nonprotein antigens - without antigen processing and presentation to T cells 2. T Cell-dependent Activation of B cells - requires the B cell to function as an APC, presenting the protein epitopes with MHC II to helper T cells T CELL-INDEPENDENT (TI) ACTIVATION OF B CELLS The TI pathway is activated by repetitive epitopes on the surface of a pathogen, which heavily crosslink the BCRs on the surface of the B cell. Results in B cell activation, maturation, and the generation of short-lived plasma cells, which primarily produce IgM Does not result in the production of memory B cells. No secondary response to subsequent exposures to T-independent antigens.  T CELL-DEPENDENT (TD) ACTIVATION OF B CELLS T cell-dependent activation can occur either in response to: 1. free protein antigens or 2. to protein antigens associated with an intact pathogen  T CELL-DEPENDENT ACTIVATION OF B CELLS Once internalized inside the B cell, the protein antigen is processed and presented with MHC II. The presented antigen is then recognized by helper T cells The TCR of the helper T cell recognizes the foreign antigen, and the T cell’s CD4 molecule interacts with MHC II on the B cell. The coordination between B cells and helper T cells that are specific to the same antigen is referred to as linked recognition.  T CELL-DEPENDENT ACTIVATION OF B CELLS Once activated by linked recognition, TH cells produce and secrete cytokines that activate the B cell and cause proliferation into clonal daughter cells (plasma cell). After several rounds of proliferation, additional cytokines provided by the TH cells stimulate the differentiation of activated B cell clones into memory B cells Plasma cells that lose their membrane BCRs, initially secrete pentameric IgM  T CELL-DEPENDENT ACTIVATION OF B CELLS After initial secretion of IgM, cytokines secreted by TH cells stimulate the plasma cells to switch from IgM production to production of IgG, IgA, or IgE. This process, called class switching or isotype switching, allows plasma cells cloned from the same activated B cell to produce a variety of antibody classes with the same epitope specificity.  3. PROLIFERATION AND DIFFERENTIATION OF B CELLS Plasma Cells Activated B cells will then multiply rapidly by cell division, cloning itself (population of identical cells) Activated B cells turn into plasma cells these produce lots of antibodies, < 1000/sec The number of plasma cells goes down after a few weeks Antibodies stay in the blood longer but eventually their numbers go down too. Memory B Cells Some of the activated B cells with remains in the body as memory cells. Memory cells will divide rapidly as soon as the antigen reintroduced. the pathogen/infection infects again is destroyed before any symptoms shows CD4 ANTIBODY  INTRODUCTION Antibodies – a specific protein produced by Plasma cell (B-lymphocytes producing Ab) in response to an antigen Members of the class of proteins called immunoglobulins When the body encounters a pathogen for the first time, B cells produce specific antibodies bind to epitopes of antibodies that specifically recognize specific antigens antigen associated with that Able to combine specifically with antigen, like ‘lock and key’ particular pathogen. to forms antigen-antibody complexes ANTIBODY BASIC STRUCTURE (1) Consists of four protein chains held together by disulfide bonds The two largest chains are identical to each other and are called the heavy chains The two smaller chains are also identical to each other and are called the light chains Joined together, the heavy and light chains form a basic Y-shaped structure  ANTIBODY BASIC STRUCTURE (2) Functional components 1. Fab region (“fragment, antigen binding”)Part that bind to antigen a. Variable region Region that changes to various structures depending on differences in antigens. Give the antibody its specificity for binding antigen. b. Constant region Determines the mechanism used to destroy antigen. Antibodies are divided into different classes based on their unique constant region structure of the heavy chain and immune function. 2. Fc region (“fragment, crystallizable”) Part that activate the immune system The site of complement factor binding and binding to phagocytic cells Fc receptors during antibody-mediated opsonization. FIVE KINDS OF ANTIBODIES IGG Percentage in plasma: 70-75% of total immunoglobulin Location: All body fluids, Secreted in high quantities in secondary exposures Structure: Monomer Number of Fab sites: 2 4-fold rise or fall indicates active Function: infection A single positive sample indicates  Neutralize microbes and toxins past exposure  Opsonize antigens for phagocytosis  Activate the complement Special abilities:  Smallest. Can penetrates efficiently into tissue spaces and is the only antibody class with the ability to cross the placenta and protecting the developing fetus. IGM Percentage in plasma: 5% to 10% Location: Blood and lymph, Secreted initially during primary infection Structure & Number of Fab sites: : Pentamer (10) Function: Presence in newborn means infection Single positive sample in serum or  Neutralization, agglutination, and complement activation. CSF indicates recent or active  The monomer form serves as the B-cell receptor. infection Used to detect early phase of Special abilities: infection  First antibody produced and secreted by B cells during the primary and secondary immune responses.  Biggest (pentamer) with high avidity (combined strength of all binding sites). IGA Percentage in plasma: 10% to 15% Location: body secretions Structure & Number of Fab sites: : Dimers (4) Function: Sero-diagnosis of tuberculosis  Neutralization and trapping of pathogens in mucus. Synthicial respiratory virus tests Special abilities:  Protect body surfaces that are exposed to outside foreign substances. IgA from breast milk protect the newborn against infection. IGD Percentage in plasma: 0.25% Location: Present on the surface of B lymphocytes Structure & Number of Fab sites: : Monomer (2) Function:  Is a membrane-bound monomer found on the surface of B cells, where it serves as an antigen receptor. Special abilities:  Acts as a B-lymphocyte activation signal  May play some role in allergic reactions IGE Percentage in plasma: 0.05% Location: Lungs, skin, and mucous membranes. On mast cells and basophils. Serodiagnosis of infectious and Structure & Number of Fab sites: : Monomer (2) non-infectious allergies (e.g., allergic bronchopulmonary Function: aspergillosis, parasitic diseases)  Activation of basophils and mast cells against parasites and allergens. Special abilities:  Stimulate mast cells and basophils to release potent pro-inflammatory mediators.  Stimulate allergic reactions. HOW ANTIBODIES WORK? Antibodies provide immunity in three ways: 1. Preventing pathogens from entering or damaging cells (neutralization & Agglutination) 2. Stimulating removal of pathogens by macrophages and other cells (opsonization, ADCC) 3. Triggering destruction of pathogens (activating complement) 1. NEUTRALIZATION Binding of antibodies on epitopes on the surface of pathogens or toxins, preventing their attachment to cells Some work as antitoxins i.e. they block toxins e.g. those causing diphtheria and tetanus 2. AGGLUTINATING AND PRECIPITATING ANTIGEN Cause agglutination (clumping together) of bacteria making them less likely to spread Involves the cross-linking of pathogens by antibodies to create large aggregates The pentameric structure of IgM provides ten Fab binding sites per molecule, making it the most efficient antibody for agglutination. Monomers like IgG has two Fab antigen-binding sites, which can bind to two separate pathogen cells, clumping them together. When multiple IgG antibodies are involved, large aggregates can also develop. 3. OPSONISATION Fc region Binding of antibodies on epitopes on the surface of pathogens, to assist in phagocyte binding to facilitate phagocytosis Some attach to bacterial flagella making them less active and easier for phagocytes to engulf Phagocytic cells such as macrophages, dendritic cells, and neutrophils have receptors on their surfaces that recognize and bind to the Fc portion of the antibodies Helps phagocytes attach to and engulf the pathogens bounded by the antibodies 4. ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC) Enhances killing of pathogens that are too large to be phagocytosed This process is best characterized by natural killer cells (NK cells), but it can also involve macrophages and eosinophils. ADCC occurs when the Fab region of an IgG antibody binds to a large pathogen; Fc receptors on effector cells (e.g., NK cells) then bind to the Fc region of the antibody, bringing them into close proximity with the target pathogen. The effector cell then secretes powerful cytotoxins (e.g., perforin and granzymes) that kill the pathogen. 5. ACTIVATING COMPLEMENT The complement system is an important component of the innate defenses Among the benefits: 1. promoting the inflammatory response 2. recruiting phagocytes to site of infection, enhancing phagocytosis by opsonization THANK YOU