Basic Immunology (Revision)2

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Transcript of Basic Immunology (Revision)2

Basic Immunology (Revision)Dr Z Makatini

Introduction Immunity (derived from immunitas: Latin for exemption from civic duties and prosecution) Means protection from disease and especially infectious disease Cells and molecules involved in such protection constitute the immune system and The response to introduction of a foreign agent is known as the immune response.

Innate and Adaptive Immunity The normal individual has two levels of defense against foreign agents. The first type is present in neonatal animals and in invertebrates namely natural or innate immunity The second type of immunity is adaptive or acquired immunity and is confined to vertebrates.

Innate and Adaptive ImmunityInnate (natural) responses occur to the same extent however many times the infectious agent is encountered, whereas acquired (adaptive) responses improve on repeated exposure to a given infection.

Innate Immunity The innate responses use phagocytic cells (neutrophils, monocytes, and macrophages), cells that release inflammatory mediators (basophils, mast cells, and easinophils), and natural killer cells. The molecular components of innate responses include complement, acute-phase proteins, and cytokines such as the interferons.

Innate (or natural) immunity Physical barriers are the first line of defense against infection Physiological factors Protein secretions Phagocytic cells

Physical barriers are the first line of defense against infection The skin and mucous membranes provide a continuous surface which must be breached and back this up with mechanical protection through cilia and mucous.

Physiological factors pH, temperature and oxygen tension limit microbial growth. The acid environment of the stomach combined with microbial competition from the commensal flora inhibits gut infection.

Protein secretions into external body fluids Eg lysozyme also help resist invasion. Soluble factors within the body such as complement, interferons and collectins and other "broadly specific" molecules such as C-reactive protein are of considerable importance in protection against infection.

Phagocytic cells Critical in the defense against bacterial and simple eukaryotic pathogens. Macrophages and Polymorphonuclear leucocytes (PMN) can recognize bacterial and yeast cell walls through broadly specific receptors (usually for carbohydrate structures) and this recognition is greatly enhanced by activated complement (opsonin) as well as by specific antibody.

Acute Inflammation The acute inflammatory response is a key part of the innate immune system. Many infections, especially where small wounds are the route of entry, are eliminated by the combination of complement and recruitment of phagocytes, which flow from the acute inflammatory response. A defining aspect of the innate immune system is that it carries no memory of an encounter with a foreign organism.

Question? Which cells and molecules constitute the innate response?

What is an antigen? An antigen is defined as "anything that can be bound by an antibody". This can be an enormous range of substances from simple chemicals, sugars, small peptides to complex protein complexes such as viruses. The small antigens are not, however immunogenic in themselves and need to be coupled to a carrier to elicit an immune response. Such small antigens are referred to as haptens.

What is an antigen? In fact antibodies interact specifically with relatively small parts of molecules. These are known as antigenic determinants or epitopes. Sometimes the epitope is composed of a string of amino acids as might be found in a short peptide, such epitopes are said to be linear. Other epitopes are formed by more complex 3dimensional structures present only as part of a native protein, such epitopes are called conformational

Adaptive immunity The second level of defence increases in strength and effectiveness with each encounter. The foreign agent is recognised in a specific manner and the immune system acquires memory towards it.

Primary Response The first encounter with an antigen is known as the primary response. Re-encounter with the same antigen causes a secondary response that is more rapid and powerful.

Adaptive Immunity Acquired immunity is a useful evolutionary adaptation because it improves the efficacy of the innate immune response by focusing the response to the site of invasion/infection as well as providing additional effector mechanisms that are unique to lymphocytes.

Lymphocytes The difference between innate and acquired immunity lies in the antigen specificity of lymphocytes. This property is conferred upon lymphocytes by the expression of cell surface receptors that recognize discrete parts of the antigen known as antigenic epitopes. The cell surface receptor of B lymphocytes, derived from Bone marrow in mammals or the Bursa of fabricius in chickens, is an immunoglobulin molecule which, when secreted by the B cell, is known as an antibody

Antibodies have two ends. One end interacts with the antigen (the variable part) leaving the other (constant) end free to interact with the immunoglobulin receptors on these cells. During an immune response, a complex lattice of interlinked antigens and antibodies, known as an immune complex, will present an array of constant regions which can activate the various cells mentioned above through ligation of their immunoglobulin receptors.

Immune cells

LYMPHOCYTES These cells have receptors for antigen and confer specificity on an immune response. Lymphocytes express receptors with varying affinity for the antigen in question. The cell with the highest affinity for the most abundant antigen will have growth advantage and will preferentially generate progeny of itself. This process is called clonal expansion and is antigen driven

B lymphocytes Produce antibodies and some soluble mediators called cytokines. They arise in the bone marrow in adult mammals.

Antibodies Antibodies work in three ways. Neutralization. blocking the biological activity of their target molecule e.g a toxin binding to it's receptor Opsonisation. interact with special receptors on various cells, including macrophages, neutrophils, basophils and mast cells allowing them to "recognise" and respond to the antigen Complement Activation. cause direct lysis by complement complement recruitment also enhances phagocytosis

T lymphocytes Arise in bone marrow but mature in the thymus. They do not produce antibody molecules but have surface receptors structurally related to Ig. T cells see antigen in a different way to B cells. They recognize peptide fragments of antigen complexed with cell surface MHC glycoproteins on neighbouring cells. The cell surface glycoproteins encoded by genes in the Major Histocompatibility Complex (MHC) bind fragments of antigen after it has been subjected to antigen processing

T cells There are two sub-types of T cell defined on the basis of function, accessory molecule expression and the type of MHC protein presenting antigen to them. This can be summarized as follows:

Natural killer (NK) cells Are large granular lymphocytes that are cytotoxic in the absence of prior stimulation. NK cells represent a first line of defence to infections, tumour growth and other pathogenic alterations of tissue homoeostasis. NK cells do not express antibodies or T cell receptors at their cell surface. They produce cytokines and express receptors for immunoglobulin. They also possess other receptor molecules which allow them to detect some infected host cells, including tumour cells, virus, or intracellular bacteria-infected cells.

MONONUCLEAR PHAGOCYTES If you inject "vital" dyes into experimental animals they will be taken up by various cell types including macrophages (mf), microglial cells in the CNS, endothelial cells of vascular sinusoids and reticular cells of lymphoid organs. These are the cells of the Reticulo-Endothelial System (RES). These cells all take up dye by pinocytosis. Only cells of the monocyte-macrophage lineage take up large particulate antigens, pieces of tissue, senescent cells, bacteria etc. by phagocytosis

MONONUCLEAR PHAGOCYTES Express receptors for antibody and complement which means that they bind immune complexes, especially if the antibody involved has complement components bound to it (if the antibody has fixed complement), and endocytose/phagocytose these rapidly. They act as scavengers for cell debris and senescent cells (Kupffer cells in the liver bind "old" erythrocytes).

DENDRITIC CELLS Cells of the dendritic cell (DC) lineage are bone marrow derived. In the skin they are known as Langerhans Cells (LC). These cells efficiently process antigen but cannot present it to T cells.

MONONUCLEAR PHAGOCYTES Have been shown to pick up antigen in skin and carry it via afferent lymphatic vessels to lymph nodes. Dendritic cells in lymph are known as "veiled" cells. In lymph nodes the cells, now known as tissue dendritic cells or interdigitating cells, may efficiently present antigen if they encounter the right T cell. In fact these are the best APC - far fewer DC are required to initiate an immune response than any other APC.

These cells have important properties they express a myeloid receptor (CD14) which serves as a recognition molecule for a wide variety of bacterial envelope molecules, such as LPS from Gram -ve organismsand components of Mycobacterial and Gram +ve cell walls. Ligation of this receptor leads to macrophage activation. they can act as antigen presenting cells (APC) for T cells. they are activated by T cell derived cytokines leading to increased phagocytosis and microbicidal activity (increased activity of degradative enzymes, nitrogen and oxygen free radical production and prostaglandins e