MBBS 1st Yr. Lecture Dr. D. Higgins October 9, 2002 – 10:40 AM LT1, G/F, Academic & Administration Block Faculty of Medicine Building

INTRODUCTION TO HEALTH AND DISEASE BLOCK ANTIBODIES AND LYMPHOCYTES The IMMUNE SYSTEM responds to stimulation by external substances called ANTIGENS. Typical antigens experienced during life are: infectious agents (parasites, bacteria, viruses), tumour cells, vaccines, tissue grafts or transfusions. Thus, it is generally believed that the immune system evolved to protect us from two major threats to life: INFECTION and CANCER. The immune system consists of many cells and proteins which interact in complex networks. Many of the major components are congregated together in the LYMPHOID ORGANS (bone marrow, thymus, lymph nodes and nodules) but are also distributed throughout the body tissues and fluids (blood, lymph, secretions). Thus, unlike other physiological systems, the immune system is not defined within discrete organs. The immune system is commonly characterized as having two modes: NON-SPECIFIC and SPECIFIC. The non-specific response (also known as INNATE) is based on a variety of cellular and humoral responses, many of which are very primitive. The specific (or APAPTIVE) response requires ANTIBODIES and LYMPHOCYTES. IMMUNE SYSTEM

INNATE (Non-specific)

Macrophages Complement Chemokines Cytokines etc.

ADAPTIVE (Specific)

Antibodies (humoral immune response)

Lymphocytes (cell-mediated immune response)

However, these three systems interact intimately. Lymphocytes and antibodies regulate the activities each of the other, and also recruit non-specific mechanisms in their fight against invaders. The adaptive immune system has four characteristics which distinguish it from all other physiological systems: 1.

Specificity: it can distinguish very finely between different antigens.

2.

Diversity: the immune system can respond to at least 108 different antigens.

3.

Memory: the immune system “remembers” its encounter with antigens. Second, third etc. encounters are faster and more vigorous than the first. This memory is specific and usually life-long. 1

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Distinction between self and non-self. The immune system aims to protect an individual from all foreign invasion, yet does not destroy self tissues (except under abnormal conditions known as AUTOIMMUNITY). Recognition of self (and everything not so recognized is “non-self”) is based on a highly polymorphic group of proteins found on the surface of cells and called the MAJOR HISTOCOMPATIBILITY COMPLEX (MHC). No two individuals of the same species (except identical twins) have the same MHC proteins.

In today’s lecture I wish to cover some of the basic aspects of the biology of the two major arms of the adaptive immune system: antibodies and lymphocytes. ANTIBODIES “Antibody”: is the activity detected in blood, lymph, plasma or serum following exposure to an antigen. It can be measured by a variety of techniques :Binding of antibody to antigen Agglutination Precipitation Complement activation Neutralization (of toxin, virus etc.) Etc. Most tests for antibody require a second event - e.g. agglutination, precipitation etc. These are generally easier methods than attempting to demonstrate binding to antigen per se. Whatever the assay, it should be possible to show that it is SPECIFIC - i.e. similar activity cannot be seen if a different antigen is tested. Many assays of antibody activity against soluble antigens require the antigen to be linked (sensitized) to a particulate carrier - e.g. erythrocytes or latex beads - so that secondary effects such as agglutination can be visualized. The most sensitive assays of interaction between an antibody and antigen are based on detection using enzyme colour changes (ELISA) or radio-isotopes (RIA). Antibody activity occurs among a group of proteins called IMMUNOGLOBULINS. Immunoglobulins are large, complex, glycoproteins. Human beings possess 5 classes (also called ISOTYPES) of immunoglobulin. The quantitatively predominant and structurally simplest immunoglobulin is called IgG. It consists of two identical heavy (H) chains and two identical light (L) chains, linked by covalent disulphide bonds. The H chains are MW ~55000 each, the L chain ~22500 each, so the total MW is ~155000.

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The combined NH2 terminals of each H-L pair form a specialized site for binding to antigen - so each IgG molecule can bind 2 units of antigen. The COOH terminals are responsible for secondary activities - e.g. complement fixation, membrane transportation. The area of disulphide bonding between the H chains is called the HINGE and allows the molecule to adopt different configurations depending on the alignment of the antigen residues:

The H and L chains are built up of repeating units of + 110 amino acids called domains. The L chain has one VARIABLE (V) domain and one CONSTANT (C) domain. The C domains are common to all light chains, the V domains differ between molecules with different antigen specificity. The H chains have a V and 3 C domains. Each C domain has a different biological function.

The four chains are wrapped around each other to form a tight globular structure. The four other classes of immunoglobulin (IgM, IgA, IgD, IgE) are either similar in structure to IgG (i.e. IgD, IgE) or use polymerization of this basic structure (i.e. IgM, IgA).

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All polymeric immunoglobulins contain J chain (MW = 15,000) and IgA in secretions contains secretory component (MW = 85,000). Secretory component protects the molecule from proteolytic degradation. Different immunoglobulins have different functions and function in different sites of the body. LYMPHOCYTES While antibodies are very important in defense, cells are the basis of immunological reactivity, diversity and specificity and are the source of all immunologically interactive proteins (including the immunoglobulins). All blood cells, all lymphoid cells, and all myeloid cells are the products of a common precursor cell in the bone marrow. This gives rise to lymphoid precursors which further mature either in the THYMUS to T cells or in the BONE MARROW to B cells. B cells mature into plasma cells which produce the immunoglobulins. The B cell is reactive to antigen and carries an antigen receptor which is monomeric IgM and IgD of a single antigen specificity. Maturation from B cell to plasma cell requires antigen stimulation and is under the control of antigen-specific T cells. Maturation of T cells in the thymus is complex and involves selection of cells based on their appropriate antigen receptors and their expression of self MHC. More than 90% of precursor cells that enter the thymus are killed. The mature T cells have 2 main functions. 1.

Regulation and control of immune responses.

2.

Cell-mediated immune responses. The T cell possesses an antigen receptor - the T cell antigen receptor (TCR). The TCR consists of 2 polypeptide chains, each of two domains and a cytoplasmic tail:

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The α/β receptor shown here occurs on 95% of T cells. The other 5% possess a receptor consisting of γ/δ polypeptides; this population of T cells is poorly understood in functional terms. Each T cell carries TCRs of a single antigen specificity. Hence, throughout the lymphoid system, lymphocytes (B or T cells) carry receptors of a single specificity. A group of T or B cells carrying identical receptors is called a CLONE.

POSTSCRIPT: THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) There are two classes of MHC - Class I and class II. We each have 6 class I and 8 class II. These are found on all our cells, but mostly on our antigen presenting cells. The MHC presents peptide fragments of antigen to T and B cells. Each MHC antigen can handle a vast repertoire of peptides (possibly 1000s), i.e. they are not specific to a single peptide. Each of us has a different profile of MHC antigens, therefore a different capacity to recognize and process antigen. The cells which receive antigenic peptides from our antigen presenting cells only recognize such peptides if they are presented by cells with MHC that is identical to the recipient cell. As an example, my antigenpresenting cells cannot present peptides to your T cells as my MHC molecules will be different to yours.

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