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Immunology Notes

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1. Acquired immunity Primary lymphoid tissues are where lymphocytes are generated and matured. Primary lymphoid tissues include:

Bone marrow Thymus gland The bursa of fabricus in birds Ileal Peyers patches in sheep, cattle, pigs, dogs and horses The caecal patch in rabbits.

Secondary lymphoid tissues are where lymphocytes interact with antigen presenting cells (APCs). These include:

Lymph nodes Mucosal-associated lymphoid tissue (MALT) Spleen

Lymphocytes are formed from lymphoid stem cells and blast cells in the bone marrow. These also form natural killer cells. B lymphocytes are responsible for producing plasma cells, and form the humoral immune response. T lymphocytes may be of the CD4+ helper or CD8+ cytotoxic type, and form the cellular immune response. Each type of lymphocyte expresses thousands of identical receptors, unique for a single antigenic peptide.


T lymphocytes

Cytotoxic T lymphocytes (CTLs) express CD8 and are MHC (major histocompatibility complex) class I restricted. They kill cells infected with intracellular pathogens. CTLs work through the effectors IFN-gamma, TNF-beta, TNF-alpha, perforin, granzymes and Fas ligand. Helper T lymphocytes (TH) express CD4 and are MHC class II restricted. Th1 cells are pro-inflammatory. They respond to TNF-alpha, IFN-gamma, and IL12 to activate effectors (such as CTLs) to kill intracellular pathogens. They work through the effectors of IFN-gamma, GM-CSF, TNF-alpha, IL-3, TNF-beta, IL-2 and CD40 ligand. Th2 cells are anti-inflammatory. They stimulate antibody production by B lymphocytes and class switching. They work through the effectors of IL-4, IL-5, IL13, IL-10, TGF-beta, GM-CSF and CD40 ligand.

T cell receptors (TCR) remain more constant than B cell receptors (BCR). The receptors of a single T cell are identical and unique to a single epitope, with variation between T cells. Diversity is essential for coverage by the immune system. Each cell has a single type of binding site on its TCR, and there are around 30,000 identical TCRs on each T cell.

T cell receptors have two forms, either alpha/beta (95%) homodimers, or gamma/delta (5%, although more common in cattle) heterodimers. Alpha/beta homodimers are classical MHC class I or II restricted and membrane bound. Gamma/delta heterodimers may be restricted by non-classical MHC class I and bind free, specialised antigens such as non-peptides or phosphorylated ligands. Somatic DNA recombination occurs in developing lymphocytes to satisfy the need for diversity. T cells must have antigen presented to them in complex of MHC and peptide. MHC is complex glycoprotein. Processes antigenic protein is presented to the T cell as a peptide in the groove of the MHC molecules, which is restricted by the MHC class. MHC class I is expressed on all nucleated cells in the body except red blood cells, platelets and nerve cells. MHC class II is expressed only on the surface of professional antigen presenting cells (APCs). Both classes show considerable genetic variation between individuals known as MHC heterozygosity. This can contribute to disease resistance. MHC functions to transport samples of intracellular proteins to the cell surface. This is part of normal physiology, and normal peptides produced will be expressed. Circulating T cells do not respond to 'self' protein expressed by MHC molecules. If the cell is abnormal, the peptides which are expressed alter. These are recognised by circulating T cells.

Although MHC primarily binds to T or B cell receptors, CD4 and CD8 can bind MHC molecules at sites distal to the peptide cleft. This binding stabilises the APC/lymphocyte interaction, reinforcing MHC restriction. In the presence of co-stimulation, clonal expansion occurs. Co-stimulatory signals occur to induce the T cell driven adaptive immune response. The primary costimulatory signal is antigen specific and is the TCR interaction with peptide-MHC molecules. Secondary co-stimulatory signals are antigen non-specific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of the APC and the T cell, such as CD40 on the APC and CD154 on the T cell. The secondary signals amplify T cell activation. Upon antigenic and co-stimulation, the cell enlarges, stops migrating and chromatin becomes less dense. Within hours the cell looks different and is referred to as a lymphoblast. Lymphoblasts can divide, giving rise to 2-4 daughter cells every 24 hours. This phase lasts 3-5 days.


B cells and antibodies

B lymphocytes have B cell receptors (BCRs) known as immunoglobulins (Ig). IgM is expressed when the B cell is immature and can bind up to 10 antigens simultaneously. IgD is also expressed at the B cell matures. They also express MHC II, which they use to present antigen to T cells. For optimal function, B cells must have antigen presented to them and be in contact with Th2 cells in T cell areas of lymphoid tissue. Cytokines IL-4 and IL-5 (produced by Th2 cells) stimulate B cell proliferation. Germinal centres form in lymph nodes where T and B cells interact and B cells proliferate. Some B cells remain in the lymph node whilst others emigrate to the site of antigen. B cells stop mitosis. Some establish memory cells whilst others differentiate into plasma cells. Antibody is synthesised by blasting B lymphocytes and plasma cells. B cells can give a primary or a secondary response, depending on whether the antigen has been encountered before. Primary responses are short-lived and low magnitude. The isotype is IgM, and the response is initiated in the local lymph nodes where antigen is presented to naïve lymphocytes. From this response, memory cells are established. Secondary responses occur when the same antigen is encountered again. They are more rapid due to the recall of memory cells, have a longer duration and a higher magnitude. They are initiated in local lymphoid tissues by the activation of primed lymphocytes. The isotype switches from IgM to predominately IgG and IgA, which have a higher affinity for antigen. Immunoglobulins have a heavy chain constant region and a light chain variable region. During class switching, the constant region actually alters whilst the variable region remains the same, as the variable region is the binding region

that is specific to antigen. It is the carbohydrate groups of the constant region that determine the class of the immunoglobulin. Class switching is stimulated by antigen, cytokines IL-4 and IL-5 and pathogenderived mitogens. Class switching is achieved by B cells altering their constant region's heavy chain during proliferation and maturation via irreversible DNA recombination. The constant region of immunoglobulins is known as the Fc region. There is therefore variation of the Fc region, allowing binding to different Fc receptors. For example, the Fc region of an IgG molecule can bind to Fc receptors on macrophages and neutrophils, allowing phagocytosis of pathogens coated with IgG antibodies, whereas the fc region of IgE binds to Fc receptors on mast cells in tissue and basophils in blood. Binding of the Fc portion of the antibody to FcRs stimulates effector functions. Passive immunity is conferred to newborn animals from the consumption of colostrum within a defined period, usually 12-36 hours, after birth. Maternal antibodies from colostrum either remain in the gut (IgA) or are transferred across the intestinal wall via FcRn receptors expressed on the intestinal epithelium into local blood vessels and then spread systemically (IgG). This provides immunological protection against pathogens to which the mother has been exposed for several months. During this time the youngster's own immune system is activated. As well as IgA and IgG, colostrum also contains IgM, IgE, cytokines, trypsin inhibitors and lymphocytes. The success of passive immunity if influenced by the type of placenta, the vaccination history of the mother and her response to vaccines, the concentration of antibodies in the colostrum, the number of young, conformation of the teat and the vigour of the offspring. Lambs, calves, foals and piglets are much more reliant on colostrum consumption because the placenta in these species is epitheliochorial or syndesmochorial, resulting in no transfer of immunity before birth. In puppies and kittens the placenta is endotheliochorial, and so some transfer of IgG occurs. Colostrum testing can be done to assess Ig transfer.

2. Antigens and antigen presenting cells An antigen is defined as anything that causes an immune response. This is usually foreign but may be from self-tissue (autoimmunity). A hapten is a small molecule that alone cannot elicit antibody production, but when attached to a larger molecule can act as an antigenic determinant and elicit antibody synthesis.

A carrier is a foreign protein to which small non-immunogenic molecules (haptens) can be coupled to stimulate an immune response. Self-proteins can also serve as carriers, such as occurs in allergy to drugs. An adjuvant is any substance which, mixed with an antigen, enhances the immune response to that antigen. Antigenic variation, drift and shift help pathogens evade the immune system. Variation occurs as pathogens exist as multiple strains, for example there are 84 serotypes of S. pneumoniae. This leads to multiple consecutive infections with the same pathogen. Antigenic drift occurs as a result of point mutations in the DNA which leads to a coding change in the amino acid which in turn results in a small change in the structure of the protein. Some antibodies may bind the new protein, giving partial protection, but the immune response is not fully protective. Often a mild epidemic will occur as there is still a degree of cross protection. Antigenic shift occurs as a result of reassortment of segments in the genome between different strains of the same pathogen, leading to dramatic changes in the expressed protein. The change is so radical that the protein(s) is no longer recognised by the immune response, causing serious pandemic disease outbreaks. Antigenic variation, drift and shift is particularly important for extracellular pathogens and their surface antigens, as antibodies are the body's primary defence against them. Antigen presenting cells include dendritic cells, macrophages and B lymphocytes. They all express MHC class II. Dendritic cells interact with naïve and memory T cells, whereas macrophages and B lymphocytes interact with memory T cells only. Dendritic cells may be naïve or primed, whereas macrophages and B lymphocytes are primed only. This means the response is fast, involves MALT and is at local site of antigen exposure. In naïve animals, the response is generated in the lymph nodes at the drainage site of antigen exposure and is slow. There are two types of antigen processing. Antigens may enter cells via phagocytosis or endocytosis (exogenous antigen processing) or by direct entry to the cytosol (endogenous antigen processing). Exogenous antigen processing is MHC class II restricted and involves extracellular pathogens. Proteins are processed via the endocytic pathway and resultant peptides are presented by MHC class II molecules on the surface of the APC. This is then recognised by T helper cells, resulting in cytokine secretion. Endogenous antigen processing is MHC class I restricted and involves intracellular pathogens. Proteins are processed via the cytosol and proteasome, and the resultant peptides presented by MHC class I molecules on the APC surface. This is recognised by cytotoxic T cells.

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