Immunity

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Chapter 5 Immunity

Immunity 88
The Adaptive Immune Response 89
Cellular Basis of the Adaptive Immune Response 90
Genetic Influences on the Immune Response 91
Cellular Immunity 92
Cytokines 93
Cytokines Involved in Adaptive Immunity 94
Humoral Immunity 95
Immunoglobulins 96, 97
Immune Reactions 98, 99
Tolerance 100
Immunopathology 101
Hypersensitivity States 102, 103
Immune Deficiency States 104
Immune Deficiency States – AIDS 105, 106
Autoimmune Diseases 107–109
Applied Immunology 110
Applied Immunology – Tissue Transplantation 111

Immunity

The immune system protects us from invading pathogenic microorganisms and cancer. Immunity – the state of protection from infectious disease – has both a less specific or INNATE and a more specific or ADAPTIVE component.

Innate Immunity

This provides the first line of defence against infection. It is a rapid response (minutes); it is not specific to a particular pathogen. It has no memory and does not confer long-lasting immunity to the host. It has 4 main components and is found in all classes of plant and animal life.

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Adaptive Immunity

This provides a specific immune response directed at an invading pathogen. Following exposure to a foreign organism there is an initial EFFECTOR RESPONSE that eliminates or neutralizes a pathogen. Later re-exposure to the same foreign organism induces a MEMORY RESPONSE with a more rapid immune reaction that eliminates the pathogen and prevents disease. This response is found only in vertebrates.

It has been known from historical times that a person who has recovered from an infectious disease, e.g. smallpox, is most unlikely to suffer from it again – even when exposed maximally – although he would remain susceptible to other infections.

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That is, during the recovery period he has acquired specific immunity to smallpox but not to other unrelated infections.

Note: This immunity may extend to related infections: the use of the immunity against smallpox conferred by world-wide vaccination with cowpox (pioneered by Jenner in the 18th century) has completely eliminated smallpox throughout the world.

The Adaptive Immune Response

Adaptive Immune Response

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ANTIGENS – Substances that can be recognised by the immunoglobulin receptor of B cells or the T cell receptor when complexed with MHC are called ANTIGENS. They are usually part of infectious agents such as bacteria and some viruses although other foreign materials are also antigenic. Most antigens are proteins but some large carbohydrate molecules such as lipopolysaccharides will induce antibody formation.

EPITOPES are the immunologically active regions of an antigen that bind to specific membrane receptors on lymphocytes or to secreted antibodies. B and T cells recognise different epitopes on the same antigenic molecule. B cells usually recognise soluble antigen (exogenous). Epitopes recognised by T cells are often internal peptides that are exposed by processing with antigen-presenting cells (endogenous).

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Cellular Basis of the Adaptive Immune Response

The main cells of the adaptive immune response are the lymphocytes. They are indistinguishable by light microscopy using conventional stains but can be separated by the presence of different surface proteins on T and B cells.

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The introduction of an antigen results in activation and proliferation of these two lymphocyte populations. This activity takes place in the lymphoid tissues.

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Genetic Influences on the Immune Response

The major histocompatibility complex, also known as the human leucocyte antigen (HLA), has an important role in the immune response and disease.

The genes controlling the system are in 2 major groups (Class I and Class II) on chromosome 6: each group has 3 genes which are highly polymorphic (i.e. show great variation within individual members of the same animal species). The multiple alleles of each gene encode for surface membrane glycoproteins.

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The important roles of HLA are:

(i) Presentation of peptides from foreign antigens to T lymphocytes

Class I antigens to cytotoxic T cells (normally CD8 +ve)
Class II antigens to helper T cells (normally CD4 +ve).

(ii) They are the main stimulus to graft rejection in incompatible hosts. (The better the HLA match, the better the chance of graft survival.)
(iii) There is a strong association with diseases – especially auto-immune disorders (p.107).

The most striking example is ankylosing spondylitis where >90% of patients carry the allele HLA B27.

(iv) They control individual resistance/susceptibility to certain infections, e.g. HLA B52 is associated with resistance to HIV infection.

Cellular Immunity

Activation of T cells requires the involvement of antigen presenting cells. Within these cells, foreign antigen is proteolytically digested to short peptides and then presented with HLA molecules to the T cell which possesses a specific receptor for that antigen.

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Cytokines

The chemical messengers of immune system are known as CYTOKINES. These small proteins are produced by virtually all cells of the innate and adaptive immune system, particularly CD4+ lymphocytes. The quantity and type of cytokine can positively and negatively regulate cells and cytokine effect is in turn controlled by expression or down-regulation of cytokine receptors on the cell surface.

Cytokines Involved in Innate Immunity

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Cytokines Involved in Adaptive Immunity

The immune response to a particular pathogen must induce an appropriate set of effector functions that can eliminate the pathogen from the host. Differences in cytokine secretion patterns among T helper cells are determinants of the type of immune response made to a particular antigenic challenge. Accordingly the cytokines secreting T helper cells are currently divided into 4 subsets:

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The balance between the two main subsets determines disease outcome, e.g. tuberculoid leprosy is characterised by a TH1 response (destructive granulomas, few parasites). In lepromatous leprosy there is a TH2 response (disseminated disease, many parasites).

Humoral Immunity

Basic Structure of Immunoglobulin

The basic immunoglobulin is a protein molecule consisting of 2 identical LIGHT chains and two identical HEAVY chains. Each light chain is bound to a heavy chain by a disulphide bond. Similarly disulphide bridges link the two heavy and light chain combinations to form the basic four chain structure.

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Antibody Mediated Effector Functions

1. Opsonisation

Fc receptors on macrophages and neutrophils can bind the Fc of Ig molecule resulting in phagocytosis of the antigen-antibody complex.

2. Complement Activation

IgM and IgG subclasses can activate the complement system.

3. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

The linking of antibody bound to target cells (e.g. virus infected cells) with the Fc receptors of natural killer (NK) cells, enables the NK cell to recognise and kill the target cell.

4. Crossing of Epithelium (Transcytosis)

The delivery of antibody to the mucosal surfaces of the eyes, nose, mouth, bronchi and gut, as well as transport to breast milk, requires the movement of immunoglobulin across epithelium, a process called transcytosis.

5. Activation of Mast Cells, Eosinophils, Basophils

This is unique to IgE (see p.102).

Immunoglobulins

Antibody Classes and Activities

These groups are named according to the composition of the heavy chains.

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IgM (heavy chain = μ) is a polymer, joined by J chains, of five identical Ig molecules, therefore called macroglobulin.

Although in low concentration in the blood, 0.5–2 mg/ml, it is the main Ig on the surface of B lymphocytes (before conversion to plasma cells). It is the first immunoglobulin class produced and is active in the primary response. It neutralises viruses. In combination with complement, it is actively bactericidal and is especially effective in bacteraemia.

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Note: The numerous (10) antigenbinding sites increase its efficiency.

The natural blood group antibodies, anti-A and anti-B are M globulins.

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IgG (heavy chain = γ) is a single molecule with two antigen binding sites.

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This is the most abundant class of immunoglobulin, with a concentration in blood of 8–16 mg/ml. There are 4 subclasses IgG1, IgG2, IgG3 and IgG4. Of its several activities the important ones are:

1. Passive transfer of IgG (IgG1, IgG3, and IgG4) from mother to baby occurs via the placenta and colostrum. The immunity only lasts a few months.

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2. Neutralisation of virus and toxins.

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3. Opsonisation (IgG1 and IgG3). See page 36.
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