Immunity

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Chapter 5 Immunity

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.

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.

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

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).

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.

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

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.

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.

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

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:

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.

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.

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.

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

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

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

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.

2. Neutralisation of virus and toxins.

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

4. Complement Activation (IgG3, IgG1 and IgG2). See page 99.

IgA (heavy chain = α) occurs in the blood (1.5–4 mg/ml) where its function is unknown.

It is the predominant immunoglobulin in secretions of eyes, nose, mouth, bronchi and gut. Its function is to protect mucous surfaces from antigenic attack and prevent access of foreign substances to the circulation and general immune system. It may neutralise toxins and prevent binding to mucous surfaces. IgA is a single molecule in the serum.

The diagram illustrates the local production of IgA in the gut.

IgD	(heavy chain Δ) of uncertain function: concentration in blood very low probably because it is not secreted by plasma cells. Like IgM it is present on the surface of B lymphocytes prior to transformation.
IgE	(heavy chain ε) – a single molecule similar to IgG and IgA. It is sometimes called REAGIN: concentration in blood is low (20–500 ng/ml). The serum level is raised in worm infestation and is probably protective. Its main activity is mediated by MAST CELLS (or BASOPHILS); it is the principal mediator of atopic and anaphylactic disease.

The range of antibodies is immense. B cells produce this vast number by rearranging the genes from the immunoglobulin light and heavy chains. The appropriate clone of plasma cells is stimulated by binding of antigen to the cell surface receptor (so-called clonal selection).

Immune Reactions

Antigen-Antibody Interactions

When an antigen (Ag) binds with an antibody (Ab) an Ag/Ab complex is formed. This reaction is reversible in varying degrees and depends on the affinity of the antibody for an individual antigen and the avidity (strength when multiple epitopes on an antigen interact with multiple binding sites).

The consequences of Ag/Ab interaction include:

1. PRECIPITATION

A soluble antigen is rendered insoluble by aggregation of the Ag/Ab complexes into a lattice.

This reaction is the basis of immunoelectrophoresis, used e.g. to identify a monoclonal band in myeloma.

2. AGGLUTINATION

Particulate antigen, e.g. bacteria and red blood cells, are aggregated in the same way as in the precipitation reaction and the process is called agglutination. Agglutination reactions are routinely performed to type red cells (ABO typing).

3. CROSS-REACTIVITY

In some cases antibody elicited by one antigen can cross-react with an unrelated antigen usually because they share a similar epitope.

e.g. Streptococcus pyogenes

Complement System

Complement consists of nine main protein components present in inactive form in the blood. There are 3 pathways of complement activation. Activation results in the formation of multi-molecular enzymes that activate further components in a cascade ultimately generating a membrane attack complex that is capable of causing cell lysis.

The mannose-binding lectin (MBL) and alternative pathways do not require antibody for activation and are therefore a component of the innate immune system.

Activation of C by Ag/Ab complex is called fixation of complement. Using red cells as markers, this fixation can detect the presence of antigen or antibody in serum.

E.g. Test serum + antigen + C.

If serum contains antibody, C is fixed, otherwise it remains free.

Add sensitised RBC (coated with Ab).

Lysis of RBC = complement still free ∴ no Ab in original serum.

No lysis = C was fixed by Ab in test serum.

Tolerance

Humoral and cell-mediated immunity are specific active immune responses with a protective function.

In certain circumstances an antigen does not evoke these active responses. This is because the lymphocytes, although recognising the antigen, do not react – this is TOLERANCE.

Tolerance is an important protective mechanism. When it breaks down, the serious effects give rise to autoimmune disease (see p.107).

Immunopathology

The complicated and delicately balanced immune mechanisms clearly have been developed to protect against antigens, particularly infections. When these immune reactions are upset, the protective mechanism can itself be a source of disease states.

There are three main categories: 1. hypersensitivity states, 2. immune deficiency states and 3. autoimmune diseases.

Hypersensitivity Reactions

These consist of an inappropriate response by an individual to an antigen, following a previous exposure. They differ from the protective immune response in that they are exaggerated, inappropriate or damaging to the host. Depending on the main type of immune response concerned, these are classified as follows:

(a) Those associated with HUMORAL ANTIBODIES

∴ immediate – types I, II, III.

(b) Those associated with CELLULAR IMMUNITY

∴ delayed (24–72 hours) – type IV.

This classification is to some extent artificial. Hypersensitivity may start as an immediate humoral reaction but end in a mixed state with both humoral and cellular activities. In the 1960s, Coombs and Gell divided hypersensitivity reactions into four types that are still used today.

Hypersensitivity States

Clinical Examples of Type I Reaction

Eosinophils are a common finding in the tissues of patients with allergies, attracted by eosinophil chemotactic factor released by mast cells. Allergic conditions are often familial with a genetic basis. Several candidate loci have been proposed including loci linked to cytokine genes and a gene for the IgE receptor on mast cells.

This cytotoxic reaction causes some forms of haemolytic anaemia (e.g. autoimmune HA (p.392): Rhesus incompatibility (p.393)) and some blood transfusion reactions. Certain drugs (e.g. penicillins) can also cause autoimmune HA by acting as a hapten. This is a small molecule that only becomes immunogenic when combined with a host protein carrier.

In some auto-immune disorders antibodies of this type are directed against specialised cell surface receptors, e.g. Graves’ disease or myasthenia gravis (see p.109).

Type III – Immune Complex (Arthus) Type

The reaction is due to the consequences of specific direct antigen/antibody combination particularly complement activation (p.99) and platelet aggregation. The antibodies involved are IgG or IgM.

Type III hypersensitivity may be systemic or localised.

Type IV – (Delayed) Type

This reaction is an antigen elicited cellular immune response which produces tissue injury independently of the presence of antibody. The reaction is usually delayed taking 24–72 hours to develop. Classic examples include the tubercle follicle, graft rejection and contact dermatitis.

Immune Deficiency States

The systems involved are:

Failure in any one alters the immune response. The deficiencies may be of a primary nature, commonly genetic in origin, or secondary to some other disease or circumstance. Equally, the alteration in any system may be quantitative or qualitative. In many of these deficiencies there is a failure in more than one system.

Primary (inherited) deficiencies of the specific system are rare. They include B cell, T cell and combined B and T cell deficits. B cell deficiency leads to infection by pyogenic bacteria. T cell deficits lead to infection by viruses, fungi and intracellular bacteria.

Secondary deficiencies of the specific system are common. Usually T cell activity is affected, resulting in deficient cellular immunity and, later, B cell deficit occurs.

The acquired immunodeficiency syndrome (AIDS) is now a major world-wide public health problem. Other predisposing conditions and diseases include:

Deficiencies of the innate immune system are rare. The disorders of neutrophil function are described on page 408.

Immune Deficiency States – Aids

The acquired immune deficiency syndrome (AIDS) is a world-wide epidemic with large numbers of cases in sub-Saharan Africa and South East Asia. Globally, an estimated 40 million people are infected with the virus.

The virus (human immunodeficiency virus (HIV)) is of the retrovirus group: it infects and destroys CD4 T-lymphocytes (macrophages, monocytes and dendritic cells are also infected). There are 2 strains of HIV: HIV1 which is more virulent and HIV2 which predominates in West Africa.

The disease is slowly progressive and untreated is usually ultimately fatal. Recently highly active antiretroviral therapy (HAART), usually a combination of drugs such as nucleoside analogues and proteases, has been shown to reduce viral load to undetectable levels and has decreased the incidence of opportunistic infections and the death rate in the USA. However these drugs are expensive and have significant side effects.

Infection	Latent period	AIDS
CD4 > 500 × 10⁶	CD4 – 200–500 × 10⁶	CD4 < 200 × 10⁶
Asymptomatic or a short febrile illness. Although the patient’s cells contain HIV, tests for antibodies may be negative for up to several months.	Virus present in lymphocytes: may be persistent lymph node enlargement and fever.	Infections and tumours

The whole range of opportunistic infection (see p.84), including disseminated virus infection (e.g. herpes simplex and cytomegalovirus), occurs.

The diagram shows the more common AIDS-associated diseases and sites:

Blood Changes

Antibodies – Specific antibodies appear up to 6 months after infection and form the basis of the diagnostic test for HIV. The antibody titre may fall greatly late in the disease.

Immunoglobulins are usually elevated in the early stages.

CD4 lymphocytes may be severely reduced, producing a lymphopenia (see above).

Epidemiology and Transmission

Although the virus may be present in many body fluids and secretions, transmission is by the parenteral route, usually by 1. sexual contact, 2. infected blood or 3. from mother to infant.

Transmission does not occur with normal social contact and there is a very low risk to medical or nursing personnel using normal procedures.

1. Sexual contact: HIV is present in semen and vaginal fluid. Transmission may occur by homosexual intercourse. The risk of transmission is increased where there is genital ulceration or abrasion.

2. Infected blood: the risk from blood transfusion and blood products has now been virtually eliminated by screening and sterilisation procedures (in the past many haemophiliacs were infected). The communal use of contaminated syringes and needles is important among drug addicts.

3. Mother to infant: around half a million infants become infected with HIV each year. The majority of these infections result from transmission of virus from HIV infected mothers during childbirth or by transfer of virus in milk during breastfeeding. Maternal antiretroviral therapy can reduce the incidence of transmission.

Cellular Mechanisms

Note: Individuals with certain mutations in the CCR5 receptor are resistant to HIV. These mutations are more prevalent in Caucasian populations compared with African populations.

Autoimmune Diseases

Autoimmune diseases result from, or are associated with, an immune response against the individual’s own cells, or in some cases cell products. Although both humoral and cellular immunity are involved, it is thought that changes in the latter are of primary importance. In autoimmunity, something occurs to destroy integrity of self tolerance. The aetiology of autoimmunity is not fully established. Potential causes include:

1. Genetic susceptibility

– Genetic predisposition to autoimmune disease in family members.

– Susceptibility to autoimmune disease may be linked to specific MHC alleles, e.g. ankylosing spondylitis HLA B27.

2. Environmental susceptiblity

– Sequestered antigen – an antigen is exposed to the immune system following injury or infection, e.g. myocarditis after myocardial infarction.

– Molecular mimicry – microbial antigens cross-react with self antigens.

– Polyclonal activation – infectious agents can act as superantigens triggering many B and T cell clones.

3. Other triggers of autoimmunity

– Hormones, e.g. SLE is more common in females and may be triggered by oestrogen.

– Drugs – certain drugs may act as a hapten rendering a self antigen immunogenic.

– T suppressor cells – loss of suppressor T cells can contribute to autoimmunity, e.g. individuals with inflammatory bowel disease and diabetes have reduced numbers of T suppressor cells.

Autoimmune diseases were traditionally classified as organ specific and non-organ specific. However, since there is some crossover between these two groups, they can be classified by the predominant effector mechanism leading to organ damage.

PREDOMINANTLY ANTIBODY-MEDIATED AUTOIMMUNE DISEASE

Autoantigen	Target Organ	Disease
Red blood cells	Red blood cells	Haemolytic anaemia
Acetylcholine receptor	Voluntary muscle	Myasthenia gravis
TSH receptor	Thyroid	Graves’ disease
Nuclear constituents e.g. DNA,	Many – Kidney, skin, blood vessels, joint, heart	Systemic lupus erythematosus

PREDOMINANTLY T CELL MEDIATED AUTOIMMUNE DISEASE

Autoantigen	Target Organ	Disease
Myelin basic protein	Central nervous system	Multiple sclerosis
β-islet cells	Pancreas	Type 1 insulin dependent diabetes mellitus
Thyroglobulin Microsomal antigens Thyroid peroxidase	Thyroid	Hashimoto’s thyroiditis
IgG	Synovium/joints	Rheumatoid arthritis