IgE causes Type 1 Hypersensitivity. What about other antibodies? Other antibodies can cause disease by directly binding to antigens in cells and tissues (type II), or by forming antigen-antibody complexes (type III) which deposit in blood vessels. Usually, the antibodies that cause the disease are against self-antigens, and rarely against microbial infections. One example of such a case is: streptococcal infections. Antibodies against these cross react with heart muscle therefore causing rheumatic fever. Sometimes the antibody can deposit in kidney glomeruli causing glomerulonephritis.
Mechanism of tissue injury and disease
Antigens may deposit in cells or tissues, and antibodies (IgG & IgM) produced against these specific antigens may deposit in cells and tissues as well causing injury by inducing local inflammation or interfering with normal cellular functions.
Clinical examples of a Type II hypersensitivity reaction are:
Foetal problems: Foetus Rh +ve, mother Rh –ve. Mother starts making antibodies against foetus. 1st pregnancy is fine, but 2nd pregnancy (if foetus is Rh +ve again) will cause problems due to maternal antibodies attacking foetus.
G rave’s Disease: antibodies act as hormones and bind to hormone receptors in the Thyroid gland. Cause increase production of thyroid hormone.
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Myasthenia gravis: antibodies against Ach receptors at neuromuscular junctions cause inhibition of receptors. Therefore skeletal muscle contraction does not occur ≫ paralysis.
IgG & IgM antibodies bind to neutrophil and macrophage Fc receptors activating these cells. This results in inflammation. The same antibodies, this time including IgM, activate the complement system by the classical pathway resulting in production of complement by-products that further recruit leukocytes ≫ inflammation. Leukocytic activation means these cells produce reactive oxygen intermediates and lysosomal enzymes that damage adjacent tissues.
Another process is by opsonisation. The antibody may fixate on platelets or red cells with antigen, which opsonises these cells therefore increasing the efficiency of phagocytosis.
Type III Hypersensitivity occurs as a result of deposition of antigen-antibody complexes – immune complexes – in tissue spaces. Usually these areas are in blood vessel sites where there is turbulence (branches of vessels) or high pressure areas. Thus, immune complex diseases are usually systemic (i.e.: vasculitis, arthritis, and nephritis). The deposition of immune complexes induces inflammation by activating leukocytes – similar to Type II Hypersensitivity.
Antibodies in immune complexes (i.e: IgG & IgM) bind to Fc receptors of neutrophils and macrophages activating them ≫ inducing inflammation.
IgM activates the complement cascade via the classical pathway, complement by-products induce further inflammation. Leukocytic activation results in enzymes released (“frustrated phagocytosis”) that cause damage to adjacent tissues.
Leukocytes also release cytokines which increase blood vessel permeability ≫ increasing ability of immune complex to deposit in local tissues.
Note the process above is exactly the same as Type II, except the initiating factor is immune complex NOT antibodies.
If the reaction is localised it is termed an Arthus reaction (i.e.: deposition of immune complex is local), if it is systemic it is termed as serum sickness (i.e.: deposition occurs in blood vessels).
Arthus Reaction – Localised Type III Hypersensitivity Reaction (Abbas pp 263)
This is an experimental immune complex mediated reaction. An Arthus reaction occurs when immune complexes deposit in local tissues ≫ local inflammatory response. IgG is already made, so injection of a foreign antigen subcutaneously means immune complexes will be formed subcutaneously locally. Because it is a low dose antigen – immune complexes are only formed locally activating leukocytes and complement system. As a result inflammatory cells infiltrate the area (↑ vascular permeability), and blood flow is increased.
Serum sickness
This is caused by injecting large doses of antigen into the blood stream. This causes immune complexes to be deposited within blood vessels. This occurs in high pressure and high turbulent areas (joints and kidneys). This causes leukocytic and complement activation causing inflammatory responses (i.e.: arthritis & vasculitis). Fever is characteristic. Symptoms resolve when foreign antigen is cleared.
The large doses of antigen arise from horse serum because they contain antitoxin antibodies.
This is referred to as delayed type hypersensitivity, and these occur as a result of T lymphocytes reacting, usually against self antigens resulting in autoimmune diseases. Most autoimmune diseases are Type IV Hypersensitivity reactions.
Mechanisms of Tissue Injury
Host is exposed to tissue antigen, which is broken down and is presented on APCs
Naïve CD4+ cells recognise these peptides and differentiate into Th1 cells. Th1 cells migrate into the blood stream and remain as a pool of memory cells. Then when the host is presented with the same antigen again, the hypersensitivity reaction is started. Delayed because T cell activation is via APC and migration to infection site.
Antigen re-presents, and are presented on APCs and Th1 cells interact with these get activated. Th1 specific cytokines are released that induce local inflammation and activate macrophages. The macrophages along with other inflammatory cells cause tissue injury.
A variant of Type IV reactions is when CD8+ T cells specific for antigens borne by autologous cells lyse these cells. The killing mechanism can be perforin-granzyme dependent or Fas-Fas ligand dependent.
The Mantoux test works on Type IV Hypersensitivity reaction principle. The antigen is Mycobacterium TB + tuberculin. In TB, granuloma formation results because the infection cannot be eradicated, so granuloma causes functional impairment (Abbas pp211).
General information
Basically, the immune system does not react to host cells. This is because it exhibits immunologic tolerance. Its ability to discriminate self from non-self is one of its cardinal features. If this is partially/fully lost, then you get self antigen reactions leading to autoimmunity autoimmune diseases.
Autoimmune disease (Abbas pp 168)
Mechanism of Tolerance
Tolerance is divided up into central and peripheral. Before this, you should understand what happens when an antigen is presented to a lymphocyte.
- It may be activated, in which case the antigen is said to be “immunogenic”,
- It may be inactivated or killed, in which the antigen is said to be “tolerogenic”,
- It may just ignore the antigen and not respond nor get inactivated/killed, called ignorance. Microbes are immunogenic, self antigens are tolerogenic/ignorance.
Immunologic tolerance, therefore, can be induced either when lymphocytes are maturing in lymphoid organs called central tolerance, or when they are matured and come into contact with self antigens called peripheral tolerance.
Peripheral Tolerance (Abbas pp 169 + 176)
If immature lymphocytes have receptors that strongly interact with self antigens within the thymus (T cells)/bone marrow (B cells), then signals are given that kill the lymphocyte. This process is termed negative selection. Peripheral tolerance has three mechanisms, and is generally recognised as when a mature T cell recognises a self antigen in peripheral tissues – but 1) get inactivated (anergy) 2) die 3) active suppression.
Anergy: this is when T cells get inactivated when they interact with antigens without adequate co-stimulators. (i.e.: 2nd signal not present). The costimulators are expressed on APCs.
Deletion: If T cells get repeatedly activated by self antigens, then they induced into apoptosis, so autoreactive T cells get deleted.
Immune suppression: Upon interaction with a self antigen, some T cells suppress themselves from activation and also regulate the inactivation of other potential autoreactive T & B cells.
Spectrum of Autoimmune diseases (Notes, Abbas pp 263)
Organ specific vs Non-organ specific
Autoimmune diseases can be split up into organ specific vs non-organ specific. An example of an organ specific disease is thyroditis where thyroglobulin is the antigen. Organ specific autoimmune diseases is when antigen is found in one particular organ (i.e.: thyroglobulin is only found in the thyroid). An example of a non-organ specific autoimmune disease is rheumatoid arthritis or SLE. This is when antigen is spread throughout the body, therefore immune complexes are deposited everywhere (usually spread by blood stream).
There is considerable overlap between these two categorises.
So what is the cause of autoimmune disease?
Basically, the cause is many.
- Some proteins/cells and other components in the body are sequestered. This means, under normal circumstances the immune system is unaware of their existence (i.e.: Think of security guards and you hiding somewhere, they cant see you!). Sometimes, infectious agents damage the tissues that sequester them, therefore now you have antigen released. For example: sperm inside testes, proteins inside eye, or DNA inside cells can be seen by T cells. Therefore an autoimmune reaction is set in motion.
- Sometimes a self antigen is not recognised by the immune system, but it is modified so that new epitopes are formed – now it is recognisable as foreign so immune system activated. (i.e.: RBCs, IgG following antigen binding. 3) Molecular mimicry (Robbins pp 215) – Some infectious agents have the same epitopes as self antigens. So an immune reaction against the microbes, means tissue damaging reactions against self antigens. Removal of microbe will still cause an immune response. An example is rheumatic fever post-strep infections. This is because an antibody against streptococcal M protein cross reacts with cardiac glycoproteins≫ Rheumatic fever.
- T suppressor cells (regulatory cells) suppress themselves and regulate the inactivation of other potential autoreactive cells. If the no. of these cells decreases, then auto-immunity can occur. Some antigen specific CD4+ T cells can suppress antigen specific proliferation of other T cells ≫ prevent autoimmune colitis (mouse model).
- Viruses: interfere with immunological control,
- Excess of autoreaction T helper cells
- Polyclonal lymphocyte activation: Clonal anergy is maintained because antigen specific 2nd signal is not present. Sometimes, microbes can cause B cells to get activated even though the 2nd signal is antigen non-specific (i.e.: activated by 1 type of antigen ≫ 1st signal, activation by 2nd type of antigen ≫ 2nd signal),
- Genetic predisposition: there is an associated familial risk, many autoimmune diseases in humans are linked to particular MHC alleles ≫ i.e.: inheritance of particular alleles of HLA means increased risk of autoimmune disease.
Sex ration & autoimmune disease
Generally, females are predisposed to autoimmune diseases when compared to males.
Signs of autoimmune disease
Just remember: GACIL (gamma globulins, autoantibodies, ↓ serum complement, immune complexes in serum, lesions found in biopsy).
Type II Hypersensitivity
- Antibodies are directed against self antigens.
- They either
- bind directly to self antigens in tissues (i.e.: myasthenia gravis and Grave’s disease ≫ where receptor is antigen)
- bind to Fc receptors on macrophages and neutrophils inducing inflammation (via complement activation ≫ lysis (i.e.: haemolytic anaemia))
- opsonise the self antigens ↑ efficiency of phagocytosis.
Type III Hypersensitivity
SLE is a good example here, where anti-nuclear antibodies are formed against cell DNA ≫ immune complexes formed. These are deposited in tissues causing inflammation ≫ tissue destruction. Rheumatoid factor (IgM) deposits in joints and activates complement ≫ cell lysis and also induces inflammation.
Type IV Hypersensitivity
Most autoimmune diseases are Type IV hypersensitivity reactions. It is mediated by T lymphocytes. Basically, antigens interact with naïve T cells which differentiate into Th1 cells. These lie as memory pool cells, and when antigen re-presents Th1 are activated ≫ cytokines produced. Sometimes CD8+ T cells specific for antigen lyse the cell (i.e.: demyelination, Islet destruction, colon cell destruction).
Diagnostic tests
Diagnosis of autoimmune disease is done by testing for autoantibodies. But remember some autoantibodies are harmless, and present no problem. Also autoantibodies are unique to autoimmune diseases. They can be found in TB infections or neoplasia. Also, specific autoantibodies are not unique to specific autoimmune diseases. I.e.: SLE has 80% ANA & 20% RF. RA has >90% RF & 20% ANA.
Autoimmune thyroiditis disease (Robbins pp 1133-1137)
Hashimoto’s thyroditis
- More common in females 10:1 – 20:1.
- More prevalent between ages 30-50 yrs old.
- It was first reported in 1912 by Hashimoto describe goitre and intense lymphocytic infiltration.
- Most common cause of hypothyroidism in areas with sufficient iodine levels.
- In this disease, autoantibodies against thyroglobulin and thyroxidase (target antigens) activate the complement system or CD8+ cells≫ lyse/cell death.
Grave’s disease (thyrotoxicosis)
- Causes hyperthyroidism.
- IgG antibodies (autoantibodies) bind to target antigen ≫ receptors for thyroid stimulating hormone , which increases adenylate cyclase activity ≫ increase thyroid hormone activity.
Thus, there are three mechanisms in which autoimmune reactions may attack the thyroid. i.e.: autoantibodies activating the complement system causing cell lysis, autoantibodies activating cytotoxic T cells causing cell death or autoantibodies causing an increase in thyroid activity.
Multiple sclerosis (Robbins pp 1326)
- MS is prevalent is most areas of the world, having an incidence of 1 in 1000 people in USA.
- It has been suggested incidence rates increase as distance increases from the equator.
- Genetic link clearly evident.
- It has been established that if you have DR2 extended haplotype of the MHC that MS susceptibility increases.
- MS is the most common demyelinating condition of the CNS.
- Clinical features: unilateral vision impairment (optic neuritis), ataxia, nystagmus, spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, impairment of voluntary control of bladder & spasticity.
- Pathogenesis: mononuclear infiltration of CNS lesion (CD4+ & CD8+ & macrophages) ≫ induce oligodendrocyte injury (via Fas-Fas ligand system).
- Increased IgG found in CSF. A transmissible infectious agent has been proposed but no a well characterised virus is yet to be identified.
Systemic Lupus Erythaematosis (Robbins 217)
- This is a classic multisystem autoimmune disease (organ-non-specific) prototype.
- It affects young woman of child bearing age, female to male ratio 9:1.
- Clinical features include: butterfly rash over face, fever, malaise, pain over joints, lethargy, weight loss.
- Diagnosis is confirmed by detection of ANA to ds, ss, DNA & histones and Sm antigen.
Rheumatoid Athritis (Robbins 1249,)
- This is a chronic inflammatory joint disease.
- Clinical features: malaise, fatigue, musculoskeletal pain, weakness. RF (IgM) deposits in joint tissues causing the autoimmune reaction.
- Rheumatoid factor is mostly IgM (they are actually autoantibodies to the Fc portion of IgG antibodies).
- Immune complexes form in joints, complement activation ≫ inflammation (“frustrated phagocytosis”).
Myasthenia gravis
ACh receptors do not function because anti-acetylcholine antibodies bind to them ≫ inhibiting them. Faulty neuromuscular transmission ≫ paralysis of skeletal muscle.
Bulbous disease (Notes)
Skin erosion caused by antibody and complement deposition
Sjogrens syndrome (Robbins pp 225)
Characterised by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). This is due to autoimmune mediate destruction of the salivary and lacrimal glands.
Goodpasture’s syndrome (Robbins pp 739)
Affects the kidneys and lung basement membranes, causing progressive glomerulonephritis and necrotising haemorrhagic interstitial pneumonitis.
Pernicious anaemia (Robbins pp 623)
Pernicious anaemia causes malabsorption of vitamin B12 due to lack of intrinsic factor (gastric parietal cells), in turn due to atrophic gastritis.
