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Next Lesson - Rheumatoid Arthritis
Contents
Abstract
- Autoimmunity is an immune response against the body’s own antigens (self-antigens). It underlies a vast array of autoimmune diseases, which represent a big burden of chronic disabling conditions.
- Autoimmunity can be localised to specific organs or have systemic effects (effects on the whole body).
- A set of criteria is used to show that a disease is autoimmune. They test whether an autoantibody (an antibody against the body’s own tissue) or an autoreactive T-cell (a T-cell, a type of lymphocyte, that reacts against the body’s own tissue) causes the disease.
- Autoimmune diseases are caused by a combination of genetic and environmental factors.
- Management of autoimmune conditions is dependent on the organ affected and the degree of damage. Treatments aim to dampen the autoimmune response. Most current treatments do this by weakening the immune system in a non-specific way, rather than by restoring tolerance (the immune system’s ability to ignore the body’s own antigens). Over the long term this can cause immunosuppression (a weakened immune system), which raises the risk of infection.
Core
Autoimmunity is the term that applies when the host (the person affected) develops an immune response against some of its own antigens (self-antigens).
An autoimmune disease is a disease resulting from subsequent tissue damage or disturbed physiological responses caused by an autoimmune response.
Autoimmune diseases can be organ-specific, where damage is localised to a single organ or tissue. They can also be non-organ-specific, where self-antigens are found throughout the body, which means the autoimmune response is systemic (it affects the whole body).
Each disease below is labelled with a hypersensitivity type. This is a way of grouping the immune reactions that damage the body’s own tissue. In type II, antibodies bind to the body’s own cells or tissue and damage them. In type III, immune complexes (clumps of antibody bound to antigen) deposit in tissues and cause inflammation. In type IV, T-cells drive a delayed reaction that damages tissue.
Organ-Specific Autoimmune Diseases
Hashimoto’s Thyroiditis - autoantibodies (antibodies against the body’s own tissue) target thyroid peroxidase (an enzyme) and thyroglobulin (a protein), which the thyroid needs to make thyroid hormones. Activated T-cells also target the thyroid, and this destroys its hormone-making cells. This damage results in hypothyroidism (an underactive thyroid). This is a type IV hypersensitivity reaction.
Type 1 Diabetes Mellitus - autoreactive T-cells destroy the insulin-producing beta cells in the pancreatic islets (clusters of cells in the pancreas). Autoantibodies against islet cells are also found in most people when type 1 diabetes is diagnosed. This results in poor blood sugar control as there is little to no insulin produced naturally. This is a type IV hypersensitivity reaction.
Multiple Sclerosis - autoreactive T-cells target the myelin sheath (the fatty coating of nerve fibres) in the brain and spinal cord. Autoantibodies against myelin may also contribute. This results in a slowdown of neural transmission. This is a type IV hypersensitivity reaction.
Goodpasture’s Syndrome (Anti-glomerular Basement Membrane Disease) - autoantibodies target the glomerular basement membrane (the thin supporting layer in the filters of the kidneys) and the similar layer in the lungs. This is a type II hypersensitivity reaction.
Addison’s Disease (the adrenal glands do not make enough steroid hormones) - in Western countries, around 90% of cases are autoimmune. Autoantibodies, known as anti-adrenal antibodies, target the adrenal cortex (the outer layer of the adrenal gland). A key target of these antibodies is 21-hydroxylase, an enzyme inside adrenal cortex cells. They are not thought to cause the damage, but they are a marker of adrenal autoimmunity. T-cells that can kill adrenal cells are a possible mechanism, so this is thought to be mainly a type IV hypersensitivity reaction.
Graves’ Disease - autoantibodies (called thyrotropin receptor antibody, TRAb) bind to and stimulate thyroid-stimulating hormone receptors on thyroid follicular cells (the hormone-making cells of the thyroid). This leads to the overproduction of thyroid hormones and so to hyperthyroidism (an overactive thyroid). This is a type II hypersensitivity reaction (the antibodies stimulate the receptor instead of destroying the cell).
Myasthenia Gravis - autoantibodies target the acetylcholine receptor found at the neuromuscular junction (the point where a nerve meets a muscle) resulting in muscle weakness. This is a type II hypersensitivity reaction.
Pernicious Anaemia - autoantibodies target parietal cells (the acid-making cells) and/or intrinsic factor (a protein needed to absorb vitamin B12) produced in the stomach, resulting in impaired vitamin B12 absorption and vitamin B12 deficiency. This is a type II hypersensitivity reaction.
Non-Organ-Specific Autoimmune Diseases
Autoimmune Haemolytic Anaemia (haemolytic means that red blood cells are destroyed) - autoantibodies target red blood cell antigens. Red blood cells circulate through the whole body, so these antigens are found throughout the body. This is a type II hypersensitivity reaction.
Rheumatoid Arthritis - several different autoantibodies are found, with examples being rheumatoid factor and anti-CCP (antibodies against cyclic citrullinated peptide, a chemically modified protein). Rheumatoid factor for instance targets the Fc region (the tail) of IgG molecules (IgG is the most common type of antibody). T-cells are also involved in the increased inflammation, especially in the joints, and there are systemic effects too. This is a type IV hypersensitivity reaction. Rheumatoid factor also forms immune complexes with IgG, which add to the inflammation (a type III mechanism).
Systemic Lupus Erythematosus (SLE) - autoantibodies like dsDNA antibodies (antibodies against double-stranded DNA) have systemic consequences. Antibodies bind to antigens to form immune complexes, which deposit in tissues such as the skin, joints and kidneys and cause inflammation. This is a type III hypersensitivity reaction.
Sjögren’s Syndrome - autoantibodies against ribonucleoproteins (complexes of protein and RNA found inside cells), for example anti-Ro and anti-La. T-cells also infiltrate the tear and salivary glands and damage them, which causes dry eyes and a dry mouth. There can be systemic effects too. This is a type IV hypersensitivity reaction.
The type of hypersensitivity involved in each autoimmune disease process is determined by the pathophysiology. In some cases, tissue damage is driven by autoantibodies. These autoantibodies lead to complement activation (complement is a group of blood proteins that damage cells and cause inflammation), antibody-dependent cellular cytotoxicity (immune cells kill cells that are coated with antibody) or neutrophil activation. In other cases, tissue damage is driven by autoreactive T-cells through cytotoxic T-cells (T-cells that kill their target cells directly) or macrophages.
Autoimmune diseases are the result of a combination of genetic factors (their importance varies between diseases) with environmental factors that seem to trigger the onset of the disease. The role of genetic components is supported by the increased risk of disease when first-degree relatives (parents, brothers, sisters or children) have the disease. It is also supported by the fact that many autoimmune diseases have been associated with MHC variants (variants of the major histocompatibility complex genes, which code for HLA, or human leukocyte antigen, proteins that present antigens to T-cells). Examples are HLA-DR3 and HLA-DR4 in type 1 diabetes.
On the other hand, environmental factors seem to be the triggers of these diseases, because the diseases commonly arise after an infection or after the use of specific drugs. Two examples follow infection: rheumatic fever (which can follow a bacterial throat infection and affects the joints and heart) and Guillain-Barré syndrome (a rare condition that affects the nerves). One example follows a drug: the antibiotic minocycline has been linked with drug-induced lupus (a lupus-like illness that usually settles when the drug is stopped). One way an infection can trigger autoimmunity is molecular mimicry: a microbe carries a protein that resembles one of the body’s own proteins, so the immune response to the microbe also attacks the body’s tissue.
Some of these diseases (e.g. Hashimoto’s, SLE) are more common in females than males. This supports the idea that hormones, or disturbances in hormone levels, may play a part in these diseases.
Autoantibodies can be detected using serum samples to assess their presence; however, not all autoimmune diseases have detectable circulating antibodies, and some antibodies may be primarily tissue-bound. A biopsy of the affected tissue can also be helpful, especially in organ-specific autoimmunity. For example, in Goodpasture’s syndrome, renal biopsy shows antibodies deposited along the glomerular basement membrane, and a blood test can detect anti-glomerular basement membrane (anti-GBM) antibodies.
Diagnostic Criteria for Autoimmune Diseases
Three types of evidence can be used to establish that a disease is autoimmune in origin (Witebsky’s postulates, as revised by Rose and Bona). They are used to classify a disease as autoimmune, not to diagnose an individual patient:
- Direct evidence: transferring autoantibodies or autoreactive T-cells to a healthy host reproduces the disease. This is usually shown in experimental models, so it is not required for routine clinical diagnosis.
- Indirect evidence: the disease can be reproduced in experimental animals, for example by immunising them with the antigen.
- Circumstantial evidence from clinical clues. Examples are autoantibodies (or autoreactive T-cells) found at the site of tissue damage (the affected organ in organ-specific disease, or the affected body systems in non-organ-specific disease). Other examples are association with other autoimmune diseases and clinical improvement with immunomodulatory therapy (treatment that alters the immune response). This kind of evidence supports an autoimmune cause but does not prove it.
Management of Autoimmune Diseases
Most autoimmune diseases have a chronic pattern and extensive tissue damage can sometimes lead to organ dysfunction. In such cases, replacement therapy (giving back what the failing organ no longer provides) may be required. Examples are insulin in type 1 diabetes and levothyroxine (thyroid hormone) in hypothyroidism. Other examples are hydrocortisone and fludrocortisone (steroid medicines that replace the missing adrenal hormones) in Addison’s disease, vitamin B12 injections in pernicious anaemia, and regular dialysis (a machine that filters the blood) when the kidneys fail. Organ transplantation can be performed in patients with autoimmune disease, although the risk of disease recurrence (the disease coming back in the new organ) or immune-mediated injury (damage caused by the immune system) varies depending on the condition.
Other existing therapeutic strategies are plasma exchange (removing the plasma, the liquid part of the blood, and replacing it), immunosuppressive drugs, anti-inflammatory drugs, and monoclonal antibodies. Monoclonal antibodies are antibodies made in a laboratory to target one specific molecule. Immunosuppressive drugs and many monoclonal antibodies dampen the host’s immunity. Dampening immunity is how these drugs work, but it also leaves patients with immunosuppression (a weakened immune system), which makes them more vulnerable to infections. Plasma exchange removes the damaging autoantibodies. It is used for conditions such as Goodpasture’s syndrome and myasthenia gravis (for example in a myasthenic crisis, when weakness affects breathing or swallowing). More rarely, it is used in thyroid storm (a life-threatening surge in thyroid hormones) caused by Graves’ disease, when other treatments have failed or cannot be used.
Edited by: Dr. Maddie Swannack
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
Quiz
- 2805
