Introduction to Autoimmunity

Core

Introduction

Autoimmunity is the term that applies when the host 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 (when damage is localised to a single organ or tissue) or non-organ-specific (when self-antigens are ubiquitous across the body and thus generate a systemic autoimmune response).

Organ-Specific Autoimmune Diseases

Hashimoto’s Thyroiditis - autoantibodies target thyroid peroxidase and thyroglobulin which are essential to ensure normal function of the thyroid glands. It results in hypothyroidism. This is a type IV hypersensitivity reaction.

Type I Diabetes Mellitus - autoantibodies target pancreatic islet cells, which are essential for the production of insulin. 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 - autoantibodies target the myelin sheath coating nerve fibres which 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 in the kidneys and the lungs. This is a type II hypersensitivity reaction.

Addison’s Disease - in most patients, autoantibodies target the adrenal gland, known as anti-adrenal antibodies. This can be a type II or IV hypersensitivity reaction.

Graves’ Disease - autoantibodies (called thyrotropin receptor antibody, TRAb) target thyroid-stimulating hormone receptors on thyroid follicular cells, leading to the overproduction of thyroid hormones and resulting in hyperthyroidism. This is a type II hypersensitivity reaction.

Myasthenia Gravis - autoantibodies target the acetylcholine receptor found at the neuromuscular junction resulting in muscle weakness. This is a type II hypersensitivity reaction.

Pernicious Anaemia - autoantibodies target parietal cells and/or intrinsic factor 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 - autoantibodies target red blood cell antigens which circulate through the whole body. This is a type II hypersensitivity reaction.

Rheumatoid Arthritis - caused by multiple different autoantibodies, with examples being rheumatoid factor and anti-CCP. Rheumatoid factor for instance targets specific regions of IgG molecules which leads to increased inflammation, especially in the joints but has also systemic effects. This is a type IV hypersensitivity reaction.

Systemic Lupus Erythematosus - autoantibodies like dsDNA antibodies have systemic consequences. This is a type III hypersensitivity reaction.

Sjogren’s Syndrome - autoantibodies against antigens found on the nucleus (e.g. anti-Ro/anti-La), leading to systemic effects. 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 fibrosis is driven by the autoantibodies which lead to complement activation, antibody-mediated cell cytotoxicity or neutrophil activation whereas in other cases, the tissue fibrosis is driven by autoreactive T-cells through cytotoxic T-cells or macrophages.

Causes of Autoimmunity

Autoimmune diseases are the result of a combination of strong genetic factors 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 occurrence when first-degree relatives present with the disease and the fact that many autoimmune diseases have been associated with MHC variants (e.g. HLADR3/DR4).

On the other hand, environmental factors seem to be the triggers of these diseases as they commonly arise following episodes of infection (e.g. rheumatic fever, Guillain-Barré syndrome) or the use of specific drugs (e.g. minocycline has been linked with SLE).

The fact that some of these diseases are more common in females than males (e.g. Hashimoto’s, SLE) supports the idea that some of these could be linked to hormonal function or disturbances.

Diagnosing Autoimmunity

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 local biopsy can also be helpful, especially in organ-specific autoimmunity (e.g. renal biopsy is used in the diagnosis of Goodpasture’s disease).

Diagnostic Criteria for Autoimmune Diseases

For a disease to be classified as autoimmune it requires the following:

• The presence of autoantibodies (or autoreactive T-cells).
• Autoantibodies (or autoreactive T-cells) must be found at the site of tissue damage (specific organ when organ-specific or across the systems affected if non-organ specific).
• Experimental models may demonstrate disease by transferring autoantibodies or autoreactive T-cells to a healthy host, but this is not required for routine clinical diagnosis.
• Clinical improvement should be achieved when using immunomodulatory therapy.

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 may be required, such as regular dialysis. Organ transplantation can be performed in patients with autoimmune disease, although the risk of disease recurrence or immune mediated injury varies depending on the condition.

Other existing therapeutic strategies are plasma exchange, immunosuppressive drugs, anti-inflammatory drugs, and monoclonal antibodies. The latter drugs dampen the host’s immunity but as a side effect can result in immunosuppression, making patients more vulnerable to infections. Plasma exchange removes the damaging autoantibodies and is used for conditions such as myasthenia gravis and Goodpasture’s syndrome, and more rarely in severe or refractory Graves’ disease.

Edited by: Dr. Maddie Swannack

Reviewed by: Dr. Thomas Burnell

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