Introduction:
An inappropriate response of the immune system leading to activation of self-reactive humoral or cell-mediated responses against self-antigens are called autoimmunity.
Autoimmune conditions that involve direct damage to cells occur when antibodies or immune cells attach to antigens on the surface of cells. This interaction can lead to cell destruction or provoke inflammation in the affected tissues. These diseases can be categorized as either systemic or localized, depending on where the auto-antigens are found.
Organ-Specific Autoimmune Disorders: In organ-specific autoimmune diseases, the immune attack is directed against antigens that are restricted to a particular organ or gland. As a result, symptoms and tissue damage are generally limited to that specific location. Damage to the organ’s cells may occur through antibody-mediated or T-cell-driven mechanisms. In some cases, antibodies may not destroy the cells but instead disrupt normal organ function by either excessively stimulating or inhibiting it.
Mechanisms for Induction of Autoimmunity:
Release of Sequestered Antigens
Self-tolerance in T cells is established when immature thymocytes are exposed to self-antigens, leading to the elimination (clonal deletion) of those that react against the body’s tissues. However, tissue damage from inflammation, reduced blood flow, or injury can uncover self-antigens that are typically hidden from the immune system. Because these antigens were not involved in the initial tolerance process, their sudden exposure may trigger immune responses. When mature T cells encounter these previously hidden antigens, they may become activated. An example of this is sperm, which develop later in life and are normally isolated from immune surveillance.
Molecular Mimicry May Contribute to Autoimmune Disease
Antigens produced by certain infectious microorganisms may resemble and interact with self-antigens. Such cross-reactions between microbial and self-antigens are known as molecular mimicry. Immune responses to these microbial antigens can induce autoimmunity. An example of this mechanism is that heart damage in rheumatic fever is believed to result from cross-reactive antibodies that form following a Streptococcus infection.
Inappropriate Expression of Class II MHC Molecules
It has been proposed that trauma or a viral infection in an organ can trigger a localized inflammatory response, leading to elevated levels of IFN-γ in the affected tissue. If IFN-γ stimulates class II MHC expression on cells that do not normally present antigens, this could lead to improper activation of helper T cells, potentially resulting in autoimmune effects. For example,
The inappropriate expression of class II MHC molecules in pancreatic beta cells in individuals with insulin-dependent diabetes mellitus (IDDM) may serve to sensitize TH cells to peptides derived from the beta cells, allowing activation of B cells or T cells against self-antigens.
Polyclonal B-Cell Activation
Numerous bacteria and viruses can induce nonspecific polyclonal B-cell activation in the absence of TH cells, which results in the development of several B cell clones that express IgM. If B cells reactive to self-antigens are activated by this mechanism, auto-antibodies can appear. For example, many AIDS patients show high levels of nonspecific antibodies and auto-antibodies to RBCs and platelets. These patients are often coinfected with other viruses, for example, Cytomegalovirus, which may induce the polyclonal B-cell activation that results in auto-antibody production.
Examples of Autoimmune Diseases:
Hashimoto’s thyroiditis
T-cells may become activated either by molecular mimicry against an infectious agent or by interacting with class II MHC molecules aberrantly present on thyroid cells from the patients. Thyroid antigen-specific sensitized TH1 cells and auto-antibodies are produced by an individual. A goiter results from the generation of the Delayed Type Hypersensitivity (DTH) response.
Systemic Lupus Erythematosus (SLE)
Some individuals generate autoantibodies targeting a wide range of tissue antigens, including DNA, histones, red blood cells (RBCs), platelets, leukocytes, and clotting factors. Hemolytic anemia and thrombocytopenia can result from complement-mediated destruction caused by autoantibodies against red blood cells and platelets. Additionally, when autoantibodies form immune complexes with nuclear antigens and deposit in the walls of small blood vessels, they can initiate a type III hypersensitivity reaction. Vasculitis and glomerulonephritis are caused by the activated complement system damaging the blood vessel wall.
Multiple Sclerosis (MS)
In patients with Multiple Sclerosis, the T cells recognize and attack components of the axonal myelin sheath, destroying myelin and the underlying axon. Activated T cells seen in the CSF fluid of patients with active multiple sclerosis (MS) cause inflammation and myelin degradation in typical lesions by penetrating brain tissue. In addition, cytotoxic T-cells may directly damage myelin, and antibodies directed against myelin constituents can cause demyelination by Antibody Dependent Cellular Cytotoxicity (ADCC), myelin opsonization, or complement activation.
Rheumatoid Arthritis (RA)
The major presentation of Rheumatoid Arthritis patients is chronic inflammation of the joints. Many individuals with Rheumatoid arthritis produce a group of auto-antibodies called rheumatoid factors that are reactive with the Fc region of IgG. An IgM antibody with that reactivity is the traditional rheumatoid factor. IgM-IgG complexes are created when these auto-antibodies attach to normal circulating IgG and are deposited in the joints. These immune complexes have the ability to trigger the complement cascade, which can cause a type III hypersensitivity reaction and chronic joint inflammation.
Treatment Strategies:
- Control at the target organ level
- In many organ-specific autoimmune conditions, metabolic control is usually sufficient. For example, insulin in Juvenile Diabetes, anti-thyroid drugs for Graves’ disease.
- Anti-inflammatory drugs
- Corticosteroids have long been used to treat autoimmune diseases like SLE, RA, as they not only suppress various aspects of the immune response but also control the inflammatory lesions.
- Idiotype control with antibody
- The powerful immunosuppressive action of anti-idiotype antibodies suggests that it may be useful in controlling autoantibody production. The pooled Ig from many normal donors is not only a source of anti-idiotype antibodies, which can interact with the idiotype of autoantibodies, but it also contains antibodies against numerous cytokines and has significant anti-inflammatory effects.
- Other biological agents inhibiting the immune response
- A variety of monoclonal antibodies and biological inhibitors have been produced, which are being tested for the treatment of autoimmune diseases. Some mechanisms of action include:
- Blockade of TNF with a specific monoclonal antibody
- Blockade of IL-1 receptors with a recombinant IL-1- receptor antagonist.
- Blockade of CD4 with a fully human anti-CD4 monoclonal antibody.
- Antibodies against the CD40 ligand.
- Inhibitors of cell signaling pathways.
- Stem cell transplantation, to restore homeostasis and regulatory cells.
References:
- Owen, J. A., Jones, P. P., Kuby, J., Punt, J., & Stranford, S. A. (2013). Kuby immunology (7th ed.). New York: W.H. Freeman
- Abbas, A. K., Lichtman, A. H., & Pillai, S. (2012). Cellular and molecular immunology. 7th ed. Elsevier/Saunders.