In this article we ill discus about the meaning and causes of autoimmunity.
Meaning of Autoimmunity:
In the beginning of 20th century, Paul Ehrlich, proposed the concept of ‘horror auto-toxicus’. In such condition a ‘normal’ body does not mount an immune response against its own tissues. Thus, any autoimmune response perceived is abnormal which was supposed to be connected with human disease.
The ability to make immune responses is heavily regulated. After infection when pathogens are eliminated, the immune response is shut down to avoid wasted resources and hypersensitivity. In spite of this regulation and mechanisms for clonal deletion of many self-reactive T and B cells, the immune system can occasionally attack self-tissues and produce autoimmunity.
Thus autoimmunity can be defined as ‘the failure of an organism to recognize its own constituent parts as ‘self which results in an immune response against its own cells and tissues’. Hence, deficiencies in the ability to make an adequate immune response can result in life-threatening infections.
Causes of Autoimmunity:
Autoimmunity is caused by an adaptive immune response against ‘self antigen. Clonal deletion and energy of self-specific lymphocytes greatly reduces the possibility of low affinity self-specific responses. Transient autoimmune responses are common but usually cause no lasting damage.
Because self antigens are continually present in the body, when autoimmune responses are prolonged the resulting tissue damage can be life-threatening. Certain individuals are genetically susceptible to developing autoimmune diseases.
This susceptibility is associated with multiple genes plus other risk factors. Genetically-predisposed individuals do not always develop autoimmune diseases. Three main sets of genes are suspected in many autoimmune diseases. These genes are related to: immunoglobulins, T-cell receptors, and the major histocompatibility complexes (MHC).
Risk factors for autoimmune disease include the presence of certain HLA alleles, sex hormone levels, infection, and other environmental factors. Autoimmune diseases are classified by corresponding type of hypersensitivity i.e. type II, type III or type IV (no type of autoimmune disease mimics type I hypersensitivity). Table 22.6 summarizes the information about some human autoimmune diseases.
Risk factors for autoimmune diseases are genetically linked to the presence of specific Class I or Class IIHLA alleles. There are two possible models that explain HLA linkage to autoimmunity.
The first model explains that certain HLA alleles are better at presenting pathogen peptides which resemble self peptides to mature T cells. The HLA B27 (Class I) allele is associated with an 80- fold increased risk of alkylosing spondylitis characterized by inflammation and damage to the spine. B27 binds the peptides in the absence of tapasin.
This is an advantage in certain virus infections where the virus interferes with production of tapasin. However, the peptides bound in the absence of tapasin are different from those bound in the presence of tapasin.
They might include some self peptides that could induce autoimmunity. Therefore, people with the B27 Class I MHC allele possibly will respond more to virus infections by producing CTL that can recognize self peptides and kill uninfected cells.
The second model for autoimmunity proposes that certain HLA alleles are less efficient at presenting self peptides to developing T cells in the thymus so that negative selection fails, for example ‘insulin-dependent diabetes mellitus’ (IDDM) or type I diabetes. IDDM is strongly linked to the presence of HLA DR3 and DR4 alleles.
When autoimmune disease is caused by autoantibodies, the disease mechanism is classified as Type II or Type III hypersensitivity. In autoimmune haemolytic anaemia, antibodies to red blood cell antigens initiate complement lysis and phagocytosis of RBC in the spleen reticuloendothelial system (RES).
Antibodies to platelets and neutrophils can also cause depletion of these cells in the RES. Leukocytes are more resistant to complement lysis than erythrocytes. Autoimmune haemolytic anaemia can be treated simply by removing the spleen.
Antibodies to cell surface receptors may stimulate or inhibit receptor function. Antibodies to thyroid stimulating hormone (TSH) receptor in the thyroid stimulate thyroid hormone production and induce hyperthyroidism (overactive thyroid) in Grave’s Disease.
Antibodies to the receptor for acetylcholine (which is a neurotransmitter) block the signals of nervous system to muscle cells and leads to myasthenia gravis, a progressive muscle weakness. Antibodies to insulin receptor mimic insulin function and cause low blood sugar and in other cases to block insulin function and cause high blood sugar.
Antibodies to basement membrane Type IV collagen, present in the kidney, lungs, and inner ear, cause Type II hypersensitivity in Good pasture’s syndrome. Antigens must be accessible for antibody-mediated autoimmune disease to occur.
Type IV collagen is exposed in the kidney; hence, Good pasture syndrome always results in kidney disease. Generally, only smokers get lung damage with Good pasture syndrome because damage from smoking exposes collagen in the lung. Hearing is rarely lost even though Type IV collagen is also present in the inner ear because it is hidden from the immune system.
IgG autoantibodies may be transferred across the placenta and cause transient symptoms in the newborn infant. Damage is usually not permanent; removal of maternal antibodies can be accomplished with plasmapheresis.
T cell-mediated damage results in several autoimmune diseases such as multiple sclerosis, rheumatoid arthritis (which also has some Type III characteristics) and insulin-dependent diabetes.
It is more difficult to identify autoimmune T cells and the antigen to which they are responding than to identify antibodies and their antigens. Since autoimmune disease is mediated by normal immune mechanisms, controlling the disease without making the patient susceptible to infection is the greatest challenge.
Tolerance:
Natural tolerance is the inability to make an immune response to an antigen. It is caused by several factors. Clonal deletion of self-reactive T and B cells during development removes lymphocytes with high avidity receptors for ubiquitous self antigen present in the thymus and marrow.
The particular HLA alleles available to present self-antigen to developing T cells influence self peptides which are presented with high avidity to induce clonal deletion, and which are presented with low avidity.
When immature B cells encounter soluble antigen that cross-links BCR and T cells encounter unprocessed antigen or processed antigen in the absence of co-stimulatory signals, clonal energy occurs in the periphery.
Clonal energy maintains tolerance to some (but not all) self antigens that are not available for clonal deletion in the thymus and marrow. Specific autoimmune diseases like those described above are probably not due to general failure of clonal deletion or clonal energy.
Immunological ignorance refers to the common occurrence of low numbers of low avidity self- specific T cells existing in the presence of low levels of presented self peptides without becoming activated to respond.
Humans make at least 105 proteins (average size 300 amino acids) which are processed to produce 3 x 107 peptides for presentation to T cells. Each APC has a maximum of 105 MHC molecules per cell to present these peptides. T cells must bind to about 10-100 identical peptides on an APC to become activated.
Hence, most peptides presented on APC would be below the threshold for T cell detection. The best chance of stimulating autoimmune T cells would be with tissue-specific antigens which are less likely to induce clonal deletion. There are relatively few autoimmune diseases and all people with a given disease respond to the same antigen(s).
It means that that autoimmunity occurs only under rare circumstances. The level of antigen presentation depends on which MHC alleles are available, and certain MHC alleles are linked with certain autoimmune diseases.
Tolerance is also maintained by regulatory (suppressor) T cells. T cells cells which can transfer tolerance to another animal are CD4+ CD25+ T cells. For example, neonatal rats injected with bone marrow cells from allogeneic rats become tolerant to skin grafts of the same allotype but not other allogeneic skin grafts.
T cells transferred from the tolerant rat to another rat make the recipient tolerant to the same MHC allotype as long as allogeneic cells are transferred with the suppressor T cells. Tolerance can be eliminated (broken) if cells are transferred from an animal immunized to the allogeneic cells. Probably these cells kill the allogeneic cells.