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Articles » Diseases of Mankind » Autoimmunity
 

Autoimmunity

Autoimmunity is a large disease category that contains almost 100 diseases. They are called "autoimmune diseases". They are caused by the body's own immune system getting confused and wrongly attacking the body's good cells. Which autoimmune diseases occur from the immune confusion depends on which body cells are mistakenly attacked. Some of the best known diseases that are believed to be autoimmune include juvenile diabetes, lupus, celiac disease, multiple sclerosis, and many less common ones.

Estimates of the prevalence of autoimmune diseases in the population may be 4% or higher. However, autoimmune diseases have only been recently classified, and are not grouped in many statistical analyses. For example, autoimmune diseases are not recorded as a cause of death in the CDC statistics, despite other research indicating they are collectively one of the top ten causes of death, particularly in women. The problem is probably that most forms and statistical recording methods simply do not have an option or grouping that says autoimmunity, so each autoimmune disease is recorded separately. Another problem is that autoimmune disorders are diverse with different problems, and do not have an obvious common feature (whereas cancers mostly have tumors as a common feature).

Features of Autoimmunity

Some important features of the various autoimmune diseases as a category include:

  • Cell death: The underlying cause of the disease is damage to cells, usually a particular type of cell. Different cells are attacked in each autoimmune disease.
  • Young people's disease: elderly people do not get autoimmune diseases. It is a syndrome of young adults and children. Surprisingly, however, the elderly have a much higher level of autoantibodies, and yet do not get AI diseases.
  • Non-neonatal disease: AI does not occur in neonatal infants, at least till around 6 months, when diseases such as Type 1 diabetes are not unknown. This delay presumably is because neonatal immune systems are not formed. (Or maybe mother's passive immunity from placenta and breast feeding affects this?)
  • Women targeted: although not all autoimmune diseases show gender bias, the overall ratio for all autoimmune cases is almost 3-1 on the side of women over men, with around 75% of AI diseases occurring in women. AI diseases have been reported as in the top ten causes of women under 65. What is the role of the hormonal flux from women's reproductive systems and its effect on AI diseases? Interestingly, women were once more likely to get cancer, until the environmental effects of male smoking and occupational hazards raised male risks. Many different AI diseases have a strong female gender bias. As the exceptions, there is no gender bias in Type 1 diabetes or autoimmune myocarditis.
  • Trigger suspects: the possible suspects for what triggers the start of an autoimmune disease are many, but include: viruses, bacteria, diet, toxins, radiation, chronic infections, and so on.
  • Risk factors: genetics (significant but not total), immune system abnormalities.
  • Non genetic: although there are some inherited sub-types, and some inheritance factors in all autoimmune disease, autoimmunity is "polygenic" (from many genes) and has an unclear inheritance pattern. Risks to children and siblings of an infected person are higher but not as high as for a true genetic disease. For example, probably only around 4-6% chance for a Type 1 diabetic to pass the disease to their child.
  • Not contagious: autoimmunity cannot be passed by fluids or blood under normal circumstances. Some autoimmune diseases have been transferred between animals by the careful transfer of immune system cells. Even this is not dangerous for most healthy animals, and only works for special immune-suppressed animal strains.
  • Cross-placental contagion: There are cases of mothers giving their unborn children an autoimmune disease, including Myasthenia Gravis and Grave's disease (thyroid). This is not common, but can occur.
  • Organ-specific or systemic: Some autoimmune diseases like Type 1 diabetes are specific to a particular organ (pancreas cells). Other autoimmune diseases like SLE and RA are systemic to multiple body organs. This seems to depend on what type of cell the disease attacks. Pancreas cells attacked by diabetes are not present in any other body organs, whereas collagen that is attacked by RA is present in many places in the body.
  • Degenerative or fluctuating with remissions: Some diseases degenerate to a final state, where all cells are dead, such as Type 1 diabetes where all insulin-producing cells die over time. Other autoimmune diseases seem to fluctuate, such as MS, SLE and RA, and have long periods of remission. (Why is this? These diseases have more of the type of cells?)
  • Immune involvement: There are several aspects that show that the immune system is involved in most autoimmune diseases. These include the presence of antibodies in the blood and immune infection features near or within the attacked cells themselves (i.e. lots of immune cells).
  • Antibodies present: Many autoimmune diseases are characterized by the presence of a particular disease-specific antibody. This is especially true of organ-specific diseases such as Type 1 diabetes, which has antibodies against pancreas islet cells (ICA antibodies) and the anti-GAD protein antibodies. Systemic autoimmune diseases such as SLE may have less specific antibodies, but there is a strong association with anti-nuclear antibodies (ANAs).
  • Multiple antibodies: A common feature of some autoimmune diseases is that there are multiple antibodies against different cells in the same organ. For example, Type 1 diabetes involves some combination of insulin autoantibodies (IAA), islet cell antibody (ICA) and GAD antibodies. Does one antibody start the situation and cause the others, or are all antibodies needed for disease?

Causes of Autoimmune Disease

Autoimmunity as a theory states that the immune system itself gets tricked into killing good normal cells. The immune system wrongly makes antibodies to normal cells, which cause these cells to be attacked and killed, just as if they were recognized as unhealthy virus-infected cells. The key questions about the cause of autoimmune diseases are:

  • Triggers: what starts the immune system on the wrong path?
  • Conversion: what causes the immune system to respond to the trigger?
  • Progression: what makes the immune system keep on with the autoimmune response?

In the prevailing theories about triggers of autoimmune diseases, the trigger does not necessarily need to stay around. For example, a viral infection may trigger the immune response, but the virus need not stay as a chronic infection for the person to develop autoimmunity.

Triggers of Autoimmune Disease

There are several suspects in the search for triggers. In fact, there is quite a lot of evidence for several types of triggers, so it seems there may be multiple triggers for autoimmune diseases. Some of the suspects include:

  • Viruses: These are probably the most studied candidate for autoimmune diseases. However, results have been somewhat unconvincing. Finding viruses directly inside the autoimmune infection site has been difficult, though perhaps the viral-infected cells are already destroyed, especially if the virus only starts the early phases of autoimmunity. Thus a key question is whether viruses simply initiate AI diseases, or whether they must stay around to continue the AI reaction. It is also unclear if viruses cause their effects because of the immune reaction against the virus specifically, or simply because of the extra inflammation their infection causes at a site. Evidence of viral-AI links is quite strong and there are some AI diseases that can actually be caused by viruses in animal experiments. Some of the diseases with associated viral suspects include:
  • Bacteria: There is not a strong link between autoimmunity and bacterial infections as a trigger. However, a few examples have been found:
  • Parasites: These are very rarely regarded as an autoimmune disease trigger. However, there are a few rare examples of a relationship between an AI disease and a parasite:
  • Diet: There are some examples where the presence of a particular substance in the diet might possibly be related to an autoimmune disease:
    • Cow's milk and Type 1 diabetes: Somewhat controversial, but there is some evidence of an association between cow's milk and Type 1 diabetes. This idea is tied to the idea of molecular mimicry theory as the underlying cause, because a particular sequence of milk protein matches the proteins of the islet cells.
    • Celiac disease and gluten: There is a clear relationship between gluten (in wheat) and celiac disease. But is this a trigger of celiac disease or a secondary issue.
  • Chemicals: There are examples where toxins and chemicals have been linked to AI diseases in humans and laboratory animals.
    • Scleroderma and metals: the risk of scleroderma to miners is high, particular silica; other possible metals involved are mercury, copper, iron.
    • Mercury and kidney autoimmunity in rats
    • Iodine and autoimmune thyroiditis: if not causal, at least contributes to the development of AI.
    • Silicon breast implants and SLE: this is a controversial issue.
  • Medicines: There have been some examples of medications that may trigger autoimmunity as a side effect.
    • ANAs from hydralazine and procaine amide
    • Erytherocyte autoantibodies and alpha methyl dopa
    • Cytochrome antibodies and tienilic acid
    • acetylcholine receptor antibodies and D-penicillamine
    • halothane (an anesthetic) causes AI through creating a new antigen in the liver
  • Genetics: Familial and individual clustering: There are several key facts that show a role of genetics in autoimmunity. The first is that getting one AI disease makes it more likely that you are at risk for a second AI disease. The second fact is that the families, siblings, and children of people with an AI disease are at risk of that AI disease, and of other AI diseases. Thirdly, certain genetically modified animals get AI diseases (e.g. NOD mice get Type 1 diabetes), and this is in fact used to study AI diseases in animal models of the disease. The study of genetics and AI diseases has found numerous genes that are involved in different AI diseases.
  • Cancers: Rarely, a cancer can cause an AI disease. There are two methods:
    • Immune system tumors: Direct tumor of an immune organ such as the thymus or bone marrow (i.e. a thymoma or lymphoma). However, AI disease is very rare from these disorders, so it seems that despite their importance to the immune system, a failure at these sites is not the only problem required for AI disease to result.
    • Paraneoplastic autoimmune disorders: Though very rare, there are a few types of autoimmune disease that are caused by cancers of a different part of the body. These are called "paraneoplastic" autoimmune disorders. Examples include:

      The mechanism of paraneoplastic AI is believed to be that the cancer causes a hidden antigen to be shown to the immune system. This antigen is attacked, but by coincidence, this antigen is also at another body site (e.g. the retina), and the immune system mistakenly attacks the retina as an innocent bystander.

  • Radiation: UV light may damage cells and release new antigens. However, there are few examples of possible relationships between radiation and autoimmunity.
  • Immune abnormalities: Because autoimmunity is related to the immune system, various abnormalities of the immune system have been considered as possible triggers or causal factors.
    • Cancers of immune organs have been mentioned under cancers.
  • Thymus abnormalities: thymectomy: removal of the thymus. Neonatal thymectomy causes oophoritis and autoimmune gastritis in mice.
  • Chronic infections or inflammation: An infection causes heightened immune response as a natural course. It is therefore plausible that a chronic inflammation could possibly cause autoimmunity, or if not actually cause, at least provide an environment in which it would flourish.
  • Cells: One strange method of causing autoimmunity is to be injected with the cells of the body. This can sometimes upset the balance of the immune system. Some examples include:
    • Brain autoimmunity from rabies vaccinations, that were once made from brain emulsions (modern rabies vaccinations are not).
    • Encephalitis in monkey brains after injection with monkey brain cells.
  • Mitochondrial disorders: Not a general theory of AI, but a possible factor in diabetes and MS. In diabetes, mitochondrial failure might accumulate glutamate, leading to an excess of GAD and thus causing anti-GAD antibodies leading to diabetes. The genetic mitochondrial disorder Leber's Hereditary Optic Neuropathy has been associated with MS, but no clear link between mitochondria and MS has been found as yet.

Research on Triggering of Autoimmune Diseases

The methods whereby a particular trigger might cause the conversion of the immune system into an autoimmune reaction.

  • Tolerance theories: thymic deletion, clonal deletion, negative selection, apoptosis, forbidden clone, anergy, peripheral tolerance, etc. B-cells don't go to the thymus.
  • Two-signal theory: co-stimulation by an APC, dendrite, macrophage, or B-cell, stimulates the T-cell into activation, proliferation, or lymphokine production. Suppressor cells. Vetoing. Anti-idiotypic (anti-id) antibodies.
  • Molecular mimicry: Difficulty getting experimental confirmation in animal models. No known molecular mimics for some substances (e.g. insulin/proinsulin, but there is for islet cells and GAD).
  • Epitope crossing
  • Danger/damage theory: tissue destruction, activation of macrophages, and a co-stimulatory second signal causing AI.
  • Inflammation areas: Another possibility is that simply the fact that a site of the body gets infected could perhaps lead to an autoimmune response against that site.
  • Superantigens: Most superantigens for humans are found in bacteria, but bacterial infections are not strongly associated with AI diseases. However, there are some possible examples of links: Kawasaki syndrome of childhood multi-system vasculitis, guttate psoriasis.
  • Balance theory: Antigen injections can cause AI by over-balancing. Paraneoplastic syndromes expose too much of an already exposed antigen (in a new site). Same as the danger theory? Rare antigens like GAD in islet cells (only pancreas and brain)

Evidence about various theories:

  • Thymus or bone marrow problems don't cause autoimmunity: The thymus and bone marrow are the places where much of the tolerance occurs according to negative selection theories. The fact that thymus abnormalities only cause rare autoimmune diseases, rather than commonly, would seem to indicate that failure of thymic selection of T-cells has only a minor causal effect on autoimmunity. A few rare AI diseases do result from thymomas and lymphomas (bone marrow disorders). This indicates that peripheral tolerance may be more important.

Autoimmunity: an Unproven Theory

The predominant theory about autoimmune diseases is that they are autoimmune. Though facetiously stated, it is important to remember that autoimmunity itself is only a theory, and in fact a relatively recent theory from the last few decades. It has taken a long time for the many disparate diseases of different body organs to be brought into a single disease class.

Strictly speaking, there could be other possible theories of autoimmune diseases. If we assume that the disease involves cell death (another assumption), then a list might look something like:

  • Theory 1: Autoimmunity: immune system kills the cells
  • Theory 2: Apoptosis error: cells commit suicide for some aberrant reason, and the immune system is only there to clean up afterwards.
  • Theory 3: External cell damage: some virus, bacteria, toxin, or event kills the cells, and the immune system cleans up.

Treatment of Autoimmune Diseases

  • Anti-inflammatory: steroids, NSAIDs.
  • Immune suppression
  • Oral tolerizations: mucosal immunotherapy, e.g. eating Myelin Basic Protein (MBP) might prevent MS; eating collagen might prevent RA. Better tolerization if use cholera toxin B as an adjuvant to the eaten antigen, actually to heighten the immune response and somehow thereby cause tolerance.
  • Monoclonal antibodies
  • Competitive ligands for T-cell receptors
  • Cytokines
  • Cytokine antagonists
    • Anti-TNF treats RA
  • Chemokine receptor interference
  • Free radical damage avoidance: nicotinamine and islet cells.
  • Genetically altered T-cells
  • Genetically altered cells to express regulatory anti-AI cytokines
 

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