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What’s wrong with immune responses in autoimmune diseases?

  • autoimmune diseases happen in people who have super-strong immune systems‘. That’s not at all accurate.
  • Rather than a sign of strength, autoimmune diseases represent inadequate control of immune responses.
  • Start, continue, stop. These are the three key control steps for any immune response.
  • The way we currently understand it, a properly controlled immune response starts when it should, continues just long enough to restore homeostasis to the tissue/organ/body and stops when this goal is achieved.
  • Even if an immune response starts when it shouldn’t as happens in autoimmune responses, as long as the next steps are properly controlled, such an immune response doesn’t continue and soon stops. Such control or rate-limiting steps are usually called regulatory feedback loops.
  • When such regulatory feedback loops aren’t properly controlled, autoimmune responses don’t stop when they should and they eventually become autoimmune diseases.
  • Thus, rather than characterizing a person’s immune responses as strong or weak, it’s more accurate to characterize them as balanced in healthy people and disproportionate in those with autoimmune diseases and allergies.
  • Another confounding factor whose importance cannot be overstated is our dramatically changed relationship with microbes*, first with the advent of agriculture and then even more exponentially with the Industrial Revolution.
    • With agriculture and then the Industrial Revolution, moving from small hunter-gatherer to larger, settled villages and cities, i.e., from small, isolated, nomadic pockets to larger, more stable groupings caused the first major change in human-associated microbiota.
    • Post-Industrial Revolution, the spread of more sophisticated sanitation systems and increasingly minimal to practically non-existent contact with nature (animals, plants, microbes, i.e., dirt) caused profound reduction in contact with microbes and other natural co-habitants of the human body (bacteria, fungi, viruses, protists, worms).
    • Why does this matter? Because it turns out, proper immune system training requires colonization by specific, defined species of microbes starting from birth itself.
    • Species, sequence and abundance, each aspect of the microbes that colonize our bodies for life is critical in ensuring our immune system functions properly (1). Imbalances explain both allergies and autoimmune diseases.
  • However, even today, there are still more questions than answers about autoimmune diseases (2).

Which tissues and organs are affected by autoimmune disease?

  • Autoimmune diseases run the gamut from single-organ such as Type I diabetes (pancreas) to multi-organ such as SLE (Systemic Lupus Erythematosus). And even then it’s not so simple.
  • For e.g., SLE can be restricted to just skin or it may be systemic, i.e., involve other tissues and organs such as joints (arthritis), blood vessels (vasculitis) and kidney (nephritis).
    • Why restricted to skin in some patients, not in others? Not clear yet.
  • OTOH, no autoantigens have been identified in psoriasis, IBD, ankylosing spondylitis.
    • Are they even autoimmune diseases or rather autoinflammatory conditions?

Thus, we don’t even have a satisfactory and common definition yet for various autoimmune conditions.

What type of immune responses are associated with autoimmune diseases?

  • Different immune responses dominate in different autoimmune diseases.
  • For e.g., autoantibodies dominate in RA (Rheumatoid Arthritis), SLE, MS (Multiple Sclerosis), T1D (Type 1 Diabetes), celiac disease.


What type of treatments work in autoimmune diseases?

  • Same treatment doesn’t work against different autoimmune diseases.
  • In fact, same treatment doesn’t even work similarly in all patients with the same autoimmune disease.
  • For e.g., treatments that block TNF-a reduce symptoms in RA, psoriasis, IBD (Inflammatory Bowel Disease) suggesting that control of TNF-a or rather its dysregulation (imbalance) may play a key role in these autoimmune diseases.
  • However, even such Rx works only in a subset of patients with these diseases (2).
  • Again, this emphasizes we haven’t even satisfactorily defined these diseases yet.
  • It’s likely subsets of patients have different diseases.
  • So a diagnosis like RA more accurately describes/applies to an overarching syndrome, not a disease.

Who gets autoimmune diseases?

  • Many autoimmune diseases predominate in women (3). Why? Still not clear.
  • Obviously suggests major role for sex hormones in autoimmune disease predisposition.


Is there a connection between autoimmune diseases and infections?

  • Yes, long-standing (3). After exposure/infection with a particular microbe, some people are more likely to get certain autoimmune diseases, others not. Why? That’s still unknown. So infection history by itself isn’t predictive.
  • Apart from microbes, there also exist several non-microbial triggers for autoimmune diseases (4). These include, but are not limited to,
    • Deficiency in body’s clearance mechanisms for properly disposing of dying and dead cells.
    • Dietary deficiency in iodine and/or vitamin D.
    • Smoking.
    • Exposure to gluten, heavy metals or ultraviolet light.
  • Role of changes in our body’s microbiota is only just beginning to be explored.
    • After all, relative to less industrialized countries, autoimmune disease prevalence is much higher in industrialized countries (5).
    • While some of this may be owing to improved autoimmune disease diagnosis in wealthier countries, there is also strong epidemiological data suggesting role for reduced exposure to microorganisms (* and 5).

Final word goes to Judah Folkman. In the late 1990s, he said ‘ If you are a mouse with cancer, we can help you, but if you are human, it may take another 20 years‘. What he said about cancer is today equally true for autoimmune diseases.

Bibliography

  1. McFall-Ngai, Margaret, et al. “Animals in a bacterial world, a new imperative for the life sciences.” Proceedings of the National Academy of Sciences 110.9 (2013): 3229-3236. Page on pnas.org
  2. Smilek, Dawn E., and E. William St Clair. “Solving the puzzle of autoimmunity: critical questions.” F1000prime reports 7 (2015). Page on nih.gov
  3. Fairweather, DeLisa, and Noel R. Rose. “Women and autoimmune diseases.” Emerging infectious diseases 10.11 (2004): 2005. Page on cdc.gov
  4. Wang, Lifeng, Fu‐Sheng Wang, and M. Eric Gershwin. “Human autoimmune diseases: a comprehensive update.” Journal of internal medicine (2015). Page on wiley.com
  5. Colafrancesco, S., et al. “Unraveling the soul of autoimmune diseases: pathogenesis, diagnosis and treatment adding dowels to the puzzle.” Immunologic research 56.2-3 (2013): 200-205. Unraveling the soul of autoimmune diseases: pathogenesis, diagnosis and treatment adding dowels to the puzzle

* Tirumalai Kamala’s answer to Is there any strong research about the effects of increased exposure to pathogens from grouping children in settings like day care centers or schools?

https://www.quora.com/Are-autoimmune-diseases-really-a-sign-of-a-very-strong-immune-system/answer/Tirumalai-Kamala

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