Basics of immunological tolerance -Why are autoimmune diseases on a rise?

Shreyasi Panja, IQ City Medical College

Paul Ehrlich, first introduced the concept of autoimmunity and termed it as   “horror autotoxicus “, because the body’s own immunologically competent cells or antibodies act against its self-antigens resulting in structural and functional damage. Immunological tolerance is a state in which an individual is incapable of developing an immune response against his own tissue antigen. Two broad mechanisms, Central and Peripheral tolerance mediate it.

• Central tolerance: Deletion of self- reactive T and B Lymphocytes during their maturation in central lymphoid organs that are the thymus via apoptosis and in the bone marrow via receptor editing and negative selection. However, the process of central tolerance is not completely perfect. Many self-reactive T and B cells bearing receptors for self-antigens escape into the periphery, for which peripheral tolerance takes a lead role.
• Peripheral tolerance is provided via several mechanisms like –

1. Ignorance: Self-reactive T cells might never encounter the self-antigen. 
2. Anergy: It is defined as unresponsiveness to antigenic stimulus. Though the self-reactive T-cells interact with the APCs presenting the self-antigen, the co-stimulatory signal remains blocked. The B7 molecules on APC bind to CTLA-4 molecules on T cells instead of CD28 molecules.
3. Phenotypic Skewing: Self-reactive T cells interact with APC but might secrete non-pathogenic cytokines and chemokines receptors profile failing to induce an autoimmune response.
4. Apoptosis via Activation Induced Cell Death-Activation of T cells induces upregulation of Fas ligand which subsequently interacts with the death receptor Fas leading to apoptosis.
5. Regulatory T cells can down-regulate the self-reactive T cells through secreting certain cytokines like IL -10, TGF-beta.
6. Certain immature and tolerogenic dendritic cells down-regulate the expression of costimulatory ligands CD40 and B7.
7. Certain self-antigens like corneal proteins, testicular antigens, and antigens from the brain evade immune recognition by sequestration in immunologically privileged sites.

Autoimmunity occurs due to the breakdown of one or more of the mechanisms of immunological tolerance.

Of late the prevalence rate of autoimmune diseases like autoimmune anaemias,  ITP, Good-pasture syndrome,  Myasthenia gravis, Grave’s Disease, Hashimoto’s thyroiditis, SLE, rheumatoid arthritis, Sjogren syndrome, Scleroderma to name a few ; has increased.

Fred Miller, director of the Environmental Autoimmunity Group, at the National Institute of Environmental Health Sciences, attributing such increase to environmental causes, says “Our gene sequences aren’t changing fast enough to account for the increases yet our environment is. We have got 80,000 chemicals approved for use in commerce, but we know very little about their immune effects. Our lifestyles are also different than they were a few decades ago, and we are getting more processed food. “Scientists have defined the various triggers broadly: Chemicals, infection, stress hormones, drugs, diet, weight gain, behaviour, and more have all been cited as etiological factors.

With such impending doom overhead, a national registry of disease hotspots and development of better biomarkers for early diagnosis (since these diseases often take years to be clinically evident) seems a ray of hope.

Also read: Basics of immunological tolerance -Why are autoimmune diseases on a rise?

Sources:

1.  https://elemental.medium.com/autoimmunity-is-a-disorder-of-our-time-a7f1c45d6907

 2. Charles .W.Schmidt, Questions persist environmental factors in autoimmune disease, 2011 Jun, 119(6):A249-53 DOI: 10.1289/ehp.119-a248  PMID: 21628113 PMCID: PMC3114837 

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