5. Questions: Tolerance and AI

Central tolerance occurs in primary lymphoid organs, thymus and bone marrow, during development and while it eliminates strongly self-reactive lymphocytes, weak self interactions are allowed in the periphery.

Peripheral tolerance mainly through Tregs (IL-10, TGFβ1, CTLA-4), immunological ignorance, and immune privilege sites (through Fas, TFGβ and barriers like the BBB) ensure that self-reactive T and B cells are kept in check.

Tolerance is our immune system’s ability to withstand or tolerate the presence of self-reactive lymphocytes. When the immune system’s tolerance is broken, then its ability to withstand these self-reactive cells is diminished or gone.

Then, self-reactive lymphocytes cannot be kept in check and can interact with their self antigen causing tissue damage leading to autoimmunity.

By infection or tissue damage → APC activation → ↑antigen + costimulation (CD80/86, cytokines) → low-affinity self-reactive T-cells get activated → autoimmunity.

Immuno-priviliged organs are organs that have poor lymphatic communication, physical barriers that prevent lymphocyte entry and/or actively suppress lymphocyte by TGFβ and FasL

examples are the brain, testis, uterus during pregnancy and eyes.

Antigen from these organs is still visible in the periphery resulting in T cell priming and if these T cellsgain access to the site (e.g. due to defects in the barrier) they can cause disease.

The “where” here refers to systemic or organ-specific and the “lymphocyte” to T or B cell mediated. This is really a rhetorical question and the answer depends entirely on the objectives of each researcher.

For example, if one wants to study the damage done tospecific organs, as is often the case in clinical medicine, then classification based ontargeted organ is appropriate.

If, however, one wants to study the cellular mechanisms that cause autoimmunity or the underlying mechanisms that led to tolerance breakdown, maybe a classification based on cell type is more fitting.

Epitope spreading

An antibody can function as an agonist (see Grave’s disease where patients make antibodies against thyroid stimulating hormone receptor, which trigger signaling and stimulate thyroid hormone production), or as an antagonist (see Myasthenia gravis where patients make antibodies against acetylcholine receptor, which block binding of acetylcholine resulting in poor Na+ influx and impaired muscle contraction). More generally, an agonist is a molecule that interacts with a signaling receptor and induces its potential to signal, whereas an antagonist is a molecule that interacts with a signaling receptor and blocks its ability to interact with agonists.

CD4⁺ T helper cells drive MS pathology indirectly, by recruiting and activating innate immune cells and inducing cytokine storms within the CNS.These secondary effector mechanisms — not the T cells themselves — cause myelin and axonal destruction.

CTLA-4 is one of the main mechanisms by which Tregs suppress immune responses (how do they do this?). Furthermore, CTLA-4 is an inhibitory receptor, which can directly signal to a responding T cell and thus limit its effector function or proliferation.

- SNPs in specific genes do not necessarily mean susceptibility to this disease and for sure do not give a causative genetic link. A specific SNP also does not mean that theexpression of the associated gene will be defective; in fact many SNPs are outside of the target gene. An AI disease like MS is multi-factorial and its causes cannot be explained simply by genetics, let alone SNPs. However, large population GWAS studies and identification of SNPs enriched in particular diseases have proven helpful in guiding us towards the effector mechanisms that mediate the disease. For example, recurrent SNPs in a cytokine receptor could implicate the involvement of this receptor in some stages of the disease.