Preaching Tolerance

INNATE-+-ADAPTIVESometimes, the immune system just backfires. It responds inappropriately, leading to autoimmune diseases like multiple sclerosis and systemic lupus erythematosus. Other times it overreacts to an otherwise harmless target, leading to allergies ranging from the mild, like hay fever, to the severe, like anaphylactic peanut allergies.

Autoimmune and allergic diseases are mostly a problem of the adaptive arm of the immune system, that part of immunity that can learn new targets and attack. But the ‘innate’, or non-specific, immune system plays its part too. Parts of it a necessary to help educate the adaptive arm, and to temper its responses. Exactly how is still not all that clear, but new research from Imperial College has shed a little more light on this process.

So why does this misfiring happen? Well, that’s an important question, but so is ‘why doesn’t it happen more often?’ Early transplant studies showed that one human’s organs can clearly cause an immune reaction against the donor organ in the recipient. Suggesting that there are more than enough substances in a human to cause an immune reaction. So why don’t we attack our own bodies more often?

The answer is education.

house-lupus2The immune system, honed over millions of years of evolution, has a number of systems for inducing immune ‘tolerance’. Broadly, they are split in to two parts. Firstly there is ‘central tolerance’, induced in T and B-cells in the thymus or bone marrow. Secondly there is ‘peripheral tolerance’, induced in the lymphnodes.

Central tolerance, for example, tests immature T-cells in the thymus for auto-reactivity – reacting against our own bodies proteins. Those immature T-cells which fail the test and react are ‘deleted’, forced to kill themselves for the hazard they represent.

Peripheral tolerance occurs after T and B-cells have matured. It’s a process made up of different cell types, such as dendritic cells (DCs) and a sub-type of T-cells called regulatory T-cells, supress auto-reactive cells, making those cells far less responsive to the antigen causing their response.

However, it’s now becoming clear that parts of the innate, or non-specific immune system, are also involved. Specifically, members of a group of circulating proteins called ‘complement’. Complement is a number of small proteins circulating in the blood, which, when activated can help dispatch invading bugs in a number of ways, either directly or by making it easier for other cells to swallow and digest them.

The first hints if complements importance came from the observation that deficiencies in two complement proteins, called C1q and C4, can predispose people to autoimmunity. But how is not yet well understood. The researchers in a recent paper in the journal ‘Immunology’ set about investigating tolerance in a handful of different mice. They investigated how well tolerance could be induced in normal, or ‘wild-type’, mice as well as groups of mice each bred to be lack one of C1q, C3, C4 and C5 complement proteins.

They found that C1q, C3 and C4 were all required for inducing tolerance in their model. However, C5 appeared to have no effect, and as such played no role in tolerance. Looking more closely at what was going on, they found that mice deficient in C3 failed to induce a tolerance forming partnership between T-reg cells and dendritic cells, called a tolerogenic loop.

They found that C3- dendritic cells failed to produce more of an enzyme called iNOS (inducible Nitric Oxide Synthase). iNOS produces nitric oxide from an amino acid called arginine and is known to be important in the proliferation of T-cells.

Current drugs for handling unwanted immune reactions are something of a blunt weapon. For example, in organ transplants immunosuppressive drugs, that depress the entire immune system, are typically used. This means that transplant patients are at a greater risk of picking up bugs and infections which would normally wouldn’t bother them.

If we can find a way to harness the ability to re-educate immune systems, to induce tolerance, towards better healing, there could be a huge positive impact on both medicine and the quality of life of people, from those with autoimmune disease to those with allergies.

 

Source: Fossati-Jimack, L., Ling, G. S., Baudino, L., Szajna, M., Manivannan, K., Zhao, J. C., … Scott, D. (2014). Intranasal peptide-induced tolerance and linked suppression: consequences of complement deficiency. Immunology, (0). doi:10.1111/imm.12358

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