The Innate Immune System and Autoimmunity

The human immune system is built on two separate foundation pillars: innate and acquired immunities (adaptive immune system).

Innate immunity can be defined as a universal and ancient form of host defence against infection. As a key component of the first line of defence against pathogen infection, the main aim of the innate immune system is to best tailor the response to the pathogen encountered. The innate immune system relies on a set of specific sensors that detect patterns frequently conserved in pathogens.

The response is specific due to the expression of cell surface pattern recognition receptors, which can recognize pathogenic polysaccharides, glycolipids, lipoproteins, and nucleic acids (DNA or RNA). Upon activation, these sensors engage potent inflammatory responses aiming at recruiting cells from the adaptive immune system to the site of infection to clear the pathogens.

Whereas the adaptive immune system arose in evolution less than 500 million years ago and is confined to vertebrates, innate immune responses have been found among both vertebrates and invertebrates, as well as in plants, and the basic mechanisms that regulate them are conserved.

Innate immunity is a rather recent field of research, which has exploded in the past 20 years – with many innate immune sensors only recently discovered. As an example, cGAS, the sensor working upstream of STING signalling, was only discovered in 2013. ^I

Chronic inflammation and autoimmune disorders

Inflammation is essential to recruit the effector cells of the immune system to the site of infection or tissue damage in the body. Inflammation is however very finely tuned and rapidly switched off following initiation, as it can also fuel tissue damage if persisting.

Inflammation operates as a balanced system that is regulated at multiple levels, and sometimes this system can go out of balance. Whether this is due to hereditary predispositions, pathogen or environmental driven stimuli, persistent inflammation can lead to uncontrolled chronic immune responses. Such immune responses are aberrantly targeted to the body, leading to pathologies referred to as auto-immune or auto-inflammatory diseases. In other words, the immune system starts attacking the body rather than protecting it.

There are more than 100 potential autoimmune diseases, including psoriasis, scleroderma, coeliac disease, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes and pancreatitis. These diseases can affect almost any bodily organ, including the brain, and in most cases more than one organ or organ system. The classic sign of autoimmune disease is inflammation, with symptoms such as joint stiffness, pain, loss of function, and rashes, with periods of remission and periods of increased disease activity (flare-ups).

Estimates of the number of individuals suffering from autoimmune diseases in the US range from 14 million to nearly 24 million, but all agree that the numbers are increasing. Auto-immune diseases are ~2 times more prevalent in females (with extreme cases such as SLE where prevalence is ~9 times greater in females). This is believed to be a direct consequence of the better fitness of immune responses in females, which are generally better protected against viral infections, and has been proposed to involve TLR7 sensing (in other words, their immune system is more sensitive which predisposes to auto-immunity).

Autoimmune diseases are the clinical correlate of a dysregulation of the immune system, involving multiple steps and multiple components of both the innate and the adaptive immune system. Innate immune sensors are sensitive to a repertoire of foreign "patterns" and normally not activated by “self” ligands. With the revolution of personalised genome sequencing technologies, the past decade has helped identify mutations in the genes which encode for these receptors, regulators, or their signalling components, to demonstrate that many auto-inflammatory diseases were initiated at the level of the innate immune system. ^II This can lead to the activation of auto-reactive cells of the adaptive immune system, thereby provoking autoimmune disease.

^I Xiao TS, Fitzgerald KA. The cGAS-STING pathway for DNA sensing. Mol Cell. 2013;51(2):135-139. doi:10.1016/j.molcel.2013.07.004
^II Rood JE, Behrens EM. Inherited Autoinflammatory Syndromes. Annu Rev Pathol. 2021 Oct 26. doi: 10.1146/annurev-pathmechdis-030121-041528. Epub ahead of print. PMID: 34699263.