This year I have been able to attend a large number of congresses all over the world. One thing that has struck me is how some people within the medical field use terminology inappropriately. Probably the major culprit is the interchangeable use of inflammatory and immune response. These are specific terms with different meanings. In autism there is little evidence for inflammation but mounting evidence of immune mediated mechanisms. Sometimes these processes make their appearance in tandem, or even work together; however, we should keep their distinguishing characteristics in mind when looking for a cause or trying to design a therapeutic intervention.
Inflammation means “being on fire” (from the Lain “inflammo” meaning “I set alight” or “I ignite”). Think of the word inflammable (something capable of being set on fire) that has a similar root and meaning as inflammation. Depending on the part of the body that is affected the pain of inflammation can be described as lancinating, burning or throbbing. People with arthritis (inflammation of the joints) understand the meaning of the term. The pain in many cases can be disabling.
Inflammation is a mechanism that is highly conserved across evolutionary species. It has also been known and described for a long time in medicine. Aulus Cornelius Celsus (25 BC- 50 AD) a Roman encyclopaedist, enumerated the cardinal signs of inflammation as being: calor (warmth), dolor (pain), tumor (swelling), and rubor (redness). Later on, Rudolf Virchow (1821-1902) a German physician added still another descriptor namely loss of function. Loss of function is a protective mechanism aimed at immobilizing a body part and preventing further damage.
Inflammation is a non-specific response that is active regardless of intruder or type of injury (e.g. ionizing radiation, trauma, infectious agent). It has no memory. This is different from the immune response as the latter is highly specific and has “memory”. The ability to recall having faced a similar threat makes it easier to activate a response whenever the immune system encounters it. The immune response is classified as a delayed response (in comparison to inflammation) but its memory allows it to mount a rapid response when rechallenged by the same offending agent. Sometimes the immune response can be chronic and last for years.
Chemical mediators account for the pain which is necessary in inflammation as a way of warning the body that it is injured. Other chemical mediators (called cytokines) are secreted from the site of inflammation and attract cells like leukocytes towards the site of inflammation. Cytokines secreted during the immune phase are more specific and selective for the offending agent.
Inflammation is primarily a vascular response. Vasodilation serves to increase blood flow to the target area and with increased capillary permeability it causes cells to move from the blood vessels to the adjacent tissue, causing swelling and pain. The swelling dilutes the environment to toxic elements and is part of the response of the body that is generic, think of diarrhea where a large volume of liquid dilutes the toxic agent in the GI tract. Swelling also tends to immobilize the affected area by mechanical constraint and pain. Microscopic examination of an inflammed tissue may reveal the presence of cells that are marginated (a process called pavementing) adhering to the vessel wall or moving out of the vessel into the tissue. Some of these cells secrete chemicals that create retracted intercellular junctions in the blood vessels. Other cells (macrophages) ingest foreign particles.
I have examined many brains of patients with autism either by neuroimaging or postmortem and I still have to find evidence of inflammation in any of them. The characteristic vascular response of the inflammatory process is absent. Some people try to correct themselves by saying that it is not an inflammatory response but “neuroinflammation” by which they mean that some intrinsic cells to the brain are involved but the vascular response is absent.
It is clear that inflammation is an extremely old evolutionary mechanism. Over the years the mediators of the inflammatory response have been taken over by Nature and adapted to work for purposes different than those for which they were originally intended. As an example, there is little need for an inflammatory response early on during brain development. Inflammatory agents during brain development however act in a different role, one promoting brain growth (they act as growth factors). Another example, is the fact that some cells involved in the inflammatory response may be involved in synaptic remodeling and memory, a role not proper to inflammation. In essence, different offending agents may be associated with a “neuroinflammatory” response yet be part of completely unrelated mechanisms having aims different from those of inflammation (see O’Callaghan et al. 2008). Neuroinflammation in this context is clearly a misnomer.
In summarym there is very little evidence of inflammation in the brains of autistic individuals. The available evidence, however, does suggest immune related abnormalities in autism. For more information see my previous blog on the subject: http://bit.ly/1q9B45Z
O’Callaghan JP, Siram K, Miller DB. Defining “neuroinflammation”. Ann NY Acad Sci 1139:318-30, 2008.