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.
Great Pos Manuel, very clear!
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Reblogged this on Reflexiones y pensamientos sociales and commented:
Diferencias entre inflamación y respuesta inmune
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Thanks. Leaving for France this Friday. Will be meeting with Joaquin Fuentes. He seems to be quite a traveler. Looking forwards to when I will go and visit you in the Canary Islands.
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Great synopsis and clarification. As a scientist, I have been thinking a lot lately about inflammation and infection and its role in neuropsychiatric disorders. I am still trying to consolidate my thoughts. One of the sticky wickets, as you point out, is that some cytokine molecules are secreted in both inflammation and infection. In particular cytokines like TNF, which is activated in inflammatory processes, and can influence astrocytes. It has also been shown to negatively regulate neurogenesis. TNF gets activated during injury and during infection. TNF activation and it’s effects on behavior intrigue me, both on a personal level since a loved one is taking anti-TNF neuromodulators for an autoimmune disease, and he has also battled depression and anxiety, but also from my background doing a PhD in the same lab that was working on Neuro HIV and the dementia it causes, and how TNF activation is part of the pathology of AIDS Dementia Complex. An interesting note is that the incidence of affective disorders is much higher (45%) in individuals with an autoimmune disorder according to a recent JAMA Psychiatry study. See this link of the layman’s description http://www.healthline.com/health-news/mental-mood-disorders-tied-to-autoimmune-diseases-infection-061213 or the next link for the primary literature :http://archpsyc.jamanetwork.com/article.aspx?articleid=1696348&resultClick=3 I also believe the Biologic drugs that are TNF blockers can promptly influence the CNS since many people on drugs like Enbrel, Humira, or Remicade experience symptoms similar to a hangover which include headache (just google Humira Hangover or Remicade Hangover). Many report migraine headaches as a side effect of these drugs. Anyway, TNF is just one candidate molecule of many. Sorry for the jumbled post, but I guess I just wanted to add, that I believe inflammation can be outside the brain, but some cytokines can cross the blood brain barrier and influence the threshold for developing mood disorders. We know so little, and how, or if, these cytokines can influence the development of ASDs. The in utero effects upon neuroglial stem cells is unknown, although TNF has been associated with decreased neurogenesis. Can cytokine activation lead to altered interneuron migration? Can TNF activate microglia which can then result in microglia that goble up more stem cells? (I’m referring here to a paper from Noctor’s lab http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711552/) Anyway, food for thought and maybe someday I’ll organize my thinking on this enough to put together a grant proposal.
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Thank you for the commentary.I hope that I made it clear that cytokines can and are part of the immune response. However, as regard to inflammation many of the factors involved in inflammation have a role in the development of the brain. I think the analogy would be that of granulation tissue, common in an inflammatory response, and its emphasis on growth as a way to bridge the sides of an an injured tissue. I would not be surprised that the same elements may have a role in coticogenesis. Thanks again.
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Tengo una niña autista con 11 años que desde hace 3 padece unas neuralgias de locura. Se esta tratando con Gabapentina y ahora tambien con amitriptilina. Llegar a encontrar un farmaco que le funciones ha sido un camino dificil. Es inevitable pensar que algún proceso inflamatorio le este causando este problema. Le dan una especie de descargas electricas en la cabeza que le producen mucho dolor punzante, porque se da golpes para soportarlo. Estas crisis no son epilepticas y le pueden durar hasta media hora, vaias al dia. Alguien nos podria ayudar acerca del diagnostico y posible solucion?
Mi correo firstname.lastname@example.org. Muchas gracias.
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La conducta autolesiva es uno de los principales problemas del autismo. Pro lo general el goleparse a si mismo con la mano u objectos cercanos, el jalarse el pelo y moderse a si mismo se ven tipicamante en estos individuos. Aunque el compartamienot va y viene no tiene que estar relacionado a un trastorno epileptico. He escrito varios blogs al respecto describiendo varias de las teorias y posibles intervenciones (tratando de escibar a los farmacos): bit.ly/1vhmYk6 y tambien ver bit.ly/1yr3BuE Espero que estos escritos puedan ser de ayuda.
Actualmente salgo para dictar un seminario en Madison, Wisconsin y no estare de regreso en la oficina hasta el proximo lunes. Tan solo para dejar saber que quizas no pueda contestar preguntas de inmediato.
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