I promised to write something about this group of diseases, which I came across during my own diagnostic journey. They are not the same as MECFS, but they have some interesting similarities, and may provide some clues as to what's going wrong in many of us. Background: The two main components of the immune system The immune system consists of two major components: the adaptive (or acquired) immune system and the innate immune system. The adaptive (or acquired) immune system learns from experience. When we encounter a new infection, this system works to create specialised antibodies that target that infection specifically. This process takes a while (days to weeks). But it means that next time we encounter the same or a similar infection, these specialised antibodies can be mobilised quickly so that the infection is vanquished super efficiently. Vaccinations target the adaptive immune system. The idea is to stimulate the creation of antibodies so that when we encounter the “real thing”, we’re ready to mount a full-scale, targetted attack. The innate immune system is the “first response” unit. It kicks in early, and its main job is to keep the infection under control until a full antibody-led attack can be mounted. It does generic things to make the body environment less habitable to the infection. e.g., raising body temperature. It mobilises certain types of white blood cells (e.g., NK cells, mast cells, neutrophils), that in turn produce inflammatory cytokines (e.g., IL-1 and TNF). This system is the main one responsible for making you feel sick. Its also responsible for many of the symptoms of common viral infections (e.g., sore throats, coughs, mucous, body aches). Autoimmune vs. Auto-inflammatory disease Autoimmune disease occurs when the adaptive immune system goes awry. This happens when something within the body is misidentified as harmful and specialised antibodies are created to attack it. The attack is usually localised to a particular type of tissue. e.g., the joints in RA. Often, symptoms are restricted to the tissue that’s affected (e.g., the joints). However, in some cases, the abnormal adaptive immune activity is also accompanied by innate immune activity, so the person may feel generally sick/tired as well. Auto-inflammatory diseases occur when the innate immune system goes awry. It overreacts, or fails to switch off when appropriate. The effect is that you feel sick all over. One of the key symptoms is recurrent fevers, but the inflammation can also set off gastrointestinal problems and cause severe headaches, rashes and a general flu-like feeling. People with these diseases generally feel much "sicker" than those with autoimmune diseases. This is because the key problem is with the system that causes "sick" feelings. These diseases are harder to diagnose because autoantibody tests naturally come back negative. And there's often no obvious tissue damage. Doctors look for things like periodic fevers, especially if accompanied by rashes and stomach problems (it varies enormously with the specific disease). They also look for raised inflammatory markers in the blood during episodes – things like C-reactive protein. Onset of symptoms can be in childhood or early adulthood. Auto-inflammatory diseases have only been recognised recently, and the forms that have been identified so far have a very extreme clinical profile that isn’t seen very often. However, there are likely to be yet more variants we don’t know of yet, and the inflammasome could turn out to be at the bottom of a much, much wider range of complaints. There is a great summary of all this here.