Last week during our weekly physician conference, I discussed a patient with an autoinflammatory disease. An elderly male, he had a history of recurrent fevers, hives, and elevated inflammatory markers, which had gone untreated for many years. Eventually, he developed renal amyloidosis (accumulation of amyloid fibers in the kidney causing kidney failure) and was finally referred to rheumatology clinic for further evaluation. Although he had many classic signs and symptoms of an autoinflammatory disease, his physicians had not recognized it. Even at the conference, some physicians were unaware of this group of diseases.
Autoinflammatory diseases are a newly described set of illnesses that cause systemic inflammation due to problems in the innate immune system. The innate immune system includes several types of white blood cells, such as neutrophils, macrophages, and natural killer cells. These cells are the first responders to infection because they recognize common patterns in many pathogens (such as the cell wall in bacteria). In response to a pathogen, these cells secrete inflammatory molecules (cytokines) that alert other immune system cells and prepare the body to fight.
Autoinflammatory diseases are often caused by genetic mutations within the cells of the innate immune system. These mutations lead to episodes of unprovoked immune system activation (production of inflammatory cytokines, recruitment of macrophages, neutrophils, etc.). In a sense, the body acts like an infection is present, even when there is none. This is why many symptoms of autoinflammatory diseases–such as fever, rashes, and joint pain–mimic infections and why these diseases are often difficult to diagnose. The best characterized autoinflammatory condition is Familial Mediterranean Fever, which causes recurrent, brief attacks (12 to 72 hours) of fever, abdominal pain, chest pain, joint pain, and evidence of inflammation on blood tests.
In contrast, autoimmune diseases arise from problems in the adaptive (humoral) immune system. The adaptive immune system is more sophisticated than the innate, consisting of specialized B and T cells. Each B and T cell in our body is unique and can only recognize a specific pathogen. Thus, it takes much longer for a B or T cell to recognize that a pathogen has invaded the body. However, once the pathogen is identified, the cell divides and multiplies, leading to a very effective and direct attack on the pathogen. B cells also produce antibodies, which help to neutralize the pathogen. Unlike the innate immune system, the humoral immune system develops “memory,” so it can better fight the pathogen when it reencounters it in the future.
In autoimmune diseases such as lupus, the B and T cells of the adaptive immune system lose the ability to differentiate self from non-self. That is, they start seeing specific organs in the body as foreign (almost as if they were pathogens!), and thus begin to mount an attack against those organs, often leading to organ damage or destruction. In lupus, B and T cells often target the kidney, lungs, or heart, leading to damage or destruction of these organs. However, autoimmune diseases can target almost any organ in the body. For example, in multiple sclerosis, cells attack the brain. In rheumatoid arthritis, the joint is the target organ. In pemphigus, the body attacks the skin. For reasons that are still unknown, autoimmune diseases more often affect women, whereas autoinflammatory diseases usually affect both sexes equally.
Ultimately, I think my patient may have had Muckle-Wells syndrome, an autoinflammatory disease caused by mutations in the NLRP3 gene. Autoinflammatory disorders are still underdiagnosed and poorly understood. It seems like every month, a new autoinflammatory disease is discovered (take a look at this week’s New England Journal of Medicine). Furthermore, various abnormal pathways in autoinflammatory diseases have been implicated to play a role in more common diseases such as heart disease and diabetes. Thus, understanding these rare disorders may provide insights into diseases afflicting millions of people worldwide.
