The Story of Sarcoidosis, the Wicked Smuggler and the Double Spies
/Explaining sarcoidosis/
The many tests that come before a diagnosis of sarcoidosis often feel to us patients like a confusing path leading to an even more enigmatic diagnosis.
Using an analogy based on how the immune system functions, I will try to explain how the disease develops.
Every disease involves a genetic predisposition that influences how our body responds to it.
Some people are naturally heavier because of their genes, some are more prone to colds, some recover from a viral infection without difficulty, while others develop a high fever and need antipyretics or antibiotics if the inflammation turns into a bacterial infection.
The same applies to sarcoidosis.
One of our ancestors may have carried a gene responsible for a dysregulated immune response to one or more unidentified antigens, and that genetic predisposition was passed on to us at conception.
The strongest genetic associations with sarcoidosis are found in the HLA class II region on chromosome 6p. Among these genes, HLA-DRB1 is the most extensively validated, with numerous associated risk variants.
What is an antigen?
An antigen, or Ag for short, is a foreign molecule—something that enters the body from outside. It may be a virus, bacterium, pollen, pesticide or another substance.
It is a foreign molecule that, once inside the body, activates a whole series of defence mechanisms provided by our innate or acquired immune system.
The activation of these defence mechanisms in response to the entry of a foreign body (an antigen) is called a trigger.
Thus, the trigger for a viral infection is a virus, the trigger for a bacterial infection is a bacterium, and the trigger for an allergy is an allergen.
In sarcoidosis, studies of immune defence mechanisms indicate that the trigger of the disease is most likely a bacterium, virus or toxin. I will call this foreign substance a smuggler at an airport.
What are defence mechanisms?
Our body has a defence service that, figuratively speaking, resembles a battlefield made up of front lines, infantry, messengers and communications officers, artillery and more.
When the smuggler (the antigen) enters our body (the airport), a type of molecule reacts like a border guard. These guards are called antibodies.
Antibodies carry receptors—receivers that act like border-control dogs sniffing luggage—which investigate who this antigen is until they determine whether it is a smuggler.
These receptors (the sniffers) bind to the foreign body (the antigen). We have countless such receptors, and each recognises its own opponent and calls the border police to capture, remove, isolate or destroy it.
It is like an airport with many types of checks: ticket control, metal detectors, and dogs trained to detect gunpowder, drugs and other substances.
Therefore, antibodies carrying receptors can be imagined as border guards with sniffer dogs.
Our border guards also include T lymphocytes. They are born in the bone marrow, travel through the lymphatic system and mature in the thymus, a gland that gradually shrinks as we grow up.
The body develops its own immunity (its army) by creating its own spies (antigens) on which it trains its border guards (antibodies). Alternatively, vaccination introduces non-self antigens so that the body can practise its defence in advance—for example, influenza antigens to strengthen defence against influenza. I call the self and non-self border targets (antigens) that are not the wicked smugglers, but are found throughout the body, our spies. I will explain shortly why I call them spies.
Border guards have many names depending on their skills and tasks: T lymphocytes, B lymphocytes, macrophages, fibroblasts and others.
Cytokines — communications officers
In addition to sniffer dogs (receptors), the border guards have a system of communications officers and messengers who carry news of the smuggler’s (antigen’s) entry from the border to the rest of the army. We call these messengers and communications officers cytokines.
There are also dendritic cells that recognise the criminal and immediately send information to the guard (the T lymphocyte).
In a healthy body, a smuggler (an antigen) enters and is detected by a dog (a receptor) held on a leash by a border guard (an antibody). The information about the type and strength of the smuggler is then sent through a communications officer (a cytokine) to a system that deploys the appropriate defence—security guards, police or the army.
In sarcoidosis, a genetic programming error occurs. Because of one unusual criminal (an antigen), our border guards (antibodies and dendritic cells) send too many chaotic messages to the system. The system then deploys not only security guards, police and the army, but an entire nuclear arsenal.
What happens then?
When the military reaction is too strong, civilians are killed—in other words, our healthy cells are damaged.
Why does this happen?
Because the smuggler (the antigen) from the beginning of the story tells the police at the airport that our spies are actually double agents.
At the place where all the spies (antigens) are detained, a war involving macrophages and T lymphocytes begins, and inflammation develops (granulomas).
Because the messengers (cytokines) travel throughout the body and carry a confusing message about an attack on the smuggler, who in sarcoidosis claims that our own antigens (those created by the body to train its guards) are double agents, our army attacks organs throughout the body—according to an unknown pattern—wherever our spies are located and creates inflammation (granulomas). In some people this is more extensive; in others, less so.
This is called an excessive immune response.
Diseases in which the guards (antibodies), because of faulty information from the messengers (cytokines), react against the body’s own antigens and damage its own cells are called autoimmune diseases.
Sarcoidosis can therefore behave like an autoimmune disease: because of an external smuggler (the antigen), it starts fighting its own spies (antigens), even though the original trigger came from outside.
Biomarkers are laboratory detectors of the messengers, border guards, police and army.
That is why doctors test during diagnosis whether our defence system is sending too many chaotic messages—for example, high levels of angiotensin-converting enzyme (ACE), which acts like a postman, or TNF-alpha, an SMS message (cytokine) from one of the guards (a macrophage).
Biopsies can also be used to determine the structure of the army on the battlefield (the granuloma). The types and proportions of defence cells can help show whether the process is sarcoidosis or another disease.
The medicines we use are intended to calm inflammation or slow down signalling.
Broadly speaking, these include corticosteroids and cytotoxic or immunosuppressive medicines.
There is no medicine that can tell our immune system who the real smuggler is and who has been falsely accused of being a double agent. For that reason, sarcoidosis is considered medically incurable.
Nevertheless, some patients’ bodies eventually find the answer on their own. These are usually people whose disease lasts for a year or two and then completely disappears.
Author: Dino-Josip Ključarić
12 January 2024.