Introduction

The human body is a marvel of multifaceted mechanisms that work collectively to ensure that we are able to endure, in spite of whatever hardships we may have to weather in life. Sometimes, as a result of life’s roulette, things can go wrong, ultimately leading to malfunction. One of the many ways that this can manifest is through disease, for example, sarcoidosis. We will look at this in more detail, concentrating specifically on sarcoidosis and its impact on the lymphatic system and the impacts this can have on daily lives.

What is Sarcoidosis?

Sarcoidosis is an inflammatory disease, characterised by the growth of granulomas on the skin. There are many types, although the lungs are affected in more than 90% of patients.1 Other commonly affected organs include the heart, skin, eyes and the brain. The immune system’s dysregulation leads to symptoms such as weight loss, fevers and tiredness as well as more specific symptoms depending on which organ is affected.^2,3,4 Granulomas (clusters of immune cells) form in the parts of the body which are affected, and these can cause either no symptoms or a large array of symptoms over a long period of time, depending on the patient.⁴ This article will outline how this may occur.

What causes Sarcoidosis? 

Sarcoidosis is a condition that is currently not entirely understood, yet women are affected more than men. Flare-ups that lead to diagnosis normally occur in those in their twenties and thirties. However, women often can experience symptoms in their sixties too, thus leading to a late diagnosis. A great number of patients experience remission within 3 years of diagnosis, so it is important to remain hopeful despite the unknown causes of this condition. 

It is thought that there is a genetic component which may lead to the onset of this disease, especially as genetic studies have indicated that 39% of those with sarcoidosis may pass on the disease to their descendants.⁵ A relatively common form of a gene called BTNL-2 (Butyrophilin-like 2 protein) may be linked to sarcoidosis. However, the specific variation in the sequence of this protein linked to sarcoidosis is present in approximately 33-45% of the world’s population.^5,6 Sarcoidosis affects 0.00001 - 0.0016 of the population, depending on the countries studied, and therefore it is a mystery how this common gene variation only leads to a rare disease in less than 10,000 people who have this variation.⁷ This leads to the conclusion that other genetic factors may be at play, or possibly environmental factors too, although a clear understanding of the causes of the disease have not yet been determined. 

How is the Lymphatic system involved?

The lymphatic system is another system of vessels within the body, like the circulatory system which has arteries and veins which travel all over the body. Unlike the circulatory system, the lymphatic system doesn’t carry blood but instead carries a clear liquid called tissue fluid (excessive fluid released from blood vessels to carry nutrients to all the cells of the body). The lymphatic system carries this fluid around the body, passing through lymph nodes. These are specialised centres for filtering the tissue fluid at various points throughout the body, allowing any germs or foreign bodies to be attacked and removed by the immune system. The lymphatic system also carries cells of the adaptive immune system, such as T cells and B cells, around the body, thus preventing them from attacking healthy parts of the body. As innate immune cells, such as macrophages, present foreign markers to activate the adaptive immune system at lymph nodes, immune cells in granulomas continue to present cells to the lymph nodes during the course of sarcoidosis, and can sometimes bring inflammation to the lymphatic system too. Consequently, granulomas can start forming in the lymph nodes, causing them to enlarge. The swelling of these lymph nodes can be seen on CTs, and often this aids in the diagnosis of sarcoidosis patients.³

Granulomas in pulmonary sarcoidosis form almost exclusively along lymphatic vessels. Some studies have found that 67% of sarcoidosis granulomas are associated with lymphatic vessels that irregularly formed after birth, suggesting that granulomas may support formation of new lymphatic vessels (evidence for cardiac and pulmonary sarcoidosis).¹² The filtering of the tissue fluid may not be as effective; immune cells may not be able to survey the body as effectively and chronic inflammation may occur if the granulomas in the lymph nodes persist. This makes the body more vulnerable to other diseases. This may be why new lymph vessels form, though it doesn’t explain why the granulomas form in these areas almost exclusively. Further research is required to determine the way this affects disease progression.

How does the immune system go wrong in sarcoidosis? 

Our immune system is a security team, which is always on duty to protect the body. There are “first responders” that attack and evaluate any immediate changes or threats to the body, for example, a small cut or a virus such as the common cold. Regardless of what happens, the first responders always deal with the issue first. In our bodies, this is called the innate immune system. Many different first responders such as neutrophils, macrophages and natural killer cells work together in the body to identify foreign threats, and then deal with them accordingly.¹⁰ They have the ability to quickly recruit other immune cells to the site of attack and sometimes deal with issues before we ourselves have consciously noticed that something is amiss. 

If something more unknown, complicated or dangerous is afoot in the body, the innate immune system can act as the first line of defence whilst recruiting secondary, more specialised defenders to the scene of the crime. This is the case in many long-term or deadly illnesses, such as chest infections, the flu, sepsis, and tuberculosis, amongst many others. When the innate immune system (the line of first defender immune cells) recognises and attacks a foreign offender, cells like macrophages take the recognising markers to lymph nodes in the lymphatic system and present it to the adaptive immune system to activate the specialised line of defence.¹¹ 

Specialised cells include T cells and B cells. T cells can be split into a few categories, such as CD8+ T cells which recognise specific markers on the surface of foreign bacteria and viruses (and any foreign objects in the body) and can then recruit the right help to the site of infection.¹⁰ T helper cells help coordinate the body’s immune response as a whole. This can be quite complicated, luring the correct cells to where they need to be as well as causing a fever when required.¹⁰ Regulatory T cells help prevent an overactivation of the immune system which is essential because that too can lead to more damage within the body.¹⁰ A response at the correct level is vital within the body, as the wrong protocol may lead to further problems. B cells are then responsible for making antibodies that are specific to the offending attacker, thus allowing the attacking infection to be more easily destroyed. 

In sarcoidosis, granulomas form which are masses of immune cells that collect together into balls of different sizes. Sometimes the body naturally makes granulomas to surround a foreign bacteria e.g. in tuberculosis (TB) granulomas surround TB bacteria in the lungs. The macrophages which cannot entirely remove the offending pathogen remain with it and are then surrounded by lymphocytes, thus forming the granuloma to continue the attack on the offensive target whilst preventing it from harming the body further.⁹ However, unlike in TB where the granulomas surround the bacteria and then die, the granulomas in sarcoidosis persist, sometimes for many years. In patients where there are no symptoms this is okay, but in cases, especially those without remission within a few years, scarring can occur in the parts of the body where the granulomas form. This could cause those body parts to start malfunctioning e.g. if they formed in the lungs then the scarring can cause difficulty breathing over time. 

In sarcoidosis, some evidence suggests that the regulatory T cells become overactive, preventing many T cells from multiplying and thus leading to the lack of lymphocytes (T cells, B cells and other adaptive immune cells) seen in the periphery of sarcoidosis patients.⁸ Others believe that the T cells are overly active at the site of disease, causing these big granulomas to form. As a result, there are fewer T cells available for the rest of the body to use hence why fewer lymphocytes are seen peripherally in the body.8 Others suggest that sarcoidosis over a prolonged period of time can cause the CD8+ T cells to become overly active.8 As these suppress the activation and multiplication of other T cells to prevent excessive damage to the body, it is possible that these too are responsible for the immune conundrum witnessed in sarcoidosis. As macrophages have also been able to differentiate into immune cells, immune dysfunction and lymphatic expansion may be connected in sarcoidosis, though further research is needed to find a mechanism.¹²

Summary

Sarcoidosis is an inflammatory disease which results from unknown causes. It can affect many different organs and results in the formation of persistent granulomas which are spheres of immune cells that attack part of the affected organ(s). As a result, the granulomas and inflammation can spread to the lymph nodes, often leading to further impairment of the immune system.