Pathophysiology of Long COVID 1: The immune system

Pathophysiology of Long COVID 1: The immune system

Pathophysiology describes functional changes that occur in our body when we’re sick. In a new series on Altea, we describe which parts of the body can be affected in Long COVID and what goes wrong. In Part One, we’re examining the immune system.

More than three and a half years since the start of the COVID-19 pandemic, we still do not quite understand why some people experience long-lasting symptoms after infection with SARS-CoV-2. Studies show that imbalances in the immune system could contribute to the development of Long COVID.

While our immune system protects us from SARS-CoV-2 infection, it can also be harmful when it reacts too strongly . Current evidence indicates that the immune system becomes unbalanced during acute COVID-19 infection, causing the development of Long COVID symptoms. To better understand this mechanism, ongoing studies are examining specific immune cells, such as T cells and B cells, as well as regulatory signaling like cytokines, which might be responsible for long-term symptoms.


Continued immune response can lead to the development of Long COVID

Researchers proposed several hypotheses as to why some people experience long-term symptoms after recovering from COVID-19:


  1. the virus causes massive damage to the body during the initial infection, which can take a long time to repair.
  2. the virus remains in some body parts for several months after infection, mainly in the digestive and nervous systems. This remaining virus continuously activates the immune system and causes inflammation.
  3. some patients with Long COVID have antibodies that mistakenly attack their own body tissues (autoimmunity). It has been known for a long time that autoantibodies can cause serious autoimmune disorders, for example, rheumatoid arthritis.


A recent study explored the connection between a continuously activated immune system and the occurrence of Long COVID. To this end, the researchers investigated specific immune cells and molecules in 127 people after the acute phase of COVID-19. About half the patients developed Long COVID. Most of them experienced severe infections and were hospitalized during their acute phase.


How B-cells and T-cells react in Long COVID

This study revealed some similarities between those who had Long COVID and those who did not have it. There are two main types of T-cells: CD8+ and CD4+. All participants had activated CD8+ T cells for up to six months after infection which suggests that immune changes due to SARS-CoV-2 last longer than previously thought. All participants also had normal levels of CD4+ T-cells six months after the infection although these cells were sparse at the onset of the disease and therefore did not expand.

The study also identified some important differences between the two subgroups of participants which could explain why Long COVID patients experience lingering symptoms. The researchers found that in patients with Long COVID, cytotoxic CD8+ T-cells (called cytotoxic due to their ability to kill other cells) produce large amounts of toxic molecules. These patients also had greater inflammation during COVID-19 and elevated levels of some cytokines (known as interferons) in their blood during prolonged disease.

B-cells, or B-lymphocytes, are another type of immune cells that are widely investigated by scientists studying Long COVID. These cells produce proteins known as antibodies which protect us from viruses or bacteria. However, the immune system can sometimes produce antibodies that inadvertently attack and destroy normal, healthy cells (autoantibodies).

An interesting observation from this study is that patients with Long COVID also had increased levels of antibodies called IgA which are mainly found in the mucosal parts of the body such as the mouth or nose. The levels of IgA were particularly high among patients who had a severe initial infection. The researchers noted that monitoring IgA could serve as a simple method for checking Long COVID patients.


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How the immune system changes in Long COVID


Autoantibodies and Long COVID

Already at the beginning of the COVID-19 pandemic, scientists assumed that autoimmunity might be a reason for the persistent symptoms that appear in some people after an infection with SARS-CoV-2. This is because COVID-19 has been associated with symptoms that are similar to some autoimmune diseases caused by other viruses.

Some studies have already corroborated the link between autoimmunity and the development of Long COVID. For example, one study demonstrated that specific autoantibodies (antinuclear antibodies, or ANAs) were present in nearly half of the patients with prolonged symptoms. High levels of these autoantibodies were also associated with more frequent neurocognitive symptoms.

It is still not fully clear whether people with Long COVID had these autoantibodies before infection with SARS-CoV-2 or whether these proteins were first produced after infection. Some studies also showed that reactivation of latent herpesviruses, for example, Epstein-Barr virus (EBV), might induce the production of autoantibodies in patients with acute COVID-19 infection. EBV reactivation is associated with some Long COVID symptoms such as fatigue and various neurocognitive symptoms, as Altea already reported.


This was Part One of our series pathophysiology of Long COVID. In the next part, we’re examining the microbiome.