How Immune System Works

17.01.2024

COVID Impacts: Immune Dysfunction


Source: Memorial Sloan Kettering Cancer Center Library / LibGuides / COVID Impacts / Immune Dysfunction

Detailed information and resources on the long-term health consequences of COVID-19 infection and the broad social impacts of the COVID-19 pandemic.

One of the most concerning long-term effects of COVID-19 is the dysregulation and dysfunction of the immune system.

Kategoria: General
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Memorial Sloan Kettering Library

COVID Impacts: Immune Dysfunction

Szczegółowe informacje i zasoby na temat długoterminowych konsekwencji zdrowotnych zakażenia COVID-19 oraz szerokich skutków społecznych pandemii COVID-19.

One of the most concerning long-term impacts of COVID-19 is immune dysregulation and dysfunction. Immune system impacts were heavily documented, even in the first waves of the pandemic, however there was a lack of understanding as to what exactly COVID-19 infections were doing to the immune system, and what that might mean both during acute infection and long-term.

 
Early Hypotheses

Early on in the pandemic, there were two main hypotheses for the pathophysiology of COVID-19 severe disease and death: hyperactive immune system and immune system failure.

 
Hyperactive Immune System

The first was due to an overactive immune system. Early on it was noted that many patients with severe COVID-19 ended up developing ARDS (acute respiratory distress syndrome). This was reminiscent of the cytokine release syndrome (CRS) - induced ARDS and secondary hemophagocytic lymphohistiocytosis (sHLH) that had been observed previously in patients with SARS-CoV and MERS-CoV (it also is a common adverse event in cancer patients treated with CAR-T cell therapies).

Therefore it lead researchers to believe that severe infections were the results of an overactive immune response caused by excessive inflammatory cytokines, which lead to inflammatory lung and vascular injuries, and that death was from subsequent respiratory failure or coagulopathy.

 
Immune System Failure

The second hypothesis took the exact opposite hypothesis, that COVID-19 caused immune collapse. In this hypothesis, COVID-19 causes the patient's protective immunity to collapse, causing uncontrolled viral replication and dissemination which lead to cytotoxicity and death. Support for this contrasting theory was based on the observed progressive and profound lymphopenia, often to levels seen in patients with AIDS.

More recent research has concluded that COVID-19 causes dysregulation to both the innate and the adaptive immune systems. Paradoxically, in COVID-19 pneumonia, the innate immune system fails to mount an effective antiviral response while also inducing potentially damaging inflammation.


COVID-19 Alters Both Innate and Adaptive Immunity

The immune system is made up of two parts: the innate, (general) immune system and the adaptive (specialized) immune system. These two systems work closely together and take on different tasks.

 
Innate Immunity

Responsible for the initial immune response and antiviral activity, the innate system functions as a single defense mechanism, crucial for host response and illness protection.

Severe COVID cases were found to have decreased production of early immune responses (INF) which in turn lead to the virus replicating and causing severe cellular lung damage. Not only is was the antiviral response of IFN delayed and reduced, but it was also accompanied an overexaggerated inflammatory response with excessive cytokines. This resulting hyperinflammation caused edema, fibrosis, and thromboses in the lungs that ultimately lead to hypoxia, acute respiratory distress syndrome (ARDS) and death.

 
Adaptive Immunity

The adaptive immune system is critical for the development of efficient host responses to invading pathogens as well as immunological memory for future infections of similar pathogens.

Although COVID-19 patients may exhibit elevated levels of inflammatory cytokines compared to non-critically-ill patients, a study comparing the immune profiles of COVID-19 and influenza noted that while a 3–4% subset of COVID-19 patients exhibited hyperinflammation characteristic of a cytokine storm, they more commonly demonstrated immunosuppression.

CD4+ helper T cells and CD8+ cytotoxic T cells have been identified as crucial in the immunologic response to SARS-CoV-2 infection. CD4+ T cells are responsive to the virus's spike protein, and the presence of CD8+ T cell expansion in bronchoalveolar lavage is correlated with illness moderation. However, one of the most remarkable characteristics of immune dysregulation in COVID-19 is an immense depletion of CD4+ and CD8+ T cells associated with disease severity.

While lymphopenia is observed in other respiratory viral illnesses such as influenza A H3N2 viral infection, COVID-19 induced lymphocytic depletion is distinctive for its magnitude and longevity. Additionally, CD8+ T cells, crucial for their cytotoxic activity against virally infected cells, may experience the more stark reduction.

The lack of intense lymphocytic infiltration found in the lungs of critical COVID-19 patients demonstrates that the peripherally observed lymphopenia may be occurring through a mechanism beyond simply recruitment to the infection site.

T Lymphocytes

T lymphocytes (T cells) form two main and distinct groups: T helper lymphocytes and T killer lymphocytes. The name T lymphocytes comes from the Latin name of the thymus – thymus – a gland located behind the sternum. T lymphocytes are produced in the bone marrow and then migrate to the thymus where they mature.

Th helper lymphocytes are the main driving force and regulator of the immune system. Their primary task is to activate B lymphocytes and killer T lymphocytes. However, the Th helper cells themselves must be activated first. This happens when a macrophage or dendritic cell that has previously absorbed the intruder moves to a nearby lymph node and presents information about the caught pathogen. The phagocyte presents a fragment of the intruder's antigen on its surface in a process known as antigen presentation. A Th helper cell is activated when its receptor recognizes an antigen. Once activated, the Th helper cell begins to divide and produce proteins that activate B and T cells as well as other cells of the immune system.

Antigen Presentation

The presentation of antigens is the task of antigen presenting cells. These include phagocytes, primarily dendritic cells (derived from macrophages) and macrophages. Their main task is to present the collected antigens. These cells present foreign antigen to other immune cells, and secrete pro-inflammatory cytokines that attract cells of the adaptive immune response. 

Natural Killer Cells (NK cells) specialize in attacking body cells infected with viruses and sometimes bacteria. It also attacks cancer cells. The killer T cell has receptors that look for any matching cell. If a cell is infected, it quickly dies. Infected cells can be recognized by tiny traces of the intruder - the antigen that can be detected on their surface.

B Lymphocytes

The B cell (B Lymphocyte) searches for an antigen that matches its receptors. If it finds such an antigen, it attaches to it and a trigger signal is activated inside the B lymphocyte. But to be fully activated, the B lymphocyte also needs a protein produced by Th helper lymphocytes. When this happens, the B lymphocyte begins to divide, producing its own cell clones, and during this process, two new types of cells are created: plasma cells and memory B lymphocytes.

The plasma cell is specialized in producing specific proteins called antibodies that will act on an antigen that fits the B cell receptor. Antibodies released by plasma cells can seek out "intruders" and help destroy them. Plasma cells produce antibodies at an extraordinary rate and can release tens of thousands of antibodies per second. When Y-shaped antibodies encounter a matching antigen, they attach to it. The attached antibodies serve as a "tasty coating" for feeding cells such as macrophages. Antibodies also neutralize toxins and disable viruses, preventing them from infecting new cells. Each arm of the Y-shaped antibody can attach to a different antigen. So when one arm attaches to one antigen on one cell, the other arm can attach to another cell. In this way, pathogens are gathered into larger groups, which are easier for phagocytosing cells. In addition, bacteria and other pathogens covered with antibodies are easier targets for attack by complement system proteins.

Memory B cells Memory lymphocytes can recognize an antigen introduced into the body during a prior infection or vaccination. Memory lymphocytes mount a rapid and strong immune response when exposed to an antigen for a second time. Both T lymphocytes (T cells) and B lymphocytes (B cells) can become memory cells.

Figure 1: B-cell–T-cell interactions.The two-way interaction between B cells and T cells provides the basis for the concept that, in certain autoimmune diseases, an amplification cycle might allow persistent immunopathology to arise from a minor 'trigger' factor. Such a trigger might initiate the cycle through events in either the B-cell or the T-cell compartment, including the stochastic generation of both B-cell receptors (BCRs) and T-cell receptors (TCRs).

Innate Immunity and Adaptive Immunity

Innate immunity is the body's first line of defence against pathogens. It is general and non-specific, which means it does not differentiate between types of pathogens. Adaptive immunity is a type of immunity that is built up as we are exposed to diseases or get vaccinated.

Innate immunity, also known as genetic or natural immunity, is immunity that an organism is born with. This type of immunity is written in one’s genes, offering lifelong protection. It is considered the more evolutionarily primitive immune system and consequently, as well as being found in vertebrates, is also found in various shapes and forms in plants, fungi and insects. The innate immune response is fast acting and non-specific, meaning it does not respond differently based on the specific invader that it detects.

We are not born with adaptive immunity and it is not “hard wired” in their genes like innate immunity. It is acquired during their lifetime as a result of exposure to specific antigens, be that through natural means such as infection or by vaccination. Consequently, it is also known as acquired immunity. An adaptive immune response is much slower than an innate response, taking days or even weeks to develop on first encounter (the primary immune response), but is specific to the antigen(s) present and can retain a long term “memory” to enable a faster response if it is encountered again in the future. Adaptive immunity does it necessarily last throughout an organism’s entire lifespan, especially if it is not regularly re-exposed, although it can.

Innate Immmunity (Nonspecific) Adaptive Immunity (Specific)
Nonspecific responce Specific responce to pathogens and antigens
Exposure leads to a complete and maximum response Delay between exposure and complete response
Cellular and humoral components Cellular and humoral components
Lack of immunological memory Exposure leads to the development of immunological memory
It occurs in almost all forms of life It occurs in vertebrates

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News

The European Medicines Agency (EMA) has approved gene therapy for the treatment of severe combined immunodeficiency due to adesine deaminase deficiency (ADA-SCID), which is the result of a genetic mutation - reports New Scientist. You can read about gene therapy, what it is and its prospects, on the website News Medical Life Sciencies

17.01.2024

Source: Memorial Sloan Kettering Cancer Center Library / LibGuides / COVID Impacts / Immune Dysfunction

Detailed information and resources on the long-term health consequences of COVID-19 infection and the broad social impacts of the COVID-19 pandemic.

One of the most concerning long-term effects of COVID-19 is the dysregulation and dysfunction of the immune system.

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