Immune system

The immune system is a complex combination of organs, circulatory networks, and cells which work together to identify, target and eliminate harmful substances that enter the body. The immune system response has many steps. Once in full effect, different parts of the system move in parallel to restore health to the host. When the immune response is no longer needed, the immune system will suppress the reaction.

Myalgic encephalomyelitis (ME) is a complex multi-systemic disorder which causes neurological impairments, energy metabolism/ion transport dysfunction, and immune, gastrointestinal and/or genitourinary symptoms.

Immune system symptoms
Symptoms related to M.E. include:
 * Flu-like symptoms (sore throat, sinus inflammation, lymph node changes) that typically begin or worsens with exertion, for instance as part of post-exertional malaise (PEM)
 * Increased risk of contacting viruses, which last for a prolonged time
 * Gastro-intestinal problems, which may include nausea, abdominal bloating, or irritable bowel syndrome (IBS)
 * Needing to urinate either more urgently or more frequently, sometimes at night (nocturia)
 * New sensitivities to smells, chemicals, or medication; food or alcohol intolerances

Innate Immune System
Prior to actually getting into the body, pathogens or toxicants have to pass the body’s most basic immune defense: the skin and mucous. Mucous especially plays an important role because it is present in all the places where infection is most likely to occur (e.g. the eyes, nose and mouth).

Innate immunity is the nonspecific method of eliminating pathogens from the body. The main agents that carry out this mass, undiscriminating disposal of pathogens and dead or defective cells are called macrophages and neutrophils. Macrophages are cells derived from monocytes which are made in the bone marrow. Initially, monocytes do not have a specific purpose. However, when these cells travel to and populate different tissues, those tissues emit signals for the type of immune cell that is needed in that area. Monocytes, therefore, alter their shape and function to satisfy work more effectively in their new location. These functions can vary from generalized (e.g. macrophages) to specific such as work done by B- and T-cells.

Macrophages are in almost every type of tissue and they are more abundant in tissue types that are especially susceptible to infection (e.g. lungs, stomach). Because macrophages float around the body until needed, they are nearby and able to quickly migrate to the sight of infection. Within a span of hours they may be done neutralizing the pathogen.

Neutrophils are the most populous white blood cell and, like macrophages, they are phagocytic and come from the bone marrow. They differ from macrophages a couple of ways: they mature in the thymus despite being produced in the bone marrow, and also contain sacs inside them called granules that aid in the breakdown process. While macrophages are migratory and generally close by and can sense sites of infection, neutrophils need to be recruited to the sites.

If pathogens make it past the skin and mucous and the macrophages are unable to clear them, the body has a second method of removing infiltrators. After the initial exposure, the body “remembers” a specific signature on the infiltrator so that it can be identified and eliminated quickly during all subsequent exposures.

Acquired or Adaptive Immunity
Adaptive immunity is so named because the body must first experience an initial infection for this type of immunity to form against that specific contagion. The first time the body experiences an infection is the worst because it does not yet know how to best eliminate the infiltrating substance. After initial exposure, however, the body has several mechanisms to remember and quickly and aggressively neutralize the pathogen. Many times this system does its job so well that a person may not even realize they are symptomatic or have an infection.

The body needs to identify a pathogen prior to eliminating it. There are several cells that the immune system uses to recognize pathogens. Dendritic cells are antigen-presenting cells that help begin this secondary immune response. Dendritic cells (Greek: dendron, meaning tree) received their name because of the arm-like branches that spread out and grab antigens released by infectious agents. The dendritic cells place the antigens, like flags, onto their surface for helper T-cells to recognize. After palpating a dendritic cell, white blood cells call helper T-cells (also called CD4 T-cells) which secrete lymphokines to direct other immune cells to target the infection. Helper T-cells also promote the production and release of proteins called antibodies. Antibodies clump around pathogens neutralizing their infectious capabilities, perforate the surface of pathogens encouraging its deterioration, and signal to other cells to engulf and destroy the invader. B-cells are produced in the bone marrow and are the antibody factories of the body. They make specific antibodies for the specific pathogen(s) that the body is currently fighting.

Another type of T-cell, killer (cytotoxic) T-cells also must first be presented with antigens by one of the body’s antigen-presenting cells for it to activate. Once given a target, killer T-cells directly destroy infectious and defective material. Similar to antibodies, they punch holes in the membranes of bacteria, and infected or malfunctioning cells.

The last kinds of T-cells are memory and regulatory. Memory T-cells engulfs the material from the infected or defective cells and store that information in case of a future infection by the same pathogen, or on locating a similar defect. This allows the immune system to react faster because it already knows what is needed to respond to that specific pathogen or defect. Regulatory T-cells keep helper and killer T-cells’ activity at higher levels only when they are necessary. These T-cells will reduce helper and killer T-cells and decrease their activity after the pathogen has been eliminated.

Components of the Immune System
White blood cells, also called leukocytes, are the main defenders of the body. They circulate throughout the bloodstream (the circulatory system), surveying the body for possible threats.

Granulocytes
Granulocytes are a type of white blood cell filled with double-membrane sacs called granules which contain a variety of substances. These substances aid in the immune response. The substances released include: The contents of granules can be released in two ways depending on the purpose of the substances that will be released. A granule can be ushered to the granulocyte’s membrane surface where the two will merge and the granule can dump its internal material into the area surrounding the cell. This method is helpful when the substances need to act directly on other tissues such as mast cells secreting histamine which act directly on the smooth muscle the mast cell in.
 * histamine, a molecule that responds to injury, allergies and inflammation by inducing smooth muscle contraction and increased blood flow;
 * cytokines, messenger proteins that induce other immune cells’ inflammatory functions;
 * enzymes, metabolic proteins that decrease the amount of time it takes to carry out chemical reactions, and that activate other white blood cells.

Alternately, granules can also release their internal material directly into the granulocyte. This process is helpful in cases where the granulocyte has engulfed a pathogen and the released elements from the granules can break it down. There are several types of granulocytes that perform functions related to both innate and adaptive immunity.

Basophils
Basophils, the least common granulocyte, help the body identify foreign substances. Once a pathogen is introduced to the body and consumed by a lymphocyte, such as a macrophage, the invader is broken down into smaller pieces. This eliminates it as a threat and makes disposal easier.

Additionally, in order for the immune cell to signal to the body that an invader was present (and that most likely there are other microbes nearby), the white blood cell will save some of the proteins from the pathogen and place it on its surface like a flag. These surface proteins are called antigens, and the process is called antigen presentation. Basophils are both capable of placing these antigens on themselves and onto other cells.

Now that the antigen can be identified, different white blood cells begin scanning cells’ surfaces in search of these markers. Helper T-cells (CD4 T-cells) are produced for this purpose. After sensing antigens, helper T-cells signal for the production of other while blood cell variants, which make inflammatory molecules that fight the infection. In addition, CD4 T-cells also help macrophages and killer T-cells perform their phagocytic and cytotoxic duties.

However, before a helper T-cell does all of this, they need to be: 1) told to function as these particular cells, and 2) stimulated to function in that manner. Basophils are the cells responsible for the programming and stimulation of these immune cells. It was initially hypothesized that basophils did not contain an essential component necessary to the differentiation of naive T-cells into helper T-cells. New evidence supports the idea that basophils do in fact possess all the necessary proteins, such as major histocompatibility complex II (see section below) and the cytokine IL-4, that stimulate the conversion of naive T-cells into helper T-cells.

Normal basophils amounts in the body range from 0-300/μL (0.000003L) of blood. Low levels are caused by afflictions such as hyperthyroidism or anaphylaxis. High levels are caused by hypothyroidism, and myeloproliferative disorders (blood disorders).

Eosinophils
Eosinophils are the next most common granulocyte. However, they store several enzymes and proteins with unidentified roles, so some the full extent of their purpose is unknown. Eosinophils inflict damage largely to parasites and to a smaller extent bacteria and viruses. These cells can also cause damage to the body’s own tissues during allergic reactions. Outside of the immune system, eosinophils help with organ development.

Eosinophils are typically less than 500/μL of blood. Infection by parasitic worms, ulcerative colitis, allergies are examples of maladies that can cause high levels of eosinophils, known as eosinophilia. Low levels may indicate alcohol intoxication, Cushing’s disease or problems with the bone marrow.

Neutrophils
Neutrophils are the most common immune cell and the first type of cell to arrive at the site of infection. These cells are flexible, bulbous, and multilobed. Normally, neutrophils travel through the blood and lymph systems but they have receptors that jut out of their surface like pins on a pincushion, that allow them to attach to cells stressed by damage or infection and perform their duty. With these receptors, neutrophils are also able to slip between cells if they’re needed in tissues outside of the blood and lymph systems.

Neutrophils are activated by chemical signals that stressed cells release. Cytokines, messenger proteins that induce different immune cell functions, can function in this capacity: switching migratory neutrophils to potent eradicator cells. Once operative, neutrophils working alongside macrophages in the innate immune system, engulfing and destroying pathogens non-specifically. This mechanism works because there are molecules present on pathogens that are not present on any of the cells in the body. These are called pathogen-associated molecular patterns (PAMPs). Cells in the body that have pattern-recognition receptors (PRRs), which neutrophils do, can identify the PAMPs and eliminate the non-self cells. Once ingested into the lumen on the neutrophil, the contents of the granules are released, which break down the microbe. Alternatively, the granules from a neutrophil can be released to the surrounding environment and break down pathogens outside of the cell.

Neutrophils are normally between 1500-8000 neutrophils/μL. High levels are caused by smoking, infection and non-infectious inflammation. Low levels appear with suppressed immune systems, autoimmune diseases and during drug treatments such as chemotherapy.

Monocytes
Monocytes are also white blood cells and are largely tasked with ingesting and eliminating microbial invaders, or identifying and presenting the proteins made by the infectious agent. They may also work in a restorative capacity to heal the affected area(s). Typically, monocytes become tissue macrophages or dendritic cells.

Macrophages
Macrophages are globular cells derived from monocytes that consume dysfunctional cells, cellular debris, and pathogens; they may be thought of as the garbage disposals of the immune system. They may be already present at sites where infection occurs, or they may migrate to the area of infection. As the name suggests, tissue macrophages exist in the different tissues in the body (e.g. liver or skin); they also are not necessarily derived from monocytes circulating in the blood and lymph system.

Dendritic cells
Dendritic cells are also monocyte-derived. They aid T-cell recognition of infectious material through the processing of antigens and production of proteins that major histocompatibility complexes (larger proteins on the surface of cells and tissues that allow the body to identify self from foreign) present to T-cells.

Bone Marrow
White blood cells are produced in bone marrow. They begin as pluripotent hematopoietic stem cells (PSCs or HSCs) meaning they are capable of becoming any of the cells listed above, as well as red blood cells or platelets. T lymphocytes (T cells) are produced in the bone marrow while B lymphocytes (B cells) are both produced and develop to their full function in the bone marrow.

Thymus
The thymus is an immune organ that ceases having a functional capacity when puberty begins. During development, including during fetal development, the thymus stores T-cells (link to lower section maybe). The thymus is also a part of the endocrine system as it produces the hormone thymosin. This hormone initiates the maturation of T-cells. Once fully developed, the T-cells leave the thymus for the lymph nodes, where they enter active circulation and begin their immune duties.

The Lymph System
The lymph system, like the circulatory system, is comprised of vessels and nodes all throughout the body. Instead of blood, these vessels carry a slightly opaque, white fluid called lymph. This circulation system is responsible for removing toxins and infectious agents from tissues. Spread throughout the lymph tubes are small, grape-shaped compartments attached in clusters on the sides of vessels. These nodes, concentrated at the neck, upper chest, armpits and groin, constantly filter the lymph liquid of harmful substances. The lymph nodes contain B and T lymphocytes that specifically recognize dangerous material and make antibodies, which further help identify the pathogens, and eliminate them.

Spleen
The spleen filters the blood of dysfunctional or malformed red blood cells and platelets. It also clears away infectious agents from the blood. Macrophages neutralize all of these potential harms and recycle the products they can for further use by the body (e.g., hemoglobin from defective red blood cells can be put in new red blood cells). Lymphocytes are also stored in the spleen.

Myalgic Encephalomyelitis
There is evidence of immune dysregulation in Myalgic Encephalomyelitis:
 * Reduced natural killer cell function.


 * Elevated regulatory T cells

"Immune system abnormalities – some people with ME/CFS have impaired natural killer cell function and/or T cell function, chronic higher production of inflammatory cytokines, and in some cases slight increase in some autoantibodies (rheumatic factor, anti-thyroid antibodies, anti-gliadin, anti-smooth muscle antibodies, and cold agglutinins)."
 * The Centers for Disease Control and Prevention ME/CFS page:

Fibromyalgia
In 2018, Zhang et al. research found inflammatory genes were involved in FM. Their paper SNPs in inflammatory genes CCL11, CCL4 and MEFV in a fibromyalgia family study concluded: "SNPs with significant TDTs were found in 36% of the cohort for CCL11 and 12% for MEFV, along with a protein variant in CCL4 (41%) that affects CCR5 down-regulation, supporting an immune involvement for FM."There is ongoing immune system research of fibromyalgia.

Videos
More on the immune system: More on neutrophils: More on eosinophils
 * Crash Course - The Immune System Part 1 (Adaptive immune system)
 * Crash Course - The Immune System Part 2 (humoral immunity & B cells)
 * Crash Course - The Immune System Part 3 (cell-mediated immunity & T cells)
 * Neutrophils and How White Blood Cells Work
 * Eosinophils