How your immune system works

The main function of B cells is to make an important group of proteins called antibodies that recognize and physically attach, or bind, to germs. All together, B cells can produce a wide variety of antibodies against almost all germs. However, each individual B cell makes only one kind of antibody that recognizes only one specific type of germ, like a lock and key. For example, there are different antibodies, made by different B cells, that recognize chicken pox virus versus staph bacteria versus athlete’s foot fungus.

Importantly, B cells in the bloodstream become plasma cells, which are literally antibody factories that live mostly in the bone marrow but also in many tissues. One B cell makes one type of antibody and turns into a plasma cell that, in turn, makes large amounts of that same type of antibody.

There are also different classes and subclasses of antibodies that differ from each other in their chemical structure. The five classes of antibodies are immunoglobulin (Ig) M, IgG, IgA, IgE, and IgD. IgG also has four different subclasses (IgG1, IgG2, IgG3, IgG4) and IgA has two subclasses (IgA1 and IgA2). Each class and subclass has a specific function in the body.

• IgM antibodies are the first class of antibodies B cells make and are important during the early days of an infection. IgM easily activates a group of immune system proteins called the complement system.
• IgG antibodies make up the majority of antibodies in the blood. They last for a few weeks and travel from the bloodstream into tissues easily. They’re also found in bodily fluids and only IgG antibodies cross the placenta from a mother to the baby. Immunoglobulin (Ig) replacement therapy contains mostly IgG. There are four IgG subclasses:
  • IgG1: 60-70% of total IgG, protects against viruses and toxins from bacteria like diphtheria and tetanus.
  • IgG2: 20-30% of total IgG, protects against the sugar coating (polysaccharide capsule) of certain bacteria like Streptococcus pneumoniae and Haemophilus influenzae.
  • IgG3: 5-8% of total IgG, also protects against viruses and toxins from bacteria like diphtheria and tetanus.
  • IgG4: 1-3% IgG4, controls immune responses.
• There are two subclasses of IgA antibodies, IgA1 and IgA2. IgA1 makes up about 80% of the IgA in the bloodstream. IgA1 and IgA2 in the bloodstream is called serum IgA and serum IgA is mostly single molecules. Both IgA1 and IgA2 in other bodily fluids like tears, bile, saliva, and mucus is called secretory IgA. There is a higher percentage of IgA2 in secretory IgA than in serum IgA. Secretory IgA is made up of two molecules joined together, which protects it from being broken down on mucous membranes and in bodily fluids. Secretory IgA protects mucous membranes in the respiratory and gastrointestinal tracts from germs.
• IgD makes up a very small percentage of antibodies in the bloodstream. Most IgD is on the surface of B cells along with IgM, and it may play a role in helping B cells develop into plasma cells.
• IgE antibodies protect against parasites and are also responsible for allergic reactions.

As part of their development in the bone marrow, B cells are tested to see if they make antibodies that could cause the immune system to attack healthy cells and tissues (autoantibodies). Any that do are weeded out. After developing, naïve B cells live in the bone marrow, lymph nodes, spleen, some areas of the intestines, and the bloodstream. These B cells make IgM and IgD and are called "naïve" because they haven’t yet come in contact with the germ their antibodies recognize.

• IgD and some IgM antibodies are anchored as single molecules on the surface of the B cells that make them.
• The other form of IgM is made up of five antibody molecules attached to each other in a ring and is found in the bloodstream.

After the IgM on a B cell comes in contact with the germ it recognizes, the B cell makes copies of itself. Some of the copies become long-lived memory B cells. Memory B cells form the ‘memory’ that allows for a fast, forceful response if the immune system sees the same germ again.

Other copies of the B cell ‘class switch’ to make other classes of antibodies, such as IgG or IgA, as they develop into plasma cells. However, regardless of the antibody class, the antibodies the plasma cells produce remain specific to the germ that was detected by the IgM on the original B cell.

Plasma cells are located in the spleen and lymph nodes throughout the body and pump out large amounts of antibodies, which end up in the bloodstream, tissues, mucus of the respiratory and gastrointestinal tracts, and other bodily fluids.

Sometimes, antibodies themselves prevent germs from causing an infection. For example, viruses must attach to and enter a person’s cells to multiply. Antibodies that bind to proteins on the surface of a virus can block it from entering cells and causing an infection.

In other cases, antibodies set off a chain of events involving other parts of the immune system that work to destroy the germ. Antibodies that recognize and attach to the surface of some types of bacteria activate the complement system, which then directly kills the bacteria. Antibody-coated bacteria are also much easier for white blood cells called neutrophils to eat and kill than uncoated bacteria. All of these actions prevent germs from successfully invading the body and causing infections.

T cells are a kind of white blood cell. Some T cells get rid of cells infected with viruses, while others help control how and when the immune system turns on or off.

T cells start developing from stem cells in the bone marrow but finish developing in the thymus, which is why they are called “T” cells. Without a thymus, a person cannot make working T cells, leading to severe immunodeficiency.

As T cells develop in the thymus, they cut out a small piece of DNA that forms a circle inside the cell. These are called T cell receptor excision circles (TRECs). The newborn screening test for severe combined immune deficiency (SCID) measures these TRECs. In the thymus, any T cells that might attack healthy body tissues (auto-reactive T cells) are also removed. When they are fully mature, naïve T cells leave the thymus and move throughout the body to places like the spleen, lymph nodes, bone marrow, and blood. They are called naïve T cells because they haven’t yet come in contact with germs.

T cells have proteins on their surfaces that detect substances outside of the cell. These are called T cell receptors. Similar to B cells and antibodies, each individual T cell makes only one kind of T cell receptor that recognizes only one specific type of germ. However, all of a person’s T cells together make so many different T cell receptors that the immune system can detect almost any possible germ.

There are different kinds of T cells with different jobs, including: 

• Killer T cells (also called cytotoxic or CD8+ T cells). 
• Helper T cells (CD4+ T cells). 
• Regulatory T cells (Treg). 

Killer T cells destroy cells infected by viruses or certain types of bacteria. Killer T cells travel to where the infection is and attach directly to infected cells to destroy them. Like natural killer (NK) cells, killer T cells inject infected cells with chemicals called cytotoxic granules, which act like a poison.

When killer T cells are fighting infections, they make copies of themselves. Some of those copies go on to become memory T cells, which help the immune system launch a faster and more aggressive response to the germ if the immune system sees it again.

Killer T cells can also attack non-self tissues, like transplanted organs, leading to rejection. In hematopoietic stem cell transplantation (HSCT), a different problem called graft-versus-host disease (GVHD) can occur if killer T cells in the stem cell graft attack the recipient’s body. When GVHD risk is high—for example, when the donor is a half-matched parent—the transplant team may process the graft to remove donor T cells (T cell depletion) to help prevent GVHD.

Helper T cells work with other immune cells. They help B cells make antibodies and support killer T cells in fighting foreign substances.

Regulatory T cells act like a stop signal, turning off T cells and B cells. These regulatory T cells keep the immune response at just the right level—not too strong and not too weak. Without regulatory T cells, the immune system fights things that are harmless like our own organs and pollen.

Natural killer (NK) cells are part of the innate immune system and do not need the same training that B or T cells need. They are called natural killer cells because they easily kill cells infected by viruses and are always ready to respond. They come from the bone marrow and low numbers of them live in the blood and tissues.

Like killer T cells, NK cells inject cytotoxic granules into cells infected with viruses to kill them. NK cells are very important for defending against herpes viruses in particular. This group of viruses includes the cold sore virus (herpes simplex), the virus that causes mononucleosis (Epstein-Barr virus), and the virus that causes chickenpox and shingles (varicella virus). NK cells may also target cancer cells.

Neutrophils, also called polymorphonuclear leukocytes (PMNs), make up more than half of all the white blood cells in your blood. Like other white blood cells, they develop from stem cells in your bone marrow. They are part of the innate immune system and mainly protect against bacteria and fungi. They do not do much to protect you from viruses.

Neutrophils respond to chemical signals to quickly move to places in your body where there is a bacterial or fungal infection. When you get an infection, neutrophils are some of the first cells to leave your blood and move into the affected tissues. They are responsible for creating pus.

When you have an infection caused by bacteria or fungi, the number of neutrophils in your blood increases, which can make your white blood cell count high. Neutrophils mainly work by eating and killing bacteria or fungi. They swallow up the germs into special pockets inside the cell. These pockets have toxic chemicals like superoxide and hydrogen peroxide, known together as reactive oxygen species, that mix with the germs to kill them [1]. This process is called the oxidative burst. Neutrophils can also release reactive oxygen species into the nearby tissue.

Monocytes are a type of white blood cell similar to neutrophils. They travel in the bloodstream and make up 5-10% of your white blood cells. They also line the walls of blood vessels in organs like the liver and spleen, where they catch germs as blood passes by. When monocytes leave the bloodstream and move into the body's tissues, they change shape and size to become macrophages.

Macrophages are important for killing fungi and a type of bacteria called mycobacteria; tuberculosis is caused by a species of mycobacteria. Like neutrophils, macrophages eat germs and use toxic chemicals to directly kill the invader. Macrophages live longer than neutrophils and are very important for slow-growing or long-lasting infections. Macrophages communicate with T cells and often work with them to kill germs.

Sometimes, immune system cells communicate by touching each other directly. However, they often communicate by releasing cytokines. Cytokines are small proteins that help cells in the immune system communicate with each other, and can affect other cells nearby or far away. These small proteins are created by many kinds of immune system cells and some cells outside of the immune system when there is a threat, and they act like messengers. Interferons are a type of cytokine that warn other cells of an invading virus, for example. This system allows information to be sent quickly and accurately to warn the body about the threat. If tested, cytokines may appear on lab reports as IL-2, IL-4, IL-6, and so on.

Immune dysregulation, which happens in some PIs, is sometimes treated with biologic medications that block cytokines, like tocilizumab (trade name Actemra), to lower the immune system’s overall activation.

There are 30 different proteins that make up the complement system. These proteins work together as part of the innate immune responses against bacteria. Most of them are made in the liver. Some complement proteins coat bacteria to make it easier for neutrophils to eat them. Other parts of the complement system attract neutrophils to the site of an infection. Complement proteins can also join together on the surface of bacteria to break their cell wall and kill them.