The Immune System and Primary Immunodeficiency

The immune system is composed of a variety of different cell types and proteins. Each element performs a specific task aimed at recognizing and/ or reacting against foreign material (germs).

Organization and Development of the Immune System

The immune system is a wonderful collaboration between cells and proteins that work together to provide defense against infection. These cells and proteins do not form a single organ like the heart or liver. Instead, the immune system is dispersed throughout the body to provide rapid responses to infection (Figure 1:1). Cells travel through the bloodstream or in specialized vessels called lymphatics. Lymph nodes and the spleen provide structures that facilitate cell-to-cell communication. The proteins may be made by immune cells or other organs such as the liver. Some immune proteins circulate in the bloodstream, while others are made by immune cells and act on the organs and tissues near where the proteins are produced.

Figure 1:1 Major Organs of the Immune System

A. Thymus: The thymus is an organ located in the upper chest where T cells mature. First, lymphocytes (a type of white blood cell) that are destined to become T cells leave the bone marrow and find their way to the thymus where they are then “educated” to become mature T cells.

B. Liver: The liver is the major organ responsible for producing proteins of the complement system. In addition, it contains large numbers of phagocytic cells (a specific type of white blood cell) that ingest bacteria in the blood as it passes through the liver.

C. Bone Marrow: The bone marrow is the location where all cells of the immune system begin their development from stem cells.

D. Tonsils: Tonsils are collections of lymphocytes in the throat.

E. Lymph Nodes: Lymph nodes are collections of B cells and T cells throughout the body. Cells congregate in lymph nodes to communicate with each other. Lymph nodes can become swollen when they are fighting an infection.

F. Spleen: The spleen is a collection of B cells, T cells, and monocytes. It serves to filter the blood and provide a site for invaders/germs and cells of the immune system to interact.

G. Blood: Blood is contained within the circulatory system that carries cells and proteins of the immune system from one part of the body to another.

Primary immunodeficiency diseases (PI) can affect a single component of the immune system or multiple cells and proteins. To better understand the forms of PI, it’s helpful to know about the organization and maturation of the immune system. It is typical to consider two broad categories of immune responses: the innate immune system and the adaptive immune system.

Innate immune responses are those that rely on cells that require no additional training to do their jobs. These cells include neutrophils, monocytes, natural killer (NK) cells, and a set of proteins known as the complement proteins. Innate responses to infection occur rapidly and reliably. Even infants have excellent innate immune responses.

Adaptive immune responses comprise the second category. These responses involve T cells and B cells, two cell types that require training or education to learn how to fight invaders (antigens) and not to attack our own cells. The advantages of the adaptive responses are their long-lived memories and the ability to adapt to new types of infections.

The bone marrow and thymus represent training grounds for two cells of the adaptive immune system (B cells and T cells, respectively). The development of all cells of the immune system begins in the bone marrow with a hematopoietic (blood-forming) stem cell (Figure 1:2). This cell is called a stem cell because all the other specialized cells arise from it. Because of its ability to generate an entire immune system, this is the cell that is most important in a bone marrow or hematopoietic stem cell transplantation. It is related to embryonic stem cells, but it is a distinct cell type, capable of developing into any type of blood cell but not other organs such as brain or muscle.

Figure 1:2 Cells of the Immune System

A. Bone marrow: The site in the body where most of the cells of the immune system develop from hematopoietic stem cells.

B. Stem cells: These cells have the potential to develop and mature into the different cells of the immune system.

C. Thymus: An organ located in the chest which instructs immature lymphocytes to become mature T cells.

D. B cells: These lymphocytes arise in the bone marrow and differentiate into plasma cells which in turn produce immunoglobulins (antibodies).

E. Cytotoxic T cells: These lymphocytes mature in the thymus and are responsible for killing cells infected with viruses.

F. Helper T cells: These specialized lymphocytes help other T cells and B cells to perform their functions.

G. Plasma Cells: These cells develop from B cells and are the cells that make immunoglobulin (antibodies).

H. Immunoglobulins: These highly specialized protein molecules, also known as antibodies, fit foreign antigens, such as polio, like a lock and key. Their variety is so extensive that they can be produced to match almost all possible microorganisms in our environment.

I. Neutrophils: (also known as polymorphonuclear cells or PMN) are a type of white blood cell found in the bloodstream that rapidly ingest microorganisms and kills them through a process called phagocytosis.

J. Monocytes: These white blood cells are cells found in the bloodstream that develop into cells called macrophages when they migrate into tissues. Like neutrophils, macrophages also ingest and kill germs via phagocytosis.

K. Red Blood Cells: The red cells in the bloodstream that carry oxygen from the lungs to the tissues.

L. Platelets: Small cells in the bloodstream that are important for blood clotting.

M. Dendritic Cells: These cells instruct T cells on what to attack, also known as antigen-presenting cells.

Central to both categories of immune responses is the ability to distinguish foreign invaders (germs), which need to be attacked, versus our own tissues, which need to be protected. Because of their ability to respond rapidly, the innate responses are usually the first to respond to an invasion. This initial response serves to alert and trigger the adaptive response, which can take several days to fully activate.

Early in life, the innate responses are most prominent. Newborn infants do have antibodies received from their mothers but do not make their own antibodies for several weeks. Maternal antibodies are passed to the baby through the placenta and protect the baby for the first few months of life, until babies should be able to make adequate amounts of antibodies on their own.

The adaptive immune system is functional at birth, but it has not gained the experience necessary for optimal memory responses. Although this formation of memory occurs throughout life, the most rapid gain in immunologic experience is between birth and three years of age. Each infectious exposure leads to training of the cells so that a response to a second exposure to the same infection is more rapid and greater in magnitude.

Over the first few years of life, most children are exposed to a wide variety of infections and produce antibodies directed at those specific infections. The B cells producing the antibodies remember the infection (germ) and provide long-lasting immunity to it. Similarly, T cells can remember viruses that the body has encountered and can make a more vigorous response when they encounter the same virus again. This rapid maturation of the adaptive immune system in early childhood makes testing young children a challenge since the expectations for what is normal change with age. In contrast to the adaptive immune system, the innate immune system is largely intact at birth.

Components of the Immune System

Each major component of the immune system will be discussed separately. PI can affect a single component or multiple components. The manifestations can be a single type of infection or a more global susceptibility to infections. Because of the many interactions between the cells and proteins of the immune system, some forms of PI can be associated with a very limited range of infections. For these forms, there are other elements that can compensate at least partly for the missing piece. In other cases, the ability to defend against infection is very weak overall, and the person may have significant problems with many types of infections.

The most common cells of the immune system can be categorized as lymphocytes (T cells, B cells, and NK cells), neutrophils, and monocytes/ macrophages. These are all types of white blood cells. The major proteins of the immune system are predominantly cytokines (a type of hormone responsible for communication between cells of the immune system), antibodies (immunoglobulins), and complement proteins.

Lymphocytes of the Immune System

B cells

B cells (sometimes called B-lymphocytes and often named on lab reports as CD19 or CD20 cells) are specialized cells of the immune system whose major function is to produce antibodies (also known as immunoglobulins or gamma-globulins). B cells develop in the bone marrow from stem cells. As part of their normal maturation in the bone marrow, B cells are trained or educated so that they do not produce antibodies to healthy tissues. When mature, B cells can be found in the bone marrow, lymph nodes, spleen, some areas of the intestine, and the bloodstream.

When B cells encounter foreign germs (antigens), they respond by maturing into another cell type called plasma cells. B cells can also mature into memory cells, which allows a rapid response if the same infection is encountered again. Plasma cells are the mature cells that actually produce the antibodies and are located in the spleen and lymph nodes throughout the body. Antibodies are highly specialized serum protein molecules that find their way into the bloodstream, tissues, respiratory secretions, intestinal secretions, and even tears. Collectively, plasma cells have the ability to produce antibodies against virtually all microbes in our environment. Each plasma cell, however, produces only one kind of antibody.

In fact, antibodies are actually specifically designed to recognize practically every germ that can cause infection. For every foreign antigen, there are antibodies molecules specially designed to fit that antigen, like a lock and key. The variety of different antibody molecules found in a healthy immune system is vast. For example, there are specific antibody molecules that can recognize poliovirus, bacteria like diphtheria, the common cold virus, or the measles virus.

When antibody molecules recognize a microorganism as foreign, they physically attach to it and set off a complex chain of events involving other components of the immune system that work to eventually destroy the infection. Antibodies vary with respect to their specialized functions in the body. These variations are determined by the antibody’s chemical structure, which in turn determines the class of the antibody (or immunoglobulin).

There are five major classes of antibodies (IgG, IgA, IgM, IgD, and IgE). IgG has four different subclasses (IgG1, IgG2, IgG3, IgG4). IgA has two subclasses (IgA1 and IgA2).

Each immunoglobulin class has distinct chemical characteristics that provide it with specific functions (Figure 1:3). For example, IgG antibodies are formed in large quantities, last in the circulation for a few weeks, and travel from the blood stream to the tissues easily. Only IgG crosses the placenta and passes some immunity from the mother to the newborn. Antibodies of the IgA class are produced near mucus membranes and find their way into secretions such as tears, intestines, bile, saliva and mucus, where they protect against infection in the respiratory tract and intestines. Some of the IgA also appears in the circulation. Antibodies of the IgM class are the first antibodies formed in response to infection. They are important in protection during the early days of an infection. Antibodies of the IgE class are responsible for allergic reactions. IgD is an immunoglobulin isotype that only makes up 0.25% of the serum immunoglobulins. IgD is expressed on mature B cells along with IgM and may play some role in helping B cells differentiate into plasma cells. Recently, studies have suggested that IgD may be important in the gut homeostasis by binding to mast cells and basophils to react against pathogenic bacteria in the gut.

Figure 1:3 Immunoglobulin Structure

Each class or type of immunoglobulin shares properties in common with the others. They all have antigen binding sites which combine specifically with the foreign antigen.

A. IgG: IgG is the major immunoglobulin class in the body and is found in the bloodstream as well as in tissues and secretions. Immunoglobulin replacement therapy contains primarily IgG.

B. Secretory IgA: Secretory IgA is composed of two IgA molecules joined by a J-chain and attached to a secretory piece. These modifications allow the secretory IgA to be secreted into mucus, intestines and tears where it protects those areas from infection.

C. IgM: IgM is composed of five immunoglobulin molecules attached to each other. It is formed very early in infection and activates complement very easily.

Antibodies protect the body against infection in a number of different ways. For example, some microorganisms, such as viruses, must attach to body cells before they can cause an infection, but antibodies bound to the surface of a virus can interfere with the virus’ ability to attach to the host cell. In addition, antibodies attached to the surface of some microorganisms can cause the activation of a group of proteins called the complement system that can directly kill some bacteria. Antibody-coated bacteria are also much easier for neutrophils to ingest and kill than bacteria that are not coated with antibodies. All of these actions of antibodies prevent microorganisms from successfully invading body tissues and causing serious infections.

The long life of plasma cells enables us to retain immunity to viruses and bacteria that infected us many years ago. For example, once people have been fully immunized with live vaccine strains of measles virus, they will almost never catch it because they retain the plasma cells and antibodies for many years and these antibodies prevent infection.

T cells

T cells (sometimes called T lymphocytes and often named in lab reports as CD3 cells) are another type of immune cell. Some T cells directly attack cells infected with viruses, and others act as regulators of the immune system.

T cells develop from hematopoietic stem cells in the bone marrow but complete their development in the thymus. The thymus is a specialized organ of the immune system in the chest. Within the thymus, immature lymphocytes develop into mature T cells (the “T” stands for the thymus) and T cells with the potential to attack normal tissues are eliminated. The thymus is essential for this process, and T cells cannot develop if the fetus does not have a thymus. It is in the thymus that T cell receptor excision circles (TRECs) are made as a by-product of T cell maturation. (TRECs are measured in blood spots from newborn screening cards to identify infants with Severe Combined Immunodeficiency (SCID), before they become sick with infections). Mature T cells leave the thymus as naïve T cells, ready to meet new antigens and populate other organs of the immune system, such as the spleen, lymph nodes, bone marrow, and blood as memory T cells after these exposures to antigen.

Each T cell reacts with one specific antigen, just as each antibody molecule reacts with one specific antigen. In fact, T cells have molecules on their surfaces that are similar to antibodies. The variety of different T cells is also so extensive that the body has T cells that can react against virtually any antigen.

T cells have different abilities to recognize antigen and are varied in their function. There are killer or cytotoxic T cells (often denoted in lab reports as CD8 T cells), helper T cells (often denoted in lab reports as CD4 T cells), and regulatory T cells. Each has a different role to play in the immune system.

Killer, or cytotoxic T cells perform the actual destruction of cells infected with viruses. Killer T cells protect the body from certain bacteria and viruses that have the ability to survive and even reproduce within the body’s own cells. In addition to fighting germs, killer T cells also recognize and respond to foreign tissues in the body, such as a transplanted kidney.

Helper T cells assist B cells to produce antibodies and assist killer T cells in their attack on foreign substances. The killer T cell must migrate to the site of infection and directly bind to its target to ensure its destruction.

When T cells are fighting infections, they grow and divide, making more T cells. Regulatory T cells suppress or turn off the T cells when an infection is controlled and they are no longer needed. Without regulatory cells, the immune system would keep working even after an infection has been treated. Without regulatory T cells, there is the potential for the body to overreact to the infection. Regulatory T cells act as the thermostat of the lymphocyte system to keep it turned on just enough—not too much and not too little.

NK Cells

Natural killer (NK) cells are so named because they easily kill cells infected with viruses. They are said to be natural killer cells as they are always ready to fight and do not require the same thymic education that T cells require. NK cells are derived from the bone marrow and are present in relatively low numbers in the bloodstream and in tissues. They are important in defending against viruses and possibly preventing cancer as well.

NK cells kill virus-infected cells by injecting them with a killer potion of chemicals called cytotoxic granules. They are particularly important in the defense against herpes viruses. This family of viruses includes the traditional cold sore form of herpes (herpes simplex) as well as Epstein-Barr virus (the cause of infectious mononucleosis or mono) and the varicella virus (the cause of chickenpox and shingles).

Neutrophils

Neutrophils or polymorphonuclear leukocytes (polys or PMNs) are the most numerous of all the types of white blood cells, making up about half or more of the total. They are also called granulocytes and appear on lab reports as part of a complete blood count (named in lab reports as CBC with differential). They are found in the bloodstream and can migrate into sites of infection within a matter of minutes. These cells, like the other cells in the immune system, develop from hematopoietic stem cells in the bone marrow.

Neutrophils increase in number in the bloodstream during infection and are in large part responsible for the elevated white blood cell count seen with some infections. They are the cells that leave the bloodstream and accumulate in the tissues during the first few hours of an infection and are responsible for the formation of pus. Their major role is to ingest bacteria or fungi and kill them. Their killing strategy relies on ingesting the infecting organisms in specialized pockets within the cell. Neutrophils contain toxic chemicals that fuse with the bacteria-containing pockets to kill the bacteria. Neutrophils have little role in the defense against viruses.

Monocytes

Monocytes are closely related to neutrophils and are found circulating in the bloodstream. They make up 5 to 10% of the white blood cells. They also line the walls of blood vessels in organs like the liver and spleen where they capture microorganisms in the blood as they pass by. When monocytes leave the bloodstream and enter the tissues, they change shape and size and become macrophages. Macrophages are essential for killing fungi and the class of bacteria to which tuberculosis belongs (mycobacteria). Like neutrophils, macrophages ingest microbes and deliver toxic chemicals directly to the foreign invader to kill it.

Macrophages live longer than neutrophils and are especially important for slow growing or chronic infections. Macrophages can be influenced by T cells and often collaborate with T cells in killing microorganisms.

Cytokines

Cytokines are a very important set of proteins in the body. These small proteins serve as messengers for the immune system. They are produced in response to a threat and represent the communication network for the immune system. In some cases, cells of the immune system communicate by directly touching each other, but often cells communicate by secreting cytokines that can then act on other cells either locally or at a distance.

This clever system allows very precise information to be delivered rapidly to alert the body as to the status of the threat. Cytokines are not often measured clinically but can appear on lab slips as IL-2, IL-4, IL-6, etc. Some cytokines were named before the interleukin (IL) numbering convention was started and have different names.

Complement

The complement system is composed of 30 blood proteins that function in an ordered fashion to defend against infection. Most proteins in the complement system are produced in the liver. Some of the proteins of the complement system coat bacteria to make them more easily taken up by neutrophils. Other complement components act to send out chemical signals to attract neutrophils to sites of infection. Complement proteins can also assemble on the surface of microorganisms forming a complex. This complex can then puncture the cell wall of the microorganism and destroy it.

Examples of How the Immune System Fights Infections

Bacteria

Our bodies are covered with bacteria and our environment contains bacteria on most surfaces. Our skin and internal mucous membranes act as physical barriers to help prevent and protect us from infection by these bacteria. When the skin or mucous membranes are broken due to disease, inflammation or injury, bacteria can enter the body. Infecting bacteria are usually coated with complement and antibodies once they enter the tissues, and this allows neutrophils to easily recognize the bacteria as something foreign. Neutrophils then engulf the bacteria and destroy them (Figure 1:4).

When the antibodies, complement, and neutrophils are all functioning normally, this process effectively kills the bacteria. Recurrent bacterial infections, however, can occur and even damage tissues and organs when the number of bacteria is overwhelming or there are defects in antibody production, complement, and/or neutrophils.

Figure 1:4 Normal Anti-Bacterial Action

In most instances, bacteria are destroyed by the cooperative efforts of phagocytic cells (most often the neutrophil), antibody, and complement.

A. Neutrophil (Phagocytic Cell) Engages Bacteria (Microbe): The bacteria is coated with
specific antibody and complement which signal to the neutrophil that it should attack the bacteria. The neutrophil then begins its attack on the microbe by attaching to the antibody and complement molecules.

B. Phagocytosis of the Bacteria: After attaching to the bacteria, the neutrophil begins to ingest it by extending itself around the microbe and engulfing it.

C. Destruction of the Bacteria: Once the bacteria is ingested, enzymes and toxic chemicals are discharged into the pocket containing the bacteria, leading to its destruction.

Viruses

Most of us are exposed to viruses frequently. The way our bodies defend against viruses is different than how we fight bacteria. Viruses can only survive and multiply inside our cells. This allows them to hide from our immune system. When a virus infects a cell, the cell releases cytokines to alert other cells to the infection. This alert generally prevents other cells from becoming infected. Unfortunately, many viruses can outsmart this protective strategy, and they continue to spread the infection.

Circulating T cells and NK cells become alerted to a viral invasion and migrate to the site where they kill the particular cells that are harboring the virus. This is a very destructive mechanism to kill the virus because many of our own cells can be sacrificed in the process. Nevertheless, it is an efficient process to eradicate the virus.

At the same time the T cells are killing the virus, they are also instructing the B cells to make antibodies. When we are exposed to the same virus a second time, the antibodies help prevent the infection. Memory T cells are also produced and rapidly respond to a second infection, which also leads to a milder course of the infection.

The Immune System and Primary Immunodeficiency Diseases

Immunodeficiencies are categorized as primary or secondary. Primary immunodeficiency diseases are primary because an inherent defect in the immune system is the primary cause. Most are caused by genetic defects that may be inherited. Secondary immunodeficiencies are so called because they have been caused by other conditions including certain diseases or medications affecting the immune system.

The most common secondary immunodeficiencies are caused by aging, malnutrition, certain medications and some infections, such as human immunodeficiency virus or HIV. The most common medications associated with secondary immunodeficiencies are chemotherapy agents and immune suppressive medications, cancer, transplanted organ rejection, or autoimmune diseases. Other secondary immunodeficiencies include protein losses in the intestines or the kidneys. When proteins are lost, antibodies are also lost, leading to low immunoglobulins or low antibody levels. These conditions are important to recognize because, if the underlying cause can be corrected, the function of the immune system can be improved and/or restored. Regardless of the root cause, recognition of the secondary immunodeficiency and provision of immunologic support can be helpful. The types of support offered are comparable to what is used for primary immunodeficiencies.

Primary immunodeficiency, or PI, are a group of disorders caused by basic defects in immune function that are inherent to the cells and proteins of the immune system. There are more than 450 forms of PI. Some are relatively common, while others are quite rare. Some affect a single cell or protein of the immune system, and others may affect two or more components of the immune system.

Although forms of PI may differ from one another in many ways, they share one important feature. They all result from a defect in one or more of the elements or functions of the normal immune system, such as T cells, B cells, NK cells, neutrophils, monocytes, antibodies, cytokines, or the complement system. Most of them are inherited diseases and may run in families, such as X-Linked Agammaglobulinemia (XLA) or SCID. Other primary immunodeficiencies, such as Common Variable Immune Deficiency (CVID) and Selective IgA Deficiency are not always inherited in a clear-cut or predictable fashion. In these disorders, the cause is unknown, but it is believed that the interaction of genetic and environmental factors may play a role in their causation.

Because the most important function of the immune system is to protect against infection, people with PI have an increased susceptibility to infection. This may include too many infections, infections that are difficult to treat, unusually severe infections, or infections with unusual organisms. The infections may be located anywhere in the body. Common sites are the sinuses (sinusitis), the bronchi (bronchitis), the lung (pneumonia), or the intestinal tract (infectious diarrhea).

Another function of the immune system is to discriminate between the healthy tissue (“self”) and foreign material (“non-self”). Examples of foreign material can be microorganisms, pollen or even a transplanted kidney from another individual. In some immunodeficiency diseases, the immune system is unable to discriminate between self and non-self. In these cases, in addition to an increased susceptibility to infection, people with PI may also have autoimmune diseases in which the immune system attacks their own cells or tissues as if these cells were foreign, or non-self.

There are also a few types of PI in which the ability to respond to an infection is largely intact, but the ability to regulate that response is abnormal. Examples of this are autoimmune lymphoproliferative syndrome (ALPS) and IPEX (X-linked syndrome of immunodeficiency, polyendocrinopathy and enteropathy). These conditions are characterized by prominent autoimmunity where the body attacks itself.

PI can occur in individuals of any age. The original descriptions of these diseases were in children. As medical experience has grown, however, many adolescents and adults have been diagnosed with PI. This is partly due to the fact that some of the disorders, such as CVID and Selective IgA Deficiency (SAD), may have their initial clinical presentation in adult life.

Effective therapy exists for many forms of PI, and many people with these disorders can live relatively normal lives. PI was initially thought to be very rare. Recent research, however, has indicated that as a group they are more common than originally thought. It is estimated that as many as 1 in every 1,200 to 2,000 people may have some form of PI.

Excerpted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases SIXTH EDITION. Copyright 2019 by Immune Deficiency Foundation, USA. This page contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical advice.