Immune System and Disorders


Your immune system is a complex network of cells, tissues, and organs that work together to defend against germs. It helps your body to recognize these “foreign” invaders. Then its job is to keep them out, or if it can’t, to find and destroy them.

Your immune system is a complex network of cells, tissues, and organs that work together to defend against germs. It helps your body to recognize these “foreign” invaders. Then its job is to keep them out, or if it can’t, to find and destroy them.

If your immune system cannot do its job, the results can be serious. Disorders of the immune system include

Allergy and asthma – immune responses to substances that are usually not harmful

Immune deficiency diseases – disorders in which the immune system is missing one or more of its parts

Autoimmune diseases – diseases causing your immune system to attack your own body’s cells and tissues by mistake.

Complications arise when the immune system does not function properly. Some issues are less pervasive, such as pollen allergy, while others are extensive, such as genetic disorders that wipe out the presence or function of an entire set of immune cells.

Immune Deficiencies

Immune deficiencies may be temporary or permanent. Temporary immune deficiency can be caused by a variety of sources that weaken the immune system. Common infections, including influenza and mononucleosis, can suppress the immune system.

When immune cells are the target of infection, severe immune suppression can occur. For example, HIV specifically infects T cells, and their elimination allows for secondary infections by other pathogens. Patients receiving chemotherapy, bone marrow transplants, or immunosuppressive drugs experience weakened immune systems until immune cell levels are restored. Pregnancy also suppresses the maternal immune system, increasing susceptibility to infections by common microbes.

Primary immune deficiency diseases (PIDDs) are inherited genetic disorders and tend to cause chronic susceptibility to infection. There are over 150 PIDDs, and almost all are considered rare (affecting fewer than 200,000 people in the United States). They may result from altered immune signaling molecules or the complete absence of mature immune cells. For instance, X-linked severe combined immunodeficiency (SCID) is caused by a mutation in a signaling receptor gene, rendering immune cells insensitive to multiple cytokines. Without the growth and activation signals delivered by cytokines, immune cell subsets, particularly T and natural killer cells, fail to develop normally. The NIAID Primary Immune Deficiency Clinic was established with the goal of accepting all PIDD patients for examination to provide a disease diagnosis and better treatment recommendations.


Allergies are a form of hypersensitivity reaction, typically in response to harmless environmental allergens like pollen or food. Hypersensitivity reactions are divided into four classes. Class I, II, and III are caused by antibodies, IgE or IgG, which are produced by B cells in response to an allergen. Overproduction of these antibodies activates immune cells like basophils and mast cells, which respond by releasing inflammatory chemicals like histamine. Class IV reactions are caused by T cells, which may either directly cause damage themselves or activate macrophages and eosinophils that damage host cells.

Autoimmune Diseases

Autoimmune diseases occur when self-tolerance is broken. Self-tolerance breaks when adaptive immune cells that recognize host cells persist unchecked. B cells may produce antibodies targeting host cells, and active T cells may recognize self-antigen. This amplifies when they recruit and activate other immune cells.

Autoimmunity is either organ-specific or systemic, meaning it affects the whole body. For instance, type I diabetes is organ-specific and caused by immune cells erroneously recognizing insulin-producing pancreatic β cells as foreign. However, systemic lupus erythematosus, commonly called lupus, can result from antibodies that recognize antigens expressed by nearly all healthy cells. Autoimmune diseases have a strong genetic component, and with advances in gene sequencing tools, researchers have a better understanding of what may contribute to specific diseases.


Sepsis may refer to an infection of the bloodstream, or it can refer to a systemic inflammatory state caused by the uncontrolled, broad release of cytokines that quickly activate immune cells throughout the body. Sepsis is an extremely serious condition and is typically triggered by an infection. However, the damage itself is caused by cytokines (the adverse response is sometimes referred to as a “cytokine storm”). The systemic release of cytokines may lead to loss of blood pressure, resulting in septic shock and possible multi-organ failure.


Some forms of cancer are directly caused by the uncontrolled growth of immune cells. Leukemia is cancer caused by white blood cells, which is another term for immune cells. Lymphoma is cancer caused by lymphocytes, which is another term for adaptive B or T cells. Myeloma is cancer caused by plasma cells, which are mature B cells. Unrestricted growth of any of these cell types causes cancer.

In addition, an emerging concept is that cancer progression may partially result from the ability of cancer cells to avoid immune detection. The immune system is capable of removing infectious pathogens and dangerous host cells like tumors. Cancer researchers are studying how the tumor microenvironment may allow cancer cells to evade immune cells. Immune evasion may result from the abundance of suppressive, regulatory immune cells, excessive inhibitory cytokines, and other features that are not well understood.

Overview of the Immune System


The overall function of the immune system is to prevent or limit infection. An example of this principle is found in immune-compromised people, including those with genetic immune disorders, immune-debilitating infections like HIV, and even pregnant women, who are susceptible to a range of microbes that typically do not cause infection in healthy individuals.

The immune system can distinguish between normal, healthy cells and unhealthy cells by recognizing a variety of “danger” cues called danger-associated molecular patterns (DAMPs). Cells may be unhealthy because of infection or because of cellular damage caused by non-infectious agents like sunburn or cancer. Infectious microbes such as viruses and bacteria release another set of signals recognized by the immune system called pathogen-associated molecular patterns (PAMPs).

When the immune system first recognizes these signals, it responds to address the problem. If an immune response cannot be activated when there is sufficient need, problems arise, like infection. On the other hand, when an immune response is activated without a real threat or is not turned off once the danger passes, different problems arise, such as allergic reactions and autoimmune disease.

The immune system is complex and pervasive. There are numerous cell types that either circulate throughout the body or reside in a particular tissue. Each cell type plays a unique role, with different ways of recognizing problems, communicating with other cells, and performing their functions. By understanding all the details behind this network, researchers may optimize immune responses to confront specific issues, ranging from infections to cancer.


All immune cells come from precursors in the bone marrow and develop into mature cells through a series of changes that can occur in different parts of the body.

Skin: The skin is usually the first line of defense against microbes. Skin cells produce and secrete important antimicrobial proteins, and immune cells can be found in specific layers of skin.

Bone marrow: The bone marrow contains stems cells that can develop into a variety of cell types. The common myeloid progenitor stem cell in the bone marrow is the precursor to innate immune cells—neutrophils, eosinophils, basophils, mast cells, monocytes, dendritic cells, and macrophages—that are important first-line responders to infection.

The common lymphoid progenitor stem cell leads to adaptive immune cells—B cells and T cells—that are responsible for mounting responses to specific microbes based on previous encounters (immunological memory). Natural killer (NK) cells also are derived from the common lymphoid progenitor and share features of both innate and adaptive immune cells, as they provide immediate defenses like innate cells but also may be retained as memory cells like adaptive cells. B, T, and NK cells also are called lymphocytes.

Bloodstream: Immune cells constantly circulate throughout the bloodstream, patrolling for problems. When blood tests are used to monitor white blood cells, another term for immune cells, a snapshot of the immune system is taken. If a cell type is either scarce or overabundant in the bloodstream, this may reflect a problem.

Thymus: T cells mature in the thymus, a small organ located in the upper chest.

Lymphatic system: The lymphatic system is a network of vessels and tissues composed of lymph, an extracellular fluid, and lymphoid organs, such as lymph nodes. The lymphatic system is a conduit for travel and communication between tissues and the bloodstream. Immune cells are carried through the lymphatic system and converge in lymph nodes, which are found throughout the body.

Lymph nodes are a communication hub where immune cells sample information brought in from the body. For instance, if adaptive immune cells in the lymph node recognize pieces of a microbe brought in from a distant area, they will activate, replicate, and leave the lymph node to circulate and address the pathogen. Thus, doctors may check patients for swollen lymph nodes, which may indicate an active immune response.

Spleen: The spleen is an organ located behind the stomach. While it is not directly connected to the lymphatic system, it is important for processing information from the bloodstream. Immune cells are enriched in specific areas of the spleen, and upon recognizing blood-borne pathogens, they will activate and respond accordingly.

Mucosal tissue: Mucosal surfaces are prime entry points for pathogens, and specialized immune hubs are strategically located in mucosal tissues like the respiratory tract and gut. For instance, Peyer’s patches are important areas in the small intestine where immune cells can access samples from the gastrointestinal tract.

Features of an Immune Response

An immune response is generally divided into innate and adaptive immunity. Innate immunity occurs immediately, when circulating innate cells recognize a problem. Adaptive immunity occurs later, as it relies on the coordination and expansion of specific adaptive immune cells. Immune memory follows the adaptive response, when mature adaptive cells, highly specific to the original pathogen, are retained for later use.

Innate Immunity

Innate immune cells express genetically encoded receptors, called Toll-like receptors (TLRs), which recognize general danger- or pathogen-associated patterns. Collectively, these receptors can broadly recognize viruses, bacteria, fungi, and even non-infectious problems. However, they cannot distinguish between specific strains of bacteria or viruses.

There are numerous types of innate immune cells with specialized functions. They include neutrophils, eosinophils, basophils, mast cells, monocytes, dendritic cells, and macrophages (See Immune Cells for detailed descriptions). Their main feature is the ability to respond quickly and broadly when a problem arises, typically leading to inflammation. Innate immune cells also are important for activating adaptive immunity. Innate cells are critical for host defense, and disorders in innate cell function may cause chronic susceptibility to infection.

Adaptive Immunity

Adaptive immune cells are more specialized, with each adaptive B or T cell bearing unique receptors, B-cell receptors (BCRs) and T-cell receptors (TCRs), that recognize specific signals rather than general patterns. Each receptor recognizes an antigen, which is simply any molecule that may bind to a BCR or TCR. Antigens are derived from a variety of sources including pathogens, host cells, and allergens. Antigens are typically processed by innate immune cells and presented to adaptive cells in the lymph nodes.

The genes for BCRs and TCRs are randomly rearranged at specific cell maturation stages, resulting in unique receptors that may potentially recognize anything. Random generation of receptors allows the immune system to respond to new or unforeseen problems. This concept is especially important because environments may frequently change, for instance when seasons change or a person relocates, and pathogens are constantly evolving to survive. Because BCRs and TCRs are so specific, adaptive cells may only recognize one strain of a particular pathogen, unlike innate cells, which recognize broad classes of pathogens. In fact, a group of adaptive cells that recognize the same strain will likely recognize different areas of that pathogen.

If a B or T cell has a receptor that recognizes an antigen from a pathogen and also receives cues from innate cells that something is wrong, the B or T cell will activate, divide, and disperse to address the problem. B cells make antibodies, which neutralize pathogens, rendering them harmless. T cells carry out multiple functions, including killing infected cells and activating or recruiting other immune cells. The adaptive response has a system of checks and balances to prevent unnecessary activation that could cause damage to the host. If a B or T cell is autoreactive, meaning its receptor recognizes antigens from the body’s own cells, the cell will be deleted. Also, if a B or T cell does not receive signals from innate cells, it will not be optimally activated.

Immune memory is a feature of the adaptive immune response. After B or T cells are activated, they expand rapidly. As the problem resolves, cells stop dividing and are retained in the body as memory cells. The next time this same pathogen enters the body, a memory cell is already poised to react and can clear away the pathogen before it establishes itself.


Vaccination, or immunization, is a way to train your immune system against a specific pathogen. Vaccination achieves immune memory without an actual infection, so the body is prepared when the virus or bacterium enters. Saving time is important to prevent a pathogen from establishing itself and infecting more cells in the body.

An effective vaccine will optimally activate both the innate and adaptive response. An immunogen is used to activate the adaptive immune response so that specific memory cells are generated. Because BCRs and TCRs are unique, some memory cells are simply better at eliminating the pathogen. The goal of vaccine design is to select immunogens that will generate the most effective and efficient memory response against a particular pathogen. Adjuvants, which are important for activating innate immunity, can be added to vaccines to optimize the immune response. Innate immunity recognizes broad patterns, and without innate responses, adaptive immunity cannot be optimally achieved.

Immune Cells

Granulocytes include basophils, eosinophils, and neutrophils. Basophils and eosinophils are important for host defense against parasites. They also are involved in allergic reactions. Neutrophils, the most numerous innate immune cell, patrol for problems by circulating in the bloodstream. They can phagocytose, or ingest, bacteria, degrading them inside special compartments called vesicles.

Mast cells also are important for defense against parasites. Mast cells are found in tissues and can mediate allergic reactions by releasing inflammatory chemicals like histamine

Monocytes, which develop into macrophages, also patrol and respond to problems. They are found in the bloodstream and in tissues. Macrophages, “big eater” in Greek, are named for their ability to ingest and degrade bacteria. Upon activation, monocytes and macrophages coordinate an immune response by notifying other immune cells of the problem. Macrophages also have important non-immune functions, such as recycling dead cells, like red blood cells, and clearing away cellular debris. These “housekeeping” functions occur without activation of an immune response.

Dendritic cells (DC) are an important antigen-presenting cell (APC), and they also can develop from monocytes. Antigens are molecules from pathogens, host cells, and allergens that may be recognized by adaptive immune cells. APCs like DCs are responsible for processing large molecules into “readable” fragments (antigens) recognized by adaptive B or T cells. However, antigens alone cannot activate T cells. They must be presented with the appropriate major histocompatiblity complex (MHC) expressed on the APC. MHC provides a checkpoint and helps immune cells distinguish between host and foreign cells.

Natural killer (NK) cells have features of both innate and adaptive immunity. They are important for recognizing and killing virus-infected cells or tumor cells. They contain intracellular compartments called granules, which are filled with proteins that can form holes in the target cell and also cause apoptosis, the process for programmed cell death. It is important to distinguish between apoptosis and other forms of cell death like necrosis. Apoptosis, unlike necrosis, does not release danger signals that can lead to greater immune activation and inflammation. Through apoptosis, immune cells can discreetly remove infected cells and limit bystander damage. Recently, researchers have shown in mouse models that NK cells, like adaptive cells, can be retained as memory cells and respond to subsequent infections by the same pathogen.

Adaptive Cells

B cells have two major functions: They present antigens to T cells, and more importantly, they produce antibodies to neutralize infectious microbes. Antibodies coat the surface of a pathogen and serve three major roles: neutralization, opsonization, and complement activation.

Neutralization occurs when the pathogen, because it is covered in antibodies, is unable to bind and infect host cells. In opsonization, an antibody-bound pathogen serves as a red flag to alert immune cells like neutrophils and macrophages, to engulf and digest the pathogen. Complement is a process for directly destroying, or lysing, bacteria.

Antibodies are expressed in two ways. The B-cell receptor (BCR), which sits on the surface of a B cell, is actually an antibody. B cells also secrete antibodies to diffuse and bind to pathogens. This dual expression is important because the initial problem, for instance a bacterium, is recognized by a unique BCR and activates the B cell. The activated B cell responds by secreting antibodies, essentially the BCR but in soluble form. This ensures that the response is specific against the bacterium that started the whole process.

Every antibody is unique, but they fall under general categories: IgM, IgD, IgG, IgA, and IgE. (Ig is short for immunoglobulin, which is another word for antibody.) While they have overlapping roles, IgM generally is important for complement activation; IgD is involved in activating basophils; IgG is important for neutralization, opsonization, and complement activation; IgA is essential for neutralization in the gastrointestinal tract; and IgE is necessary for activating mast cells in parasitic and allergic responses.

T cells have a variety of roles and are classified by subsets. T cells are divided into two broad categories: CD8+ T cells or CD4+ T cells, based on which protein is present on the cell’s surface. T cells carry out multiple functions, including killing infected cells and activating or recruiting other immune cells.

CD8+ T cells also are called cytotoxic T cells or cytotoxic lymphocytes (CTLs). They are crucial for recognizing and removing virus-infected cells and cancer cells. CTLs have specialized compartments, or granules, containing cytotoxins that cause apoptosis, i.e., programmed cell death. Because of its potency, the release of granules is tightly regulated by the immune system.

The four major CD4+ T-cell subsets are TH1, TH2, TH17, and Treg, with “TH” referring to “T helper cell.” TH1 cells are critical for coordinating immune responses against intracellular microbes, especially bacteria. They produce and secrete molecules that alert and activate other immune cells, like bacteria-ingesting macrophages. TH2 cells are important for coordinating immune responses against extracellular pathogens, like helminths (parasitic worms), by alerting B cells, granulocytes, and mast cells. TH17 cells are named for their ability to produce interleukin 17 (IL-17), a signaling molecule that activates immune and non-immune cells. TH17 cells are important for recruiting neutrophils.

Regulatory T cells (Tregs), as the name suggests, monitor and inhibit the activity of other T cells. They prevent adverse immune activation and maintain tolerance, or the prevention of immune responses against the body’s own cells and antigens.


Immune cells communicate in a number of ways, either by cell-to-cell contact or through secreted signaling molecules. Receptors and ligands are fundamental for cellular communication. Receptors are protein structures that may be expressed on the surface of a cell or in intracellular compartments. The molecules that activate receptors are called ligands, which may be free-floating or membrane-bound.

Ligand-receptor interaction leads to a series of events inside the cell involving networks of intracellular molecules that relay the message. By altering the expression and density of various receptors and ligands, immune cells can dispatch specific instructions tailored to the situation at hand.

Cytokines are small proteins with diverse functions. In immunity, there are several categories of cytokines important for immune cell growth, activation, and function.

Colony-stimulating factors are essential for cell development and differentiation.

Interferons are necessary for immune-cell activation. Type I interferons mediate antiviral immune responses, and type II interferon is important for antibacterial responses.

Interleukins, which come in over 30 varieties, provide context-specific instructions, with activating or inhibitory responses.

Chemokines are made in specific locations of the body or at a site of infection to attract immune cells. Different chemokines will recruit different immune cells to the site needed.

The tumor necrosis factor (TNF) family of cytokines stimulates immune-cell proliferation and activation. They are critical for activating inflammatory responses, and as such, TNF blockers are used to treat a variety of disorders, including some autoimmune diseases.

Toll-like receptors (TLRs) are expressed on innate immune cells, like macrophages and dendritic cells. They are located on the cell surface or in intracellular compartments because microbes may be found in the body or inside infected cells. TLRs recognize general microbial patterns, and they are essential for innate immune-cell activation and inflammatory responses.

B-cell receptors (BCRs) and T-cell receptors (TCRs) are expressed on adaptive immune cells. They are both found on the cell surface, but BCRs also are secreted as antibodies to neutralize pathogens. The genes for BCRs and TCRs are randomly rearranged at specific cell-maturation stages, resulting in unique receptors that may potentially recognize anything. Random generation of receptors allows the immune system to respond to unforeseen problems. They also explain why memory B or T cells are highly specific and, upon re-encountering their specific pathogen, can immediately induce a neutralizing immune response.

Major histocompatibility complex (MHC), or human leukocyte antigen (HLA), proteins serve two general roles.

MHC proteins function as carriers to present antigens on cell surfaces. MHC class I proteins are essential for presenting viral antigens and are expressed by nearly all cell types, except red blood cells. Any cell infected by a virus has the ability to signal the problem through MHC class I proteins. In response, CD8+ T cells (also called CTLs) will recognize and kill infected cells. MHC class II proteins are generally only expressed by antigen-presenting cells like dendritic cells and macrophages. MHC class II proteins are important for presenting antigens to CD4+ T cells. MHC class II antigens are varied and include both pathogen- and host-derived molecules.

MHC proteins also signal whether a cell is a host cell or a foreign cell. They are very diverse, and every person has a unique set of MHC proteins inherited from his or her parents. As such, there are similarities in MHC proteins between family members. Immune cells use MHC to determine whether or not a cell is friendly. In organ transplantation, the MHC or HLA proteins of donors and recipients are matched to lower the risk of transplant rejection, which occurs when the recipient’s immune system attacks the donor tissue or organ. In stem cell or bone marrow transplantation, improper MHC or HLA matching can result in graft-versus-host disease, which occurs when the donor cells attack the recipient’s body.

Complement refers to a unique process that clears away pathogens or dying cells and also activates immune cells. Complement consists of a series of proteins found in the blood that form a membrane-attack complex. Complement proteins are only activated by enzymes when a problem, like an infection, occurs. Activated complement proteins stick to a pathogen, recruiting and activating additional complement proteins, which assemble in a specific order to form a round pore or hole. Complement literally punches small holes into the pathogen, creating leaks that lead to cell death. Complement proteins also serve as signaling molecules that alert immune cells and recruit them to the problem area.

Immune Tolerance

Tolerance is the prevention of an immune response against a particular antigen. For instance, the immune system is generally tolerant of self-antigens, so it does not usually attack the body’s own cells, tissues, and organs. However, when tolerance is lost, disorders like autoimmune disease or food allergy may occur. Tolerance is maintained in a number of ways:

When adaptive immune cells mature, there are several checkpoints in place to eliminate autoreactive cells. If a B cell produces antibodies that strongly recognize host cells, or if a T cell strongly recognizes self-antigen, they are deleted.

Nevertheless, there are autoreactive immune cells present in healthy individuals. Autoreactive immune cells are kept in a non-reactive, or anergic, state. Even though they recognize the body’s own cells, they do not have the ability to react and cannot cause host damage.

Regulatory immune cells circulate throughout the body to maintain tolerance. Besides limiting autoreactive cells, regulatory cells are important for turning an immune response off after the problem is resolved. They can act as drains, depleting areas of essential nutrients that surrounding immune cells need for activation or survival.

Some locations in the body are called immunologically privileged sites. These areas, like the eye and brain, do not typically elicit strong immune responses. Part of this is because of physical barriers, like the blood-brain barrier, that limit the degree to which immune cells may enter. These areas also may express higher levels of suppressive cytokines to prevent a robust immune response.

Read more about Immune Tolerance.

Fetomaternal tolerance is the prevention of a maternal immune response against a developing fetus. Major histocompatibility complex (MHC) proteins help the immune system distinguish between host and foreign cells. MHC also is called human leukocyte antigen (HLA). By expressing paternal MHC or HLA proteins and paternal antigens, a fetus can potentially trigger the mother’s immune system. However, there are several barriers that may prevent this from occurring: The placenta reduces the exposure of the fetus to maternal immune cells, the proteins expressed on the outer layer of the placenta may limit immune recognition, and regulatory cells and suppressive signals may play a role.

Read more about MHC proteins in Communication.

Transplantation of a donor tissue or organ requires appropriate MHC or HLA matching to limit the risk of rejection. Because MHC or HLA matching is rarely complete, transplant recipients must continuously take immunosuppressive drugs, which can cause complications like higher susceptibility to infection and some cancers. Researchers are developing more targeted ways to induce tolerance to transplanted tissues and organs while leaving protective immune responses intact.

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