The immune system is the complex collection of cells and organs that destroys or neutralizes pathogens that would otherwise cause disease or death. The lymphatic system, for most people, is associated with the immune system to such a degree that the two systems are virtually indistinguishable. The lymphatic system is the system of vessels, cells, and organs that carries excess fluids to the bloodstream and filters pathogens from the blood. The swelling of lymph nodes during an infection and the transport of lymphocytes via the lymphatic vessels are but two examples of the many connections between these critical organ systems.

Anatomy of the Lymphatic System

Lymphatic vessels in the arms and legs convey lymph to the larger lymphatic vessels in the torso.

Overview

The lymphatic system is a series of vessels, ducts, and trunks that remove interstitial fluid from the tissues and return it the blood. The lymphatics are also used to transport dietary lipids and cells of the immune system. Cells of the immune system all come from the hematopoietic system of the bone marrow. Primary lymphoid organs, the bone marrow and thymus gland, are the locations where lymphocytes of the adaptive immune system proliferate and mature. Secondary lymphoid organs are site in which mature lymphocytes congregate to mount immune responses. Many immune system cells use the lymphatic and circulatory systems for transport throughout the body to search for and then protect against pathogens.

Function

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.

Location

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.​

The Organization of Immune Function

The immune system is a collection of barriers, cells, and soluble proteins that interact and communicate with each other in extraordinarily complex ways. The modern model of immune function is organized into three phases based on the timing of their effects. The three temporal phases consist of the following:

• Barrier defenses such as the skin and mucous membranes, which act instantaneously to prevent pathogenic invasion into the body tissues
• The rapid but nonspecific innate immune response, which consists of a variety of specialized cells and soluble factors
• The slower but more specific and effective adaptive immune response, which involves many cell types and soluble factors, but is primarily controlled by white blood cells (leukocytes) known as lymphocytes, which help control immune responses

The cells of the blood, including all those involved in the immune response, arise in the bone marrow via various differentiation pathways from hematopoietic stem cells (image). In contrast with embryonic stem cells, hematopoietic stem cells are present throughout adulthood and allow for the continuous differentiation of blood cells to replace those lost to age or function. These cells can be divided into three classes based on function:

• Phagocytic cells, which ingest pathogens to destroy them
• Lymphocytes, which specifically coordinate the activities of adaptive immunity
• Cells containing cytoplasmic granules, which help mediate immune responses against parasites and intracellular pathogens such as viruses

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.

Communication

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.

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. 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

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.

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.

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.

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.

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.

Allergy

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

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.

Cancer

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.

What are autoimmune diseases?

Your immune system protects you from disease and infection by attacking germs that get into your body, such as viruses and bacteria. Your immune system can tell that the germs aren't part of you, so it destroys them. If you have an autoimmune disease, your immune system attacks the healthy cells of your organs and tissues by mistake.

There are more than 80 types of autoimmune diseases. They can affect almost any part of your body. For example, alopecia areata is an autoimmune disease of the skin that causes hair loss. Autoimmune hepatitis affects the liver. In type 1 diabetes, the immune system attacks the pancreas. And in rheumatoid arthritis, the immune system can attack many parts of the body, including the joints, lungs, and eyes.

What causes autoimmune diseases?

No one is sure why autoimmune diseases happen. But you can't catch them from other people.

Autoimmune diseases do tend to run in families, which means that certain genes may make some people more likely to develop a problem. Viruses, certain chemicals, and other things in the environment may trigger an autoimmune disease if you already have the genes for it.

Who is at risk for autoimmune diseases?

Millions of Americans of all ages have autoimmune diseases. Women develop many types of autoimmune diseases much more often than men. And if you have one autoimmune disease, you are more likely to get another.

What are the symptoms of autoimmune diseases?

The symptoms of an autoimmune disease depend on the part of your body that's affected. Many types of autoimmune diseases cause redness, swelling, heat, and pain, which are the signs and symptoms of inflammation. But other illnesses can cause the same symptoms.

The symptoms of autoimmune diseases can come and go. During a flare-up, your symptoms may get severe for a while. Later on, you may have a remission, which means that your symptoms get better or disappear for a period of time.

How are autoimmune diseases diagnosed?

Doctors often have a hard time diagnosing autoimmune diseases. There's usually not a specific test to show whether you have a certain autoimmune disease. And the symptoms can be confusing. That's because many autoimmune diseases have similar symptoms. And some symptoms, such as muscle aches, are common in many other illnesses. So it can take a long time and some visits to different types of doctors to get a diagnosis.

To help your doctor find out if an autoimmune disease is causing your symptoms,:

• Learn about the health conditions in your family history. What health problems did your grandparents, aunts, uncles, and cousins have? Write down what you learn and share it with your doctor.
• Keep track of your symptoms, including how long they last and what makes them better or worse. Share your notes with your doctor.
• See a specialist who deals with the symptoms that bother you most. For example, if you have rash, see a dermatologist (skin doctor).

What are the treatments for autoimmune diseases?

The treatment depends on the disease. In most cases, the goal of treatment is to suppress (slow down) your immune system, and ease swelling, redness, and pain from inflammation. Your doctor may give you corticosteroids or other medicines to help you feel better. For some diseases, you may need treatment for the rest of your life.

What are vaccines?

Vaccines are injections (shots), liquids, pills, or nasal sprays that you take to teach your body's immune system to recognize and defend against harmful germs. For example, there are vaccines to protect against diseases caused by:

• Viruses, like the ones that cause the flu and COVID-19
• Bacteria, including tetanus, diphtheria, and pertussis

What are the types of vaccines?

There are several types of vaccines:

• Live-attenuated vaccines use a weakened form of the germ.
• Inactivated vaccines use a killed version of the germ.
• Subunit, recombinant, polysaccharide, and conjugate vaccines use only specific pieces of the germ, such as its protein, sugar, or casing.
• Toxoid vaccines that use a toxin (harmful product) made by the germ.
• mRNA vaccines use messenger RNA, which gives your cells instructions for how to make a protein (or piece of a protein) of the germ.
• Viral vector vaccines use genetic material, which gives your cells instructions for making a protein of the germ. These vaccines also contain a different, harmless virus that helps get the genetic material into your cells.

Vaccines work in different ways, but they all spark an immune response. The immune response is the way your body defends itself against substances it sees as foreign or harmful. These substances include germs that can cause disease.

What happens in an immune response?

There are different steps in the immune response:

• When a germ invades, your body sees it as foreign.
• Your immune system helps your body fight off the germ.
• Your immune system also remembers the germ. It will attack the germ if it ever invades again. This "memory" protects you against the disease that the germ causes. This type of protection is called immunity.

What are immunization and vaccination?

Immunization is the process of becoming protected against a disease. But it can also mean the same thing as vaccination, which is getting a vaccine to become protected against a disease.

Why are vaccines important?

Vaccines are important because they protect you against many diseases. These diseases can be very serious. So getting immunity from a vaccine is safer than getting immunity by being sick with the disease. And for a few vaccines, getting vaccinated can actually give you a better immune response than getting the disease would.

But vaccines don't just protect you. They also protect the people around you through community immunity.

What is community immunity?

Community immunity, or herd immunity, is the idea that vaccines can help keep communities healthy.

Normally, germs can travel quickly through a community and make a lot of people sick. If enough people get sick, it can lead to an outbreak. But when enough people are vaccinated against a certain disease, it's harder for that disease to spread to others. This type of protection means that the entire community is less likely to get the disease.

Community immunity is especially important for people who can't get certain vaccines. For example, they may not be able to get a vaccine because they have weakened immune systems. Others may be allergic to certain vaccine ingredients. And newborn babies are too young to get some vaccines. Community immunity can help to protect them all.

Are vaccines safe?

Vaccines are safe. They must go through extensive safety testing and evaluation before they are approved in the United States.

What is a vaccine schedule?

A vaccine, or immunization, schedule lists which vaccines are recommended for different groups of people. It includes who should get the vaccines, how many doses they need, and when they should get them. In the United States, the Centers for Disease Control and Prevention (CDC) publishes the vaccine schedule.

It's important for both children and adults to get their vaccines according to the schedule. Following the schedule allows them to get protection from the diseases at exactly the right time.

This section is about how the immune system goes wrong. When it goes haywire, and becomes too weak or too strong, it leads to a state of disease. The factors that maintain immunological homeostasis are complex and incompletely understood.

Immunodeficiencies

The immune system is quite complex. It has many pathways using many cell types and signals. Because it is so complex, there are many ways for it to go wrong. Inherited immunodeficiencies arise from gene mutations that affect specific components of the immune response. There are also acquired immunodeficiencies with potentially devastating effects on the immune system, such as HIV.

Inherited Immunodeficiencies

A list of all inherited immunodeficiencies is well beyond the scope of this book. The list is almost as long as the list of cells, proteins, and signaling molecules of the immune system itself. Some deficiencies, such as those for complement, cause only a higher susceptibility to some Gram-negative bacteria. Others are more severe in their consequences. Certainly, the most serious of the inherited immunodeficiencies is severe combined immunodeficiency disease (SCID). This disease is complex because it is caused by many different genetic defects. What groups them together is the fact that both the B cell and T cell arms of the adaptive immune response are affected.

Children with this disease usually die of opportunistic infections within their first year of life unless they receive a bone marrow transplant. Such a procedure had not yet been perfected for David Vetter, the “boy in the bubble,” who was treated for SCID by having to live almost his entire life in a sterile plastic cocoon for the 12 years before his death from infection in 1984. One of the features that make bone marrow transplants work as well as they do is the proliferative capability of hematopoietic stem cells of the bone marrow. Only a small amount of bone marrow from a healthy donor is given intravenously to the recipient. It finds its own way to the bone where it populates it, eventually reconstituting the patient’s immune system, which is usually destroyed beforehand by treatment with radiation or chemotherapeutic drugs.

New treatments for SCID using gene therapy, inserting nondefective genes into cells taken from the patient and giving them back, have the advantage of not needing the tissue match required for standard transplants. Although not a standard treatment, this approach holds promise, especially for those in whom standard bone marrow transplantation has failed.

Human Immunodeficiency Virus/AIDS

Although many viruses cause suppression of the immune system, only one wipes it out completely, and that is the previously mentioned HIV. It is worth discussing the biology of this virus, which can lead to the well-known AIDS, so that its full effects on the immune system can be understood. The virus is transmitted through semen, vaginal fluids, and blood, and can be caught by risky sexual behaviors and the sharing of needles by intravenous drug users. There are sometimes, but not always, flu-like symptoms in the first 1 to 2 weeks after infection. This is later followed by seroconversion. The anti-HIV antibodies formed during seroconversion are the basis for most initial HIV screening done in the United States. Because seroconversion takes different lengths of time in different individuals, multiple AIDS tests are given months apart to confirm or eliminate the possibility of infection.

After seroconversion, the amount of virus circulating in the blood drops and stays at a low level for several years. During this time, the levels of CD4+ cells, especially helper T cells, decline steadily, until at some point, the immune response is so weak that opportunistic disease and eventually death result. HIV uses CD4 as the receptor to get inside cells, but it also needs a co-receptor, such as CCR5 or CXCR4. These co-receptors, which usually bind to chemokines, present another target for anti-HIV drug development. Although other antigen-presenting cells are infected with HIV, given that CD4+ helper T cells play an important role in T cell immune responses and antibody responses, it should be no surprise that both types of immune responses are eventually seriously compromised.

Treatment for the disease consists of drugs that target virally encoded proteins that are necessary for viral replication but are absent from normal human cells. By targeting the virus itself and sparing the cells, this approach has been successful in significantly prolonging the lives of HIV-positive individuals. On the other hand, an HIV vaccine has been 30 years in development and is still years away. Because the virus mutates rapidly to evade the immune system, scientists have been looking for parts of the virus that do not change and thus would be good targets for a vaccine candidate.

Hypersensitivities

The word “hypersensitivity” simply means sensitive beyond normal levels of activation. Allergies and inflammatory responses to nonpathogenic environmental substances have been observed since the dawn of history. Hypersensitivity is a medical term describing symptoms that are now known to be caused by unrelated mechanisms of immunity. Still, it is useful for this discussion to use the four types of hypersensitivities as a guide to understand these mechanisms (image).

Immediate (Type I) Hypersensitivity

Antigens that cause allergic responses are often referred to as allergens. The specificity of the immediate hypersensitivity response is predicated on the binding of allergen-specific IgE to the mast cell surface. The process of producing allergen-specific IgE is called sensitization, and is a necessary prerequisite for the symptoms of immediate hypersensitivity to occur. Allergies and allergic asthma are mediated by mast cell degranulation that is caused by the crosslinking of the antigen-specific IgE molecules on the mast cell surface. The mediators released have various vasoactive effects already discussed, but the major symptoms of inhaled allergens are the nasal edema and runny nose caused by the increased vascular permeability and increased blood flow of nasal blood vessels. As these mediators are released with mast cell degranulation, type I hypersensitivity reactions are usually rapid and occur within just a few minutes, hence the term immediate hypersensitivity.

Most allergens are in themselves nonpathogenic and therefore innocuous. Some individuals develop mild allergies, which are usually treated with antihistamines. Others develop severe allergies that may cause anaphylactic shock, which can potentially be fatal within 20 to 30 minutes if untreated. This drop in blood pressure (shock) with accompanying contractions of bronchial smooth muscle is caused by systemic mast cell degranulation when an allergen is eaten (for example, shellfish and peanuts), injected (by a bee sting or being administered penicillin), or inhaled (asthma). Because epinephrine raises blood pressure and relaxes bronchial smooth muscle, it is routinely used to counteract the effects of anaphylaxis and can be lifesaving. Patients with known severe allergies are encouraged to keep automatic epinephrine injectors with them at all times, especially when away from easy access to hospitals.

Allergists use skin testing to identify allergens in type I hypersensitivity. In skin testing, allergen extracts are injected into the epidermis, and a positive result of a soft, pale swelling at the site surrounded by a red zone (called the wheal and flare response), caused by the release of histamine and the granule mediators, usually occurs within 30 minutes. The soft center is due to fluid leaking from the blood vessels and the redness is caused by the increased blood flow to the area that results from the dilation of local blood vessels at the site.

Type II and Type III Hypersensitivities

Type II hypersensitivity, which involves IgG-mediated lysis of cells by complement proteins, occurs during mismatched blood transfusions and blood compatibility diseases such as erythroblastosis fetalis (see section on transplantation). Type III hypersensitivity occurs with diseases such as systemic lupus erythematosus, where soluble antigens, mostly DNA and other material from the nucleus, and antibodies accumulate in the blood to the point that the antigen and antibody precipitate along blood vessel linings. These immune complexes often lodge in the kidneys, joints, and other organs where they can activate complement proteins and cause inflammation.

Delayed (Type IV) Hypersensitivity

Delayed hypersensitivity, or type IV hypersensitivity, is basically a standard cellular immune response. In delayed hypersensitivity, the first exposure to an antigen is called sensitization, such that on re-exposure, a secondary cellular response results, secreting cytokines that recruit macrophages and other phagocytes to the site. These sensitized T cells, of the Th1 class, will also activate cytotoxic T cells. The time it takes for this reaction to occur accounts for the 24- to 72-hour delay in development.

The classical test for delayed hypersensitivity is the tuberculin test for tuberculosis, where bacterial proteins from M. tuberculosis are injected into the skin. A couple of days later, a positive test is indicated by a raised red area that is hard to the touch, called an induration, which is a consequence of the cellular infiltrate, an accumulation of activated macrophages. A positive tuberculin test means that the patient has been exposed to the bacteria and exhibits a cellular immune response to it.

Another type of delayed hypersensitivity is contact sensitivity, where substances such as the metal nickel cause a red and swollen area upon contact with the skin. The individual must have been previously sensitized to the metal. A much more severe case of contact sensitivity is poison ivy, but many of the harshest symptoms of the reaction are associated with the toxicity of its oils and are not T cell mediated.

Autoimmune Responses

The worst cases of the immune system over-reacting are autoimmune diseases. Somehow, tolerance breaks down and the immune systems in individuals with these diseases begin to attack their own bodies, causing significant damage. The trigger for these diseases is, more often than not, unknown, and the treatments are usually based on resolving the symptoms using immunosuppressive and anti-inflammatory drugs such as steroids. These diseases can be localized and crippling, as in rheumatoid arthritis, or diffuse in the body with multiple symptoms that differ in different individuals, as is the case with systemic lupus erythematosus (image).

There are genetic factors in autoimmune diseases as well. Some diseases are associated with the MHC genes that an individual expresses. The reason for this association is likely because if one’s MHC molecules are not able to present a certain self-antigen, then that particular autoimmune disease cannot occur. Overall, there are more than 80 different autoimmune diseases, which are a significant health problem in the elderly. image lists several of the most common autoimmune diseases, the antigens that are targeted, and the segment of the adaptive immune response that causes the damage.

Overview

The immune response can be under-reactive or over-reactive. Suppressed immunity can result from inherited genetic defects or by acquiring viruses. Over-reactive immune responses include the hypersensitivities: B cell- and T cell-mediated immune responses designed to control pathogens, but that lead to symptoms or medical complications. The worst cases of over-reactive immune responses are autoimmune diseases, where an individual’s immune system attacks his or her own body because of the breakdown of immunological tolerance. These diseases are more common in the aged, so treating them will be a challenge in the future as the aged population in the world increases.

Antibodies are made by B cells, and each antibody recognizes a unique molecule. This specificity makes antibodies a powerful research, diagnostic, and therapeutic tool. Antibodies are used by researchers for a variety of reasons, but they are mainly used for labeling, in one form or another. For instance, scientists studying a protein, like a cytokine, need a way to isolate this protein from samples. With an antibody specific for the protein, they may easily separate the protein through binding assays.

VRC01 antibody (blue and green) binding to HIV (grey and red).

Scientists also may want to visualize a protein on a cell to understand how it works. Antibodies coupled with other tags, like a fluorescent label, allow researchers to image a cell and see how the protein is expressed. This concept also is useful for separating cells. For example, scientists studying T cells need to isolate T cells from all others. By identifying proteins expressed only on T cells, an antibody specific for this protein allows researchers to pull T cells out of a sample.

Antibodies are used clinically and are the subject of numerous clinical trials. Conceptually, antibodies may be used to soak up or block harmful proteins in a disease setting. For instance, tumor necrosis factor (TNF) is an inflammatory cytokine that may worsen symptoms in several diseases, like Crohn's disease and rheumatoid arthritis. There are several Food and Drug Administration-approved drugs that target TNF, and these drugs are actually antibodies that block TNF and alleviate disease symptoms. Antibodies also are used in cancer therapy. Proteins that suppress immune cells may be targeted by antibodies, so that immune cells remain active to clear away cancer cells.

Genetic Engineering

Genetic engineering is another useful research tool. In model systems, scientists can study and manipulate genes, in animals ranging from fruit flies to mice, to understand what causes various diseases and how to treat them. Gene therapy has been studied in clinical trials to treat diseases. For instance, patients with genetic immune disorders, like severe combined immunodeficiency (SCID), may receive a copy of the gene they are missing, to potentially restore healthy immune function. Gene therapy studies are ongoing, to understand long-term effectiveness and side effects.

Epigenetics

Epigenetics is the study of gene expression, particularly factors unrelated to changes in gene sequence that may turn it "on" or "off." Genes are DNA blueprints that code for RNA, which is translated into protein, like a cytokine. When an immune cell activates and needs to produce cytokines to signal other cells, the cytokine gene needs to be in an "on" state for this to occur. If the gene is in an "off" state, it cannot be stimulated, no matter what cues are present around the cell.

Scientists study how gene status is regulated through epigenetic processes that alter the on/off state, generally by regulating how tightly DNA is packed around proteins in the nucleus. Tightly wound DNA is inaccessible and "off," while loosely wound DNA is accessible and "on." Understanding epigenetic mechanisms may lead to new therapy, and drugs that target epigenetic processes are currently being studied in clinical trials. Instead of blocking a harmful protein with antibodies, a drug that targets epigenetic mechanisms may potentially prevent that harmful protein from being made in the first place.

Immunotherapy

Immunotherapy is the manipulation of the immune system to solve a health problem. There are many clinical trials examining immunotherapy for cancer by directing the patient's own immune system to attack cancer cells. Researchers have examined the potential of innate and adaptive cells to fight cancer. Similar to how vaccines induce memory responses against a particular microbe, cancer immunotherapy is an attempt to induce effective immune responses against a specific cancer.

Immunotherapy may be used to treat food allergy, another focus of clinical trials. Oral immunotherapy is feeding small, increasing amounts of a food allergen—milk, egg, or peanut—to an allergic person over time. Studies show that this can decrease sensitivity to an allergen, but it must be done under the supervision of a physician. New clinical trials are testing other routes, like a skin patch, to deliver immunotherapy for allergies.

Metabolism

In recent years, scientists have focused on the role of the immune system in regulating metabolism. The activity of immune cells, like macrophages, may influence a variety of diseases including diabetes, obesity, and atherosclerosis. For example, signals secreted by macrophages may affect the activity and size of adipocytes, which are the cells that store fat as energy. More research must be done to understand how the immune system and inflammatory responses contribute to metabolic disorders.

Microbiome

The human microbiome is the trillions of relatively harmless microorganisms (bacteria, fungi, and viruses) that reside on and in the human body. These resident microbes also are referred to as commensals. Scientists are beginning to understand the essential role of the microbiome in human health. Without commensals, the immune system fails to develop properly.

Studies in animal models have shown that commensals play an important role in altering the activity of immune cells, which may lead to different outcomes in disease settings. More work is needed however, to understand how different commensals skew immune responses and how these changes may affect various human diseases.