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Read Now: News and Research From ICAAC 2014

The Immune System: Behind the Scenes

Winter 2001/2002


This article is part of The Body PRO's archive. Because it contains information that may no longer be accurate, this article should only be considered a historical document.

The human immune system is a dazzlingly complicated mix of many different cells, tissues and chemical factors that work together to try to maintain health. The immune system has evolved over billions of years to accomplish a multitude of tasks, including responding to infections but also tolerating substances -- like pollen and food ingredients -- that pose no danger to the body. The system, as we know, is not perfect. Allergies represent a potentially dangerous overreaction to things that are ordinarily harmless, while weak or ineffective responses to harmful infections can lead to disease. The mounting of an immune response can be thought of as a major production, involving a vast cast of characters and a rough script to guide communications between them. The production often progresses seamlessly, but at other times, missed cues and forgotten lines may spell disaster.

Curtain Up

The immune system can be broken down into various divisions that help make the complexity understandable. Innate immunity is the first line of defense, encompassing a variety of cells and substances (including neutrophils, basophils, natural killer cells, macrophages and complement) that respond to infections in a non-specific way due to an ability to recognize certain common features of bacteria or other infectious agents. Due to their role as barriers to the outside world, the skin and the linings of the respiratory, intestinal, urinary and reproductive tracts are key sites of innate immune activity. Many smaller creatures (non-vertebrates like insects and worms) rely on innate immunity alone to protect them from disease.

Acquired (or adaptive) immunity is a more advanced add-on (major players are dendritic cells, macrophages, T-cells, B-cells and antibodies) that allows recognition of specific infectious agents and, most importantly, allows the immune system to "remember" a prior infection and prevent it from occurring again. Some cells, such as macrophages, fall into both innate and acquired categories because they can act as links between the two systems.

The important capacity for retaining "memory" of infections resides in T-cells and B-cells. Your body maintains two vast pools (of several billion cells apiece) of T-cells and B-cells. One pool is made up of naïve or rookie cells that have not yet responded to any infection but are on the look out for any new infectious invaders. The second pool is made up of memory or experienced cells that developed in response to a previous infection and are ready in case that same infection shows up again.

Immunity's Stage

Immune system cells can travel with relative freedom around the body, but certain locations are vital to immune activity. The bone marrow is the source of all immune system cells, but T-cells must also travel through a specialized organ called the thymus, located just behind the breastbone, before they enter the circulation. The lymphatic system is an immunological highway around the body that is separate from the blood and used only by immune system cells. Critical command centers along the way are called the secondary lymphoid organs. These include the spleen, an organ located in the abdominal region, lymph nodes, such as those under the ears, under the arms, and in the groin, and mucosal lymphoid tissue, such as areas in the gut known as Peyer's Patches. Much of the communication between the players of the acquired immune system takes place in these secondary lymphoid organs.

Immunity's Script

Cytokines and Chemokines

Immune system cells can send messages by releasing substances known as cytokines and chemokines. Many of these substances have been identified and grouped into categories including interleukins, interferons and alpha- and beta-chemokines. The ability of a cell to respond to a particular cytokine or chemokine depends on whether a matching "receptor" or docking bay is displayed on the cell's surface. For example, interleukin-2 (IL-2) is a well-known cytokine that can send a message to T-cells telling them to copy themselves (see article on IL-2). In order to receive this message, the T-cell must be displaying its interleukin-2 receptor (IL-2R), which binds to the IL-2 and delivers the cytokine's message to the genetic machinery inside the cell.

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Chemokines can attract cells that display appropriate receptors to specific locations within the body, acting as a type of guidance system. An ongoing immune response to an infection can be thought of as a very noisy time, with many different cytokine and chemokine messages being sent and "heard" by many different immune system cells. How well an infection is controlled can be influenced by the levels of particular cytokines or chemokines. Our understanding of this system of cellular communication has led researchers to test some of these substances as therapies (see article on immune-based therapies).

Immunity's Actors

Granulocytes

Granulocytes are a family of white blood cells involved in innate immunity. They're produced in large numbers by the bone marrow but live only 2-3 days. The majority are neutrophils, whose job is to engulf and eat up dangerous bacteria in a process called phagocytosis. Low levels of neutrophils (called neutropenia) can lead to increased susceptibility to bacterial infection. Eosinophils represent a smaller proportion of granulocytes. They are also capable of phagocytosis, but their main job is releasing substances that damage parasitic infections such as worms. Eosinophils can also participate in allergic reactions, where their overabundance is called eosinophilia. Basophils and mast cells make up the remainder of the granulocyte population. These two very similar populations of cells can release substances that make it easier for cells and fluids to pass through the walls of blood vessels. This process can improve access to the site of an immune response, but can also lead to fluid build-up (edema) and swelling, as can occur during allergic reactions.

Mononuclear Phagocytes

This grouping of cells plays a role in both the innate and acquired immune systems. They are capable of engulfing and digesting harmful organisms (phagocytosis). These cells have various names, depending on where they reside in the body and the specific functions they perform. They all start out in the bone marrow as monocytes -- literally, "single cells" -- but undergo a maturation process as they migrate to specific tissues. Macrophages are a type of grown-up monocyte that can scavenge for infectious invaders, surrounding and then digesting them. Under certain conditions, macrophages can also display fragments of infectious organisms (called antigens) on their surface where they can be seen by passing T-cells. This function is called antigen presentation. If T-cells recognize the antigen, the acquired immune system may be called into action.

Dendritic Cells

Dendritic cells (DCs) specialize in antigen presentation. These cells are the most effective kick-starters of the acquired immune response and are often called "professional" antigen-presenting cells for this reason. The skin and mucosal linings in the gut, vagina, mouth and nose, for example, are packed with DCs. Their role is to act as lookouts at the body's exposed surfaces, where infectious organisms are likely to enter. DCs absorb infectious organisms, digest them into small fragments and then present these fragments as antigens on the DC surface. This process is accompanied by a migration of the DC to the secondary lymphoid organs, where passing T-cells are better able to take a look at the antigen being presented.

In an inhaled viral infection like influenza, for example, thousands of DCs will pick up virus as it enters the body through the nasal or oral passages. These DCs will process the flu virus into fragments, travel to the lymph nodes and display the flu fragments as antigens to patrolling T-cells. DCs and other antigen-presenting cells also interact with responding T-cells in other ways. Signals are exchanged through "co-stimulatory" molecules on the DC and T-cell surfaces, and these signals can boost or limit the immune response. Cytokines released by DCs may enhance the survival of certain T-cells over others. Recent studies have revealed that DCs can play a critical role as middlemen, passing messages between CD4 and CD8 T-cells.

Natural Killer Cells

Natural killer (NK) cells are lymphocytes with the ability to destroy a limited range of virus-infected or cancerous cells. They can also be triggered to kill cells coated with antibodies. NK cells are part of the innate immune system and do not remember past infections.

Complement

The complement system comprises a group of more than 30 different proteins that play a role in the immune response. These proteins normally circulate around the body in an inactive or "precursor" form. During an infection, complement proteins are broken down into active fragments that can perform a variety of functions, including: signaling to immune system cells (e.g. recruiting them to particular sites in the body), enhancing phagocytosis, direct killing of some pathogens, and amplifying T-cell responses.

T-Cells

One part or "arm" of the acquired immune system is referred to as cellular and comprises the T-lymphocytes, or T-cells. There are different families of T-cells that perform specific functions, and these T-cells are identified by markers on the cell's surface. Most familiar are the CD4 "helper" T-cells, which typically act as both coordinators (hence the name helper) and participants during immune responses. Important partners are the CD8 T-cells, which include cytotoxic T-lymphocytes (CTLs), also known as "killer" T-cells. The major role of CTLs is to eliminate cells in the body that are harboring infectious agents. The majority (>80%) of the body's T-cells are either CD4 or CD8, with the ratio normally around two to one in favor of CD4 T-cells. Most of the remaining T-cells belong to a small subset called gamma-delta T-cells whose precise function is not yet well understood.

T-cells "recognize" specific antigens from the flu to HIV using a docking bay structure on their surface called a T-cell receptor (TCR). Antigens that dock snugly with the TCR can trigger the T-cell to mount an immune response. Any given infection is usually recognized by several thousand T-cells. The first encounter with a new infectious agent must be dealt with by naïve or rookie T-cells. During this initial encounter, the naïve T-cells copy themselves and acquire the ability to perform key infection-fighting functions such as cell-killing and cytokine production. After the infection is controlled or eliminated, some of these highly skilled T-cells are retained as memory cells. Each infection you're exposed to (like measles and chickenpox) triggers the development of a team of memory T-cells whose job is to prevent the disease from recurring.

New technologies are allowing memory T-cell teams to be broken down even further. It's now known that each team is made up of T-cells with a variety of skills and functions. These include CD4 T-cells that make the cytokine interferon-gamma, which seem to work alongside CD8 T-cells and help them maintain their ability to kill infected cells in the body. These CD4 T-cells are called type 1 or Th1 helper cells. Other CD4 T-cells produce different cytokines such as IL-4 and work alongside B-cells, assisting in the production of antibodies. These are called type 2 or Th2 helper cells. Some CD4 T-cells make the cytokine IL-10 and seem to play a role in dampening down the immune response.

Both CD4 and CD8 T-cells can make chemokines with odd names like MIP-1 alpha, MIP-1 beta and RANTES that can inhibit the replication of some infectious organisms, including HIV. CD8 T-cells are able to kill infected cells by making specialized cell-destroying substances called granzymes and perforin. This complexity among each team of memory T-cells is, without doubt, confusing. It becomes important because the balance between different functions can determine how well an infection is controlled. Some immune-based therapies are designed to change the balance between responses -- boosting the number of Th1 vs. Th2 CD4 T-cells, for example.

B-Cells and Antibodies

The other arm of the acquired immune system is referred to as humoral and involves B-lymphocytes or B-cells. The main role of B-cells is to act as factories for the manufacture of antibodies. Antibodies are small protein fragments that can bind to foreign material (such as parts of infectious agents) and interrupt their life cycle and/or mark them for elimination from the body.

Like T-cells, B-cells have a receptor (a BCR) that allows recognition of antigens. They undergo a similar transition from naïve to memory during the first encounter with an infection. In this case, the enhanced talent of memory B-cells is that they make antibodies that are more effective. Antibodies fall into different subclasses: IgM antibodies are made early in an immune response, but memory B-cells switch to making IgG antibodies that bind to their target more efficiently. Some B-cells, mainly those in the mucosal areas, make antibodies of a class called IgA. Most of the time, antibody production by B-cells requires signals from CD4 T-cells specific for the same antigen. Tests can look for the presence of antibodies to specific infections, allowing doctors to know which common infections people have been exposed to in the past.

The Finale

The interaction between the players of the immune system and infections ultimately determines our health. Scientists are gaining a better understanding of what goes on behind the scenes during the production of an immune response, but many mysteries remain. Further progress in this field of research -- immunology -- promises to inform the design of new and improved immune-based therapies for HIV and other hard-to-treat diseases.





This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 

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