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Understanding the Puzzle That Is Our Immune System

By Matt Sharp

September/October 2011

HIV begins its life cycle

Image by Mike Tyka.

If ever there was a silver lining to the AIDS pandemic, it might be the scientific contribution HIV has brought to understanding the immune system. Only a few decades ago, not much was understood about our chameleon-like, self-protective immune system because of its enigmatic complexity. Yet today, more is known about the immune system than ever before, although harnessing the knowledge to create immune-based treatments will continue to be challenging.

Surviving the roller coaster ride of HIV with its ups and downs, I have personally witnessed a remarkable attribute of the immune system: its resiliency -- or ability to maintain a balance, especially with a long-term condition such as HIV. HIV disrupts this balance, yet overcoming a broken immune system is entirely possible with improvements in treatment, and a further understanding of how to "correct" the disruption made by HIV.


What Is the Immune System?

Simply put, the immune system is composed of organs, tissues, cells, and chemicals that work in a specific, coordinated response to fight foreign invaders such as bacteria, viruses, parasites, and proteins. You might consider our immune system to be like computer software or an "app" on your phone that, through a complex series of biological processes and cellular signaling, works collectively to keep us healthy.

Despite the immune system's remarkable ability to fight infections and heal, it has taken thousands of years to evolve to where it is today. Yet it is not perfect. Allergies, for example, are overreactive immune responses to things that are not necessarily harmful. The immune system also has a weaker response to certain infections that can lead to diseases such as cancer.


The Pieces of the Puzzle

Understanding the immune system is like putting together one of those jigsaw puzzles with thousands of pieces. For the sake of this review, I will attempt to deconstruct that puzzle piece by piece, then put it back together by explaining how the immune system works. Finally, I will explain what we currently know about how HIV impacts the immune system and our hopes for the future.


Blood Cells

All cells in the body come from the bone marrow and eventually divide and expand to provide the cellular make-up of bones, tissues, organs, and blood. Blood cells take on their individual roles, separating into white and red blood cells in a process called "hematopoesis." Lymphoid cells form that are the major immune white blood cells known as T-cells, B-cells and natural killer cells. CD4 and CD8 cells are types of T-cells.

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APCs, or antigen presenting cells, such as macrophages and dendritic cells, are also immune cells. They sweep and gobble up invaders, digesting them into antigens that are presented to the T-cells in the lymph nodes.

CD4 T-cells (also known as CD4s) are known as the generals of the immune system, as they coordinate signals and responses. When the CD4 T-cell becomes activated, it signals to the CD8 T-cell to kill the infected cell. These two types of cells work as partners to eliminate pathogens. CD4s are also the main target of HIV and over time, without treatment, the total pool of CD4 cells in the body will die.

Different kinds of CD8 T-cells have different functions. Cytotoxic lymphocytes, or CTLs, kill infected cells -- the cells release cytokines that have their own immune functions, but they also inject a chemical called perforin that is like a killing potion. Without a CD4 T-cell signaling to a CD8 T-cell, this potion would never be released and a critical moment of immune protection would be lost. Suppression of overreactive immune responses is the job of CD8 suppressor cells.

These are the most important white blood cells that carry out the bulk of the infection fighting that occurs in our bodies. But there are many other types of cells that help fend off invaders that, for the sake of this review, are smaller, less significant pieces of the puzzle.


Getting the Full Picture

There are several other pieces of our immune system puzzle that are necessary for understanding how it all fits together.


Thymus

Another major player in the immune system is the thymus. This organ lies directly under our breastbone and covers almost the entire top portion of the chest when we are born, then shrinks and even disappears with age. The thymus can be thought of as a "school" for CD4 and CD8 T-cells. In the thymus, cells go through a process called "thymopoesis," that instructs the T-cells on how to carry out their function. Studies have shown that there can still be thymopesis even in older folks or people with HIV who have a shrunken thymus. This is critical to maintaining the large pool of T-cells that are ready to encounter a new pathogen. In the thymus, CD8 T-cells are developed in a similar way as the CD4s. Memory CD8 T-cells will also be made after an encounter with a pathogen.


Lymphatic System

The lymphatic system is comprised of an interconnected system of vessels and nodes where much of the immune action takes place. The lymph nodes are small peanut-sized glands located at particular places throughout the body where antigens meet up with CD4 cells, sort of like train stations or coffee houses. The CD4 cells then mobilize the rest of the immune system cells to fight the infection. Other secondary lymph tissues involved are the spleen, mucosal tissue in the gut, and tonsils.


Reverse transcription

Image by Mike Tyka.


Antibodies

Antibodies are made by B-cells when you are exposed to a pathogen. They are small Y-shaped proteins that stick to and red-flag pathogens for immune system recognition that leads to their destruction.


Cytokines and Chemokines

Similar to data being sent over the wire, these are immune system signaling chemicals that either tell the immune system to start, slow down, or stop, as well as where to target. They also employ the body's mucous, saliva, tears, and pus to help rid the body of the foreign invader. These chemicals are responsible for many of the symptoms of an infection, including inflammation.

Mucosal Immunity

Mucosal immunity includes a one-inch barrier of mucous membrane cells which is often the first line of defense. Gut-associated lymph tissue is a lining in the gut where a lot of HIV is found and is a big area of current research efforts.


T-Cell Receptors

T-cell receptors are on the surface of every T-cell and "introduce" a foreign invader to antigen-presenting cells. The receptors help to recognize the cell type.


Putting the Puzzle Together

There are two "arms" or divisions in our immune system puzzle that incorporate separate cells and immune functions to deliver a team approach in fighting infections.

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One arm is known as the innate immune system that can also be referred to as "non-specific" and is the first line of defense. Key sites of innate immune activity are the skin and the lining of the respiratory, intestinal, urinary, and reproductive systems that are natural barriers to outside germs. APCs -- macrophages and dendritic cells -- and certain antibodies patrol these key sites and react to anything they do not recognize, anything different or foreign to the body. APCs make antigens to the invader and either gobble them up and destroy them, or deliver them to a CD4 cell. In our puzzle analogy, you might think of the innate immune system as the first pieces you lay out on the table, like the border of the jigsaw puzzle.

The more advanced second arm is known as adaptive or "acquired" immune response. Once the body has been exposed to a pathogen, a phenomenon known as immunologic memory occurs. This is where T-cells, B-cells, macrophages, dendritic cells, and antibodies remember a specific pathogen and prevent it from invading again. Some cells such as macrophages fall into both arms of the immune system, acting as links between the two divisions.

There are also two different strategies that are employed to get the job done in ridding the immune system of pathogens. One is called the humoral immune response that uses antibodies to help identify and destroy invaders. The cellular immune response involves cell-to-cell killing using T-cells. Both are essential for the most effective immune response.

Without one of these immune system divisions or strategies you would be like a knight wearing only your suit of amour without the helmet. These mechanisms work collectively to make the immune system a complex yet comprehensive protection for our bodies.


From Birth to Death: The Life of a CD4 Cell

People with HIV and their care providers discuss CD4s for life, as they are an important measurement of the status of the immune system. It is part of the language of HIV to understand the function of these cells and the significance of their number. An AIDS diagnosis is based on having 200 or fewer CD4s. Treatment guidelines currently recommend starting antiretroviral therapy at 350-500 CD4s, or earlier.

As mentioned above, CD4s are responsible for the coordination of the immune response. They are born in the bone marrow as "progenitor" white blood cells. If the destiny of the immature cell is to become a T-cell, it goes to school in the thymus. It is here where the cell will be made a CD4 T-cell (or CD8) for the span of its life. The T-cell receptor or TCR is randomly determined in the thymus. TCRs are like keys that enable the baby cells to enter their target, therefore starting an immune response.

When roaming in key lymphatic organs, the new, or "naive," CD4s will eventually encounter an invader and begin the process of the immune response. Here is where the cell is activated and proliferation begins. Many duplicate cells are made, sort of like adding new troops to an invasion. As in a battle, some of the cells die, but some survive to become "memory" CD4s. The cells have graduated and are now equipped to protect the body from pathogens they have met before if they ever encounter them again. After they do their jobs, they will either divide and make more of themselves, or die in a process known as apoptosis.

Certain memory cells go into hiding or what is called a "quiet" state. These elite cells are a growing area of interest in HIV cure research since they can harbor what is known as "latent" HIV. If scientists can figure out a way to activate these quiet memory cells, new HIV virions (baby viruses) would be unleashed into the plasma where effective antiretroviral therapy could functionally rid the body of HIV.


Assembly

Image by Mike Tyka.


How HIV Dislodges the Puzzle

Now that our puzzle is nearly completed, think about how upset you'd be if the table it was on was upended. This is what happens when HIV invades the immune system, dislodging and even destroying pieces of the puzzle.

HIV enters the body, most often in the mucosa, and interacts with the dendritic cell that does its job in sweeping up the virus and presenting it to the CD4 cell. Once inside the lymph node, if the HIV antigen on the dendritic cell fits into the CD4 T-cell's receptor, it will begin its invasion. HIV has already hitchhiked its way into the CD4 T-cell just because the immune system is doing what it's supposed to do.

At this point, naive CD4s are becoming infected as they are recruited by the entry of HIV into the body. HIV will multiply and many virions will be produced by the activated CD4s. It's like a copy machine gone wild. This is the point of acute infection where viral load skyrockets.

We also know that some HIV-specific memory cells die, but some go off and rest in what are known as reservoirs. Still others remain defective. Some of these cells remain infected after they are activated and return to a resting state, hiding out for years until they are awakened again with the HIV inside of them.

CD8 T-cells go about their normal response to HIV as they are employed by the CD4 cell to kill. Yet because of HIV, the infected CD4 cells don't properly grow up, so they give weak or ineffective helper signals to the CD8 cells. This process is called anergy. Helpless CD8 T-cells are also ineffective, all caused by HIV in the first place.

Now that HIV has messed up the memory T-cell component, it will also duplicate itself, adding new fuel for the over 700 million naive T-cells being produced in the thymus every day. The entire cycle repeats itself, over and over, again and again, day after day, until the immune system loses much of its work force.

In most cases, HIV will eventually win if treatment is not initiated, employing its insidious and underhanded ability to upend the immune system puzzle.


Ending HIV Once and for All?

There has been great success with antiretroviral therapy in turning around the devastation of the early days of the epidemic when sickness and death were common. But with many unknowns as to how to mend the immune system, even when people are successfully treated, there still remains smoldering HIV hiding in those resting cells.

Yet there is new hope in controlling inflammation caused by the immune response, which would hopefully prevent some of the longer-term non-AIDS conditions now experienced by many people living with HIV into their golden years.

It is also exciting that research into a cure is gaining momentum, especially after Timothy Brown -- the Berlin Patient -- was cured of HIV. His case is providing the needed push, evidence that a cure for HIV is possible. Now, four years after his cure, more research is entering into clinical trials, including treatment vaccines, gene therapy, and other immune-based therapies such as IL-7. The possibility of a cure has opened the door for fitting the pieces of the immune system puzzle together once and for all.

Diagnosed with HIV in 1988, Matt Sharp's long history as an AIDS advocate includes belonging to ACT UP Golden Gate; directing the education programs at Test Positive Aware Network in Chicago and Project Inform in San Francisco; and helping to found the AIDS Treatment Activists Coalition. Currently, he acts as an international consultant, providing training services to HIV service providers, non-profit organizations, and the pharmaceutical industry.

About these images:

Mike Tyka is a Research Fellow at the University of Washington. Using molecular visualized software called PyMOL, Tyka created these images. He is also author of the Beautiful Proteins blog (http://beautifulproteins.blogspot.com).




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