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Among people with HIV, combination antiretroviral therapy (ART) has dramatically reduced the risk of AIDS-defining opportunistic illnesses (OIs) and mortality directly related to immune suppression. But as HIV positive people survive longer, they are at increased risk for a variety of non-AIDS conditions even when their CD4 cell counts are high.
At the annual Conference on Retroviruses and Opportunistic Infections (CROI) in February, some attendees dubbed 2010 "the year of inflammation." A growing body of evidence implicates chronic inflammation and immune activation in the development of non-AIDS conditions, and some experts blame inflammation for what looks like accelerated aging in people with HIV.
Immunosenescence: Age-related decline in immune function.
Inflammation refers to the complex cascade of events that happen when the immune system recognizes a threat and goes into action, including migration and activation of various types of white blood cells (leukocytes) and release of chemical messengers known as cytokines.
The word "inflammation" often brings to mind the immune system's immediate response to acute injury or infection. When bacteria enter the body through a cut, for example, these microorganisms, the toxins they produce, and other signals from injured cells and blood vessels alert macrophages and other leukocytes present in tissues. A cellular protein called nuclear factor kappa-B (NF-kB) is released and switches on genes involved in immune response. Newly activated macrophages then begin producing pro-inflammatory cytokines, including interleukin 1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha).
Soon, neutrophils and other immune cells migrate to the site, where they ingest pathogens (a process called phagocytosis) or kill them by releasing toxic substances. Reactive forms of oxygen and nitrogen generated by these cells cause oxidative stress and damage to DNA (genetic material) in the body's cells. Basophils and mast cells release histamine, best known for its role in allergic reactions. This innate branch of the immune system is nonspecific -- it responds to multiple threats.
Within cells, signals produced by these "first responders" stimulate release of locally acting hormones known as prostaglandins. They also trigger an acute-phase reaction, causing the liver to produce acute-phase proteins such as C-reactive protein (CRP), fibrinogen, and plasminogen.
At the local level, these chemicals induce physiological changes, including blood vessel dilation and increased permeability (leakiness), leading to the classic inflammatory signs of redness, swelling, heat, and pain. They also play a role in coagulation (blood clotting) and tissue repair.
On a systemic level, pro-inflammatory signals act on the brain and elsewhere in the body, causing fever, loss of appetite, fatigue, and other flu-like symptoms. An extreme version of this reaction, known as a "cytokine storm," has proven fatal in clinical trials of experimental therapies and has been proposed as an explanation for the high death rate during the 1918 influenza pandemic.
Early responders release additional cytokines, including interferon-gamma, that promote longer-term immune activation mediated by the lymphocytes: T-cells, B-cells, and natural killer cells. Antigen-presenting cells such as macrophages capture pathogens and display pieces of them (antigens) on their surface. Lymphocytes interact with these cells and learn to recognize and directly target those particular pathogens. This adaptive branch of the immune system responds to specific threats.
T-cells -- key players in adaptive immune response -- mature and differentiate into CD4 and CD8 cells in the thymus, an organ in the chest; B-cells are produced in the bone marrow. New T-cells and B-cells are naive, meaning they are able to respond to newly encountered antigens. After an immune response, a subset of these cells evolve into long-lived memory cells that remember a specific pathogen and are primed to respond rapidly if it appears again.
Chief among the lymphocytes are CD4 ("helper") T-cells -- the primary target of HIV -- which manage the overall immune response. CD8 ("killer") T-cells destroy virus-infected and malignant cells. CD8 T-cells, macrophages, and natural killer cells are responsible for cell-mediated immunity, in which immune cells themselves attack pathogens or compromised cells. B-cells produce antibodies, the basis of humoral immunity.
The inflammatory response, therefore, is the result of a complex interplay of many different types of immune cells that use hundreds of chemical messengers to communicate among themselves, forming cascades, chains of command, and feedback loops. (See table below for a partial list of some important cytokines and mediators that play a role in inflammation.)
The table below lists key chemical messengers contributing to inflammation that are discussed in this article; the immune system uses hundreds of signaling chemicals and this list is by no means complete. Some of these chemicals build up in the bloodstream and can be measured in laboratory tests as biomarkers of inflammation, coagulation, or endothelial dysfunction. Biomarkers may not play a direct causal role in these processes, but their presence in the blood can provide clues about immune system activity.
|Adiponectin||anti-inflammatory adipokine hormone, signals increased inflammation|
|C-reactive protein (CRP)||acute phase protein, signals increased inflammation|
|D-dimer||byproduct of blood clot breakdown, signals increased coagulation|
|Fibrinogen||acute phase protein, mediator of blood clotting, signals coagulation|
|Intercellular adhesion molecule 1 (ICAM-1)||cell adhesion molecule, enables leukocytes to bind to endothelial lining, signals endothelial dysfunction|
|Interleukin 1 (IL-1)||pro-inflammatory cytokine, signals increased inflammation|
|Interleukin 4 (IL-4)||anti-inflammatory cytokine|
|Interleukin 6 (IL-6)||pro-inflammatory cytokine, signals increased inflammation|
|Interleukin 10 (IL-10)||anti-inflammatory cytokine|
|Leptin||pro-inflammatory adipokine hormone|
|Monocyte chemoattractant protein 1 (MCP-1)||inflammatory chemokine, promotes monocyte migration|
|Macrophage inflammatory protein 1 (MIP-1)||inflammatory chemokine, promotes neutrophil migration|
|Plasminogen||acute phase protein, mediator of blood clot breakdown, involved in wound healing|
|P-selectin||cell adhesion molecule, enables leukocytes to move along endothelial lining, signals endothelial dysfunction|
|Transforming growth factor-beta (TGF-beta)||anti-inflammatory cytokine|
|Tumor necrosis factor-alpha (TNF-alpha)||pro-inflammatory cytokine, promotes death of cancer cells, signals increased inflammation|
|Vascular adhesion molecule 1 (VCAM-1)||cell adhesion molecule, enable leukocytes to bind to endothelial lining, signals endothelial dysfunction|
Differentiating Immune Cells
Lymphocytes and other immune cells are classified according to cell-surface molecules designated by a CD ("cluster of differentiation") number. Human leukocytes have more than 300 CD markers, and an individual cell may carry several of them. Helper T-cells with the CD4 marker, for example, coordinate immune responses, while killer T-cells carrying CD8 attack virus-infected and malignant cells.
CD molecules are not simply markers, however, but also have their own functions. Many act as cell surface receptors or ligands (molecules that bind to receptors), often triggering signaling cascades. HIV uses the CD4 receptor as a gateway to enter helper T-cells, macrophages, and dendritic cells.
CD markers also indicate the status of immune cells. The CD25, CD38, and CD69 markers show that a CD4 or CD8 T-cell is activated. The CD45 marker indicates whether a T-cell or B-cell is a naive (CD45RA) or memory (CD45RO) cell. T-cells expressing CD57 in the absence of CD28 are typically senescent, having exhausted their ability to proliferate.
Pro-inflammatory prostaglandins and acute-phase proteins are short-lived and their effects are temporary unless there is an ongoing signal to produce more. And just as some chemical messengers promote immune activation, opposing signals act to dampen responses. Anti-inflammatory cytokines include IL-4, IL-10, and transforming growth factor-beta (TGF-beta).
This fine-tuned system can go awry, however, when the immune system is faced with a threat it cannot overcome. This occurs, for example, during persistent infection. Other causes of chronic inflammation include autoimmune conditions (in which the immune system attacks the body's own tissues), obesity, chronic stress, and exposure to toxins such as tobacco smoke.
Numerous pathogens, including HIV, hepatitis B and C viruses (HBV and HCV), and herpes viruses, can remain in the body over the long term. Though the immune system may respond by producing antibodies and activating killer T-cells, this response is not always enough to clear infection. For some pathogens, such as HCV, a proportion of people can clear the infection either spontaneously or with treatment. Others, like HIV, appear to always persist for life.
In contrast with localized acute inflammatory responses, chronic inflammation may be systemic, affecting the entire body. The overall effect is persistent immune activation, but it is more accurately thought of as immune dysregulation, characterized by a shift in leukocyte activity. During chronic inflammation, neutrophils become less active, while T-cells and other lymphocytes take on a larger role.
Persistent activation of T-cells accelerates their maturation and progression through the cell cycle of growth and division. Eventually, T-cells burn out prematurely and may undergo apoptosis (programmed cell death, or "cell suicide") or lose their ability to divide (replicative senescence).
Long-term immune activation and sustained high levels of pro-inflammatory cytokines can cause damage throughout the body, and chronic inflammation is increasingly recognized as a common denominator underlying a host of progressive and age-related diseases.
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