Cindy, Steph, and Vincent reveal that lymphocyte trafficking through lymph nodes and lymph is circadian – it is dependent on the time of day.
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Antibodies produced by infection with a virus, or after immunization with viral vaccines, are effective at preventing viral disease. However humans and higher primates contain “natural antibodies” which are present in serum before viral infection. Natural antibodies can activate the classical complement pathway leading to lysis of enveloped virus particles long before the adaptive immune response is activated.
Many natural antibodies are directed against the disaccharide galactose α(1,3)-galactose (α-Gal) (illustration), which is found as a terminal sugar on glycosylated cell surface proteins. Humans, apes, and Old World monkeys lack the gene encoding the enzyme galactosyltransferase, which attaches α-Gal to membrane proteins. Lower primates, most other animals, and bacteria synthesize the disaccharide.
Human serum contains high levels of antibodies specific for α-Gal because the human gut contains bacteria that produce this sugar. Over 2% of serum IgM and IgG antibodies are directed against α-Gal. This antibody binds to the membrane of enveloped viruses that contain α-Gal antigens and triggers the classical complement cascade, leading to lysis of virions and loss of infectivity.
The anti-α-Gal antibody-complement reaction is probably the main reason why humans and higher primates are not infected by enveloped viruses of other animals. Many of these viruses infect human cells efficiently in culture because the complement proteins in serum are inactivated by heating. For example, when vesicular stomatitis virus, human immunodeficiency virus type 2, and human foamy virus are grown in non-human cells which produce α-Gal, the virions can be inactivated by fresh (i.e. not heat-inactivated) human serum. When the same viruses are propagated in human cells, which lack α-Gal, fresh human serum has no effect on viral infectivity. Because of these findings, virus vectors for gene therapy are produced in cells lacking galactosyltransferase to avoid complement-mediated inactivation of the viruses in humans.
When strains of mice that cannot produce any antibodies are infected with vesicular stomatitis virus, titers in the kidney and brain are 10-100 times higher than in normal mice. Furthermore, virus titers in lymph nodes are 10-100 times lower than in antibody-producing mice.
Anti-α-Gal antibodies are an example of how the adaptive immune system cooperates with the innate complement cascade to provide immediate action before specific anti-viral antibodies are developed. Natural antibodies prevent the spread of viruses to vital organs, and improve immunogenicity by enhancing the trapping of antigen in secondary lymphoid organs such as lymph nodes.
Takeuchi Y, Liong SH, Bieniasz PD, Jäger U, Porter CD, Friedman T, McClure MO, & Weiss RA (1997). Sensitization of rhabdo-, lenti-, and spumaviruses to human serum by galactosyl(alpha1-3)galactosylation. Journal of Virology, 71 (8), 6174-8 PMID: 9223512
Ochsenbein AF, Fehr T, Lutz C, Suter M, Brombacher F, Hengartner H, & Zinkernagel RM (1999). Control of early viral and bacterial distribution and disease by natural antibodies. Science (New York, N.Y.), 286 (5447), 2156-9 PMID: 10591647
With the looming prospect of mass immunization against influenza, it’s important to understand how vaccines work. To do this we must have a good understanding of adaptive immune defenses. Today we’ll begin a discussion of the humoral arm of the adaptive immune response – antibodies.
Antibodies are large proteins produced by vertebrates that play important roles in identifying and eliminating foreign objects. The basic structural unit is composed of two heavy chains and two light chains, as shown in this diagram.
Antibodies bind other molecules known as antigens. Binding occurs in a small region near the ends of the heavy and light chain called the hypervariable region (labeled only on one arm in the figure). As the name implies, this region is extremely variable, which is why vertebrates can produce millions of antibodies that can bind many different antigens. The part of the antigen that is recognized by the antibody is known as an epitope.
There are five classes of immunoglobulin—IgA, IgD, IgE, IgG, and IgM—defined by the amino acid sequence of the heavy chain. They have different roles in immune responses; IgG, IgA, and IgM are commonly produced after viral infection.
During the first encounter with a virus, a primary antibody response occurs. IgM antibody appears first, followed by IgA on mucosal surfaces or IgG in the serum. The IgG antibody is the major antibody of the response and is very stable, with a half-life of 7 to 21 days. When an infection occurs with the same or a similar virus, a rapid antibody response occurs that is called the secondary antibody response. The specificity and memory of the antibody response are illustrated in the following graph.
A typical adaptive antibody response is shown as the relative concentration of serum antibodies weeks after injection of an animal with antigen A or a mixture of antigens A and B. Maximal primary response to antigen A occurs in 3 to 4 weeks. When the animal is injected with a mixture of both antigens A and B at 7 weeks, the secondary response to antigen A is more rapid and stronger than the primary response, demonstrating immunological memory. As expected, the primary response to antigen B requires 3 – 4 weeks. Antibody levels (also called antibody titers) decline with time after each immunization, a property known as self-limitation or resolution.
Antibodies are critical for preventing many viral infections, and may also contribute to the resolution of infection. We’ll next explore how antibodies accomplish these diverse activities.
The immune response to viral infection comprises innate and adaptive defenses. The innate response, which we have discussed previously, functions continuously in a normal host without exposure to any virus. Most viral infections are controlled by the innate immune system. However, if viral replication outpaces innate defenses, the adaptive response must be mobilized.
The adaptive defense consists of antibodies and lymphocytes, often called the humoral response and the cell mediated response. The term ‘adaptive’ refers to the differentiation of self from non-self, and the tailoring of the response to the particular foreign invader. The ability to shape the response in a virus-specific manner depends upon communication between the innate and adaptive systems. This communication is carried out by cytokines that bind to cells, and by cell-cell interactions between dendritic cells and lymphocytes in lymph nodes. This interaction is so crucial that the adaptive response cannot occur without an innate immune system.
The cells of the adaptive immune system are lymphocytes – B cells and T cells. B cells, which are derived from the bone marrow, become the cells that produce antibodies. T cells, which mature in the thymus, differentiate into cells that either participate in lymphocyte maturation, or kill virus-infected cells.
Both humoral and cell mediated responses are essential for antiviral defense. The contribution of each varies, depending on the virus and the host. Antibodies generally bind to virus particles in the blood and at mucosal surfaces, thereby blocking the spread of infection. In contrast, T cells recognize and kill infected cells.
A key feature of the adaptive immune system is memory. Repeat infections by the same virus are met immediately with a strong and specific response that usually effectively stops the infection with less reliance on the innate system. When we say we are immune to infection with a virus, we are talking about immune memory. Vaccines protect us against infection because of immune memory. The first adaptive response against a virus – called the primary response – often takes days to mature. In contrast, a memory response develops within hours of infection. Memory is maintained by a subset of B and T lymphocytes called memory cells which survive for years in the body. Memory cells remain ready to respond rapidly and efficiently to a subsequent encounter with a pathogen. This so-called secondary response is often stronger than the primary response to infection. Consequently, childhood infections protect adults, and immunity conferred by vaccination can last for years.
The nature of the adaptive immune response can clearly determine whether a virus infection is cleared or causes damage to the host. However, an uncontrolled or inappropriate adaptive response can also be damaging. A complete understanding of how viruses cause cause disease requires an appreciation of the adaptive immune response, a subject we’ll take on over the coming weeks.
In response to viral infection, many organisms mount a remarkable defense known as the immune response. This response to viral infection consists of an innate, or nonspecific component, and an adaptive, or specific defense. The innate response is considered the first line of immune defense because it is active even before infection begins. In fact, many viral infections are halted by the innate immune system, which responds very quickly – within minutes to hours after infection.
A key property of the innate immune system is the ability to recognize viruses as ‘foreign’. Viral proteins and nucleic acids are distinguished from cellular counterparts by cellular proteins called pattern recognition receptors (illustrated). These are proteins present either in the cell cytoplasm or on cellular membranes, where they detect viral components. For example, the cytoplasmic protein RIG-I detects double-stranded RNA (dsRNA) or single-stranded RNA (ssRNA) with a 5′-triphosphate. These types of RNAs are usually not found in the cytoplasm of unifected cells; rather they are typically products of viral replication. When RIG-I binds these viral RNAs, a series of reactions occur which lead to the synthesis of cytokines, the primary output of the innate defense system. Other detectors of viruses are the membrane-bound toll-like receptors (TLRs), which sense viral glycoproteins, dsRNA, ssRNA, and the sequence CpG in viral DNA. Engagement of TLRs by these virus-specific ligands also leads to the synthesis of cytokines, albeit by different pathways.
The presence of cytokines in the blood is typically one of the earliest indications that the host has been infected with a virus. Over 80 known cytokines are secreted by infected cells. The first that are produced after viral infection include interferon-α and -β (IFN-α, IFN-β), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-12, and IFN-γ.
Cytokines function locally by binding receptors on other cells. For example, IFN produced by infected cells engages receptors on neighboring cells. Those cells then produce hundreds of cellular proteins which have antiviral activities. When cytokines enter the circulation, they elicit symptoms typical of many viral infections, including fever, sleepiness, lethargy, muscle pain, loss of appetite, and nausea.
Another key component of the innate response are the so-called sentinel cells: dendritic cells and macrophages present in peripheral compartments such as skin and mucosal surfaces. Sentinel cells patrol the body, seeking signs of infection. Dendritic cells bind cytokines produced by virus-infected cells, and also take up viral proteins released from dying virus-infected cells. They respond by producing more cytokines to amplify the original response.
In many viral infections, the early action of cytokines produced by infected cells and dendritic cells is sufficient to eliminate the pathogen. If innate defenses are overwhelmed and virus replication continues unabated, then the second-line defenses are mobilized to ensure host survival. These comprise the adaptive immune response – antibodies and immune cells. Days to weeks are required to mount an adaptive immune response that is specifically tailored to the infecting virus. The innate response therefore serves as a crucial rapid response that provides sufficient time for the activation of the adaptive immune system.