Yale scientists have solved a puzzle of the immune system—how antibodies enter the nervous system to control viral infections. Their finding may have implications for the prevention and treatment of a range of conditions, including herpes and Guillain-Barre syndrome, which has been linked to the Zika virus.
How antibodies could gain access to nerve tissue in order to control infection
Many viruses, such as West Nile, Zika, and the herpes simplex virus enter the nervous system, where they were thought to be beyond the reach of antibodies. Yale immunobiologists Dr. Akiko Iwasaki and Norifumi Iijima used mice models to investigate how antibodies could gain access to nerve tissue in order to control infection.
In mice infected with herpes, they observed a previously under-recognized role of CD4 T cells, a type of white blood cell that guards against infection by sending signals to activate immunity.
In response to herpes infection, CD4 T cells entered the nerve tissue, secreted signaling proteins, and allowed antibody access to infected sites. Combined, CD4 T cells and antibodies limited viral spread.
“This is a very elegant design of the immune system to allow antibodies to go to the sites of infection,” said Iwasaki. “The CD4 T cells will only go to the site where there is a virus. It’s a targeted delivery system for antibodies.”
The implications of the finding are multiple. Without CD4 T cells, antibody-based therapies that are being developed for conditions like herpes may not be sufficient to control infection, Iwasaki noted. Conversely, for antibody-mediated autoimmune diseases such as Guillain-Barre, “it may be beneficial to block CD4 from entering the neuronal tissues,” she said.
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More information: Norifumi Iijima et al, Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help, Nature (2016). DOI: 10.1038/nature17979
Journal reference: Nature search and more info website
Provided by: Yale University
Eur J Immunol. 1990 Aug;20(8):1877-80.
Human breast milk T lymphocytes display the phenotype and functional characteristics of memory T cells.
Bertotto A1, Gerli R, Fabietti G, Crupi S, Arcangeli C, Scalise F, Vaccaro R.
Naive (unsensitized) and memory (antigen-primed) T cells can be phenotypically distinguished on the basis of the high or low intensity with which they express a number of immunologically relevant lymphocyte membrane antigens, including CD45R, CDw29, UCHL1, LFA-1, LFA-3, CD2 and Pgp-1. Here we report that in contrast to the two major T cell subsets found in the blood, milk T lymphocytes are almost exclusively composed of the one which exhibits the CD45Rlow, CDw29, UCHL1, LFA-1high memory T cell phenotype. In addition, while milk and autologous blood cells expressed similar levels of CD3 surface antigens, CD2 and ICAM-1 expression was approximately twofold greater on the milk T lymphocytes. This agrees with the finding that whereas colostrum T cells respond poorly to PHA, they proliferate and produce interferon-gamma normally when stimulated with either the anti-CD3 or anti-CD2 monoclonal antibodies. The selective colonization of the mammary gland during lactation by a population of T lymphocytes which displays the phenotype and functional characteristics of memory T cells may be one of the mechanisms whereby the suckling infant benefits from its mother’s immunological experience.
Breast Milk Antibodies
Antibodies, which are also called immunoglobulins, take five basic forms, denoted as IgG, IgA, IgM, IgD and IgE. All have been found in human milk, but by far the most abundant type is IgA, specifically the form known as secretory IgA, which is found in great amounts throughout the gut and respiratory system of adults. These antibodies consist of two joined IgA molecules and a so-called secretory component that seems to shield the antibody molecules from being degraded by the gastric acid and digestive enzymes in the stomach and intestines. Infants who are bottle-fed have few means for battling ingested pathogens until they begin making secretory IgA on their own, often several weeks or even months after birth.
The secretory IgA molecules passed to the suckling child are helpful in ways that go beyond their ability to bind to microorganisms and keep them away from the body’s tissues. First, the collection of antibodies transmitted to an infant is highly targeted against pathogens in that child’s immediate surroundings. The mother synthesizes antibodies when she ingests, inhales or otherwise comes in contact with a disease-causing agent.
The molecules in milk have other valuable functions as well. Each molecule of a protein called lactoferrin, for example, can bind to two atoms of iron. Because many pathogenic bacteria thrive on iron, lactoferrin halts their spread by making iron unavailable. It is especially effective at stalling the proliferation of organisms that often cause serious illness in infants, including Staphylococcus aureus. Lactoferrin also disrupts the process by which bacteria digest carbohydrates, further limiting their growth. Similarly, B12 binding protein, as its name suggests, deprives microorganisms of vitamin B12. Bifidus factor, one of the oldest known disease-resistance factors in human milk, promotes the growth of a beneficial organism named Lactobacillus bifidus. Free fatty acids present in milk can damage the membranes of enveloped viruses, such as the chicken pox virus, which are packets of genetic material encased in protein shells. Interferon, found particularly in colostrum-the scant, sometimes yellowish milk a mother produces during the first few days after birth-also has strong antiviral activity. And fibronectin, present in large quantities in colostrum, can make certain phagocytes more aggressive so that they will ingest microbes even when the microbes have not been tagged by an antibody. Like secretory IgA, fibronectin minimizes inflammation; it also seems to aid in repairing tissue damaged by inflammation.
The next most common milk leukocyte is the macrophage, which is phagocytic like neutrophils and performs a number of other protective functions. Macrophages make up some 40 percent of all the leukocytes in colostrum. They are far more active than milk neutrophils, and recent experiments suggest that they are more motile than are their counterparts in blood. Aside from being phagocytic, the macrophages in breast milk manufacture lysozyme, increasing its amount in the infant’s gastrointestinal tract. Lysozyme is an enzyme that destroys bacteria by disrupting their cell walls.
In addition, macrophages in the digestive tract can rally lymphocytes into action against invaders. Lymphocytes constitute the remaining 10 percent of white cells in the milk. About 20 percent of these cells are B lymphocytes, which give rise to antibodies; the rest are T lymphocytes, which kill infected cells directly or send out chemical messages that mobilize still other components of the immune system. Milk lymphocytes seem to behave differently from blood lymphocytes. Those in milk, for example, proliferate in the presence of Escherichia coli, a bacterium that can cause life-threatening illness in babies, but they are far less responsive than blood lymphocytes to agents posing less threat to infants. Milk lymphocytes also manufacture several chemicals-including gamma-interferon, migration inhibition factor and monocyte chemotactic factor-that can strengthen an infant’s own immune response.