Influenza Virus Genetics, Reassortment, and Antigenic Shift
Influenza virus has 8 separate gene segments (made of RNA rather than DNA). When two (or more) different strains of influenza infect the same cell their gene segments go into a big pool and they can get get mixed up. This process is known as reassortment. Reassortment allows for the almost instantaneous creation of a brand new strain of virus, called antigenic shift. Influenza viruses are named for their two most important virulence genes: hemagglutinin (HA, H) and neuraminidase (NA, N). This is why influenza viruses are often referred to as H1N1, H3N2, etc. (Tamiflu is a NA inhibitor). If an H1N1 virus and an H3N2 virus infect the same cell, reassortment can lead to the emergence of a new H3N1 virus, or H1N2, etc. If the human population is not prepared immunologically for the new strain, an epidemic can result. Each year flu experts and the CDC have to predict which strains of influenza are expected to emerge in the coming year and those are the strains vaccine manufacturers produce vaccines for. If the experts guess wrong, the efficacy of the vaccine can be greatly compromised.
Why Southeast Asia?
In rural Southeast Asia, there are lots of ducks and other birds living in and around the rice paddies. In addition local farmers live in close proximity to their livestock, including pigs. This creates the perfect storm for the emergence of new strains of influenza: people living in close proximity to influenza-infected birds and influenza-infected pigs. Bird flu and swineflu, ring a bell? Through reassortment all these different viruses can exchange genetic material and create brand new viruses.
A recent story by Rob Stein from NPR describes the relationship between gut flora, brain activity, and psychiatric symptoms. The implication is that someday we may be able to treat brain disorders such as autism, bipolarism, anxiety, and depression with probiotics. This is one of the most fascinating stories I’ve read for quite a while.
When we think of serotonin we think of the neurotransmitter in the brain that regulates mood, anxiety, etc… Selective Serotonin Re-uptake Inhibitors, SSRI’s, are used to treat anxiety and depression. But it turns out that >90% of our body’s serotonin is found in the gut. The enteric nervous system (ENS) of the gut is referred to as the second brain. The relationship between the gut and brain is complicated. Gut flora and serotonin both play a role in inflammatory bowel diseases. Current research now suggests that there is also a relationship between our gut flora and our brain function, moods, anxiety, and possibly certain psychological disorders such autism and bipolarism.
There’s no doubt that our ENS is really important for a lot of things, including regulating inflammatory conditions within the gut, possibly controlling our moods, and even regulating bone metabolism. For example, serotonin may play a key role in the development (or not) of osteoporosis. While we don’t yet know which cocktail or cocktails of bugs will to do the real magic, perhaps one day we’ll have probiotics with different cocktails of microbes to treat a variety of different diseases.
Gut Bacteria Might Guide The Workings Of Our Minds, By Rob Stein, NPR, Nov. 18, 2013.
Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA. 2013. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144(7):1394-401.
Gershon MD. 2013. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 20(1): 14-21.
Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH. 2012. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 109(31):12776-81.
Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM. 2011. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141(2):599-609.
Think Twice: How The Gut’s “Second Brain” Influences Mood and Well-Being, By Adam Hadhazy, Scientific American, Feb. 12, 2010.
A former colleague of mine has started a biotech company, Memcine, to provide personalized cancer treatments based on a novel antibody-based technology called Immunoplex (TM).
Memcine is currently seeking funding to establish its pipeline. The following excerpts are from their crowdsource campaign page at Indiegogo.com.
Memcine is a small biotech company with a patent-pending technology that will enable patient-specific tumor therapy. Our technology, known as Immunoplex, can be used to create individualized vaccines that are able to ramp up the immune response against a patient’s tumor. Imagine, a technology that, within hours, can be used to create a vaccine for anyone’s tumor! Our technology truly is personalized medicine.
Immunoplex technology is based on decades of research showing the benefits of antibody coated tumor cells in inducing an anti-tumor response. Our technology was developed to streamline the process and universalize production of the antibody coated tumor cells from any patient. This therapy has the promise of being effective, with the added bonus of having little to no side-effects. Just think! A cancer treatment that doesn’t have debilitating side-effects and helps reduce tumor size and metastasis! Your dollars will go toward non-animal mechanistic studies and stability assays required for new drugs and therapies submitted to the FDA.
Interested? Visit the site and consider making a contribution.
To learn more about Memcine and its technology visit their website: http://memcine.com/
“Hematogone” is a term used to describe B cell precursors in normal bone marrow. Amazingly, in my nearly 30 years as an immunologist who got his start studying human B cells, I had never come across this term until I recently started researching the origins of leukemias and lymphomas. B cell precursors in normal bone marrow form a constellation of cells that can be identified by flow cytometry using Side Scatter (SSC) vs. CD45 staining. Three major subsets of B cell precursors are easily recognizable. The early B cell precursors have low SSC and low CD45 expression, intermediate stage precursors have intermediate SSC and CD45 expression, and late precursors have the highest levels of SSC and CD45 expression. The pattern formed by these three populations in a 2D flow cytometric plot of SSC vs CD45 is often referred to as “Kentucky Sign” because the pattern resembles the shape of the state of Kentucky.
Differential diagnosis of B cell Acute Lymphoblastic Leukemia (B-ALL) is complicated by these so-called hematogones present in normal bone marrow. Hematogones make up 5-10% of the bone marrow cells in children, and less than 5% in adults, but these numbers can vary. In normal bone marrow hematogones are usually interspersed with more mature B cells, while lymphoblasts in the marrow of B-ALL patients often form large clusters.
Atlas of Hematopathology. F. Naeim, P.N. Rao, S.X. Song, and W.W. Grody, Eds. Academic Press, 2013.
McKenna RW, Washington LT, Aquino DB, Picker LJ, and Kroft SH. 2001. Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood 98:2498-2507.
Rimsza LM, Larson RS, Winter SS, Foucar K, Chong YY, Garner KW, and Leith CP. 2000. Benign Hematogone-Rich Lymphoid Proliferations Can Be Distinguished From B-Lineage Acute Lymphoblastic Leukemia by Integration of Morphology, Immunophenotype, Adhesion Molecule Expression, and Architectural Features. Am J Clin Pathol 114:66-75.
As I researched my article on leukemias and lymphomas I discovered that the majority of all leukemias and lymphomas were of the B lymphocyte lineage. Even as an immunologist I was not aware of this. In this article I investigate why this might be the case. This article is a little bit more technical than the previous one because of the genetic mechanisms involved in B cell differentiation and cancer development. At least, I think most of my non-science readers will be able to follow it and get the big picture. At best, it might spark further interest in immunology and the development of the immune system in some of you. If you are so inspired and want to know more, please use the comment box to ask me a question and I’ll answer it in a future article or post.
The majority of leukemias and lymphomas are derived from B cells. B-ALL, B-CLL, Hodgkin’s Lymphoma (HL), the majority of non-Hodgkin’s Lymphomas (NHL) including DLBCL, FL, Burkitt’s Lymphoma, and many others, and plasma cell malignancies such as multiple myeloma, are all thought to be derived from B cells.
To download and read the complete article, click the title link below.
Link to Article: Most Leukemias and Lymphomas Are B cells
This article was inspired by a paper I read as graduate student. I was fascinated by the observation that leukemia and lymphoma cells could be matched to a specific type of normal cell, and that they retained some of the functions of the normal cells. As an immunologist we use leukemia and lymphoma cells from patients to study the functions of normal cells and to develop specific treatments for these types of tumors. I’m happy to share these ideas with you and I hope that my article provides you with some useful and valuable information. Please let me know if you find the information useful or if you have any comments or suggestions for future topics you would like to learn about.
Cancers of the cells of the blood and immune system are called leukemias or lymphomas depending on where and in what kind of cell they originate. Leukemias originate in stem cells in the bone marrow, while lymphomas originate in mature cells in peripheral tissues such as lymph nodes. Leukemias and lymphomas arise from normal cells at a certain stage of maturation or differentiation. The leukemia and lymphoma cells retain many of the characteristics of the normal cells from which they are derived. The cells’ lineage, the kind of normal cell it started as, can tell us what kind of prognosis to expect. In some cases the cells’ physical and molecular characteristics can form the basis of specialized treatments aimed at one or more of these characteristics.
Leukemias and Lymphomas Begin As Normal Cells
Leukemia and Lymphoma cells come from normal cells at a certain stage of differentiation. The type of cell the cancer comes from determines your diagnosis. Knowing what cell type leukemia or lymphoma cells look like allows us to place them on the map of normal blood cell development. Most leukemias come from immature cells in the bone marrow or thymus, while lymphomas usually come from mature T cells or B cells that have been reactivated in lymph node germinal centers.
Abbreviations: ALL, Acute Lymphocytic Leukemia; T-ALL, ALL with characteristics of T lymphocytes; B-ALL, ALL with characteristics of B lymphocytes; CLL, Chronic Lymphocytic Leukemia; CML, Chronic Myelogenous Leukemia; AML, Acute Myelogenous Leukemia; HL, Hodgkin’s’ Lymphoma; NHL, Non-Hodgkin’s Lymphoma; MM, Multiple Myeloma.
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