Antibodies, Epigenetics, Rebecca Tallmadge, PhD and a Bit of Hay Maria Julia Bevilaqua Felippe, MV, MS, PhD ‘The overall focus of our work is to gain insight into the development and function of the immune system, then applying that knowledge to the benefit of immunodeficient horses and young foals during that period of time where they are especially susceptible to pathogens.’ – Dr Tallmadge ANTIBODIES, EPIGENETICS, AND A BIT OF HAY Dr Julia Felippe and Dr Rebecca Tallmadge of Cornell University’s College of Veterinary Medicine are attempting to understand the complex world of the equine immune system. We talk to them about their discoveries and plans. Imagine a gingerbread house, tall as a the womb, babies tend to be born in an is newer to the field than Dr Felippe, but mountain, warm and cosy, full of all the immunologically ‘naïve’ state – they have not nonetheless brings an exceptionally broad proteins and nutrients which you could yet had any exposure to the outside world, array of knowledge and experience derived possibly need to grow, reproduce, and start full of bacteria and other antigens. This from both equine immunology and genetics. a giant family. Sounds tempting, doesn’t means that the intrinsic protection provided As she comments, her current role allows it? This is you, from the point of view of the by exposure has not yet been developed and her to ‘provide insight from my training in millions of microbes swarming over your so newborn mammals have a much higher equine immunogenetics – combining data skin, your hair, in your gut and in your nose. risk of catching disease than those just a we obtain in the lab with genome sequences A delicious mountain of food protected only few months older. To offset this window to characterise the strength or limitations by the tireless defence offered by the bodies’ of vulnerability, the newborn receives the of an immune system, whether it be an own immune system. Small wonder then that antibodies produced by its mother – these immunodeficient horse or a young foal.’ those who lose this vital protection rapidly antibodies continue to circulate for a succumb to diseases which would barely while after birth and so effectively act as a Their studies focus on the role of the even irritate a healthy individual. borrowed immune system. Borrowed, but developing immune system in diseases such not as effective as it could be; newborns as those caused by pathogenic infections There are many ways in which we can be ranging from human babies through to horse or developmental difficulties. The two have The trick, then, is to develop a way to target body, this leads to a rapid drop in circulating be modified at a later stage, changing the left without a functioning immune system. foals are highly susceptible to pathogenic been, in Dr Tallmadge’s words, ‘gaining a bacterium which can hijack and kill the antibodies and thus significantly weakens expression of the genes involved without Perhaps the most famous is AIDS, in which attack. insight into the development and function very immune cells which are meant to be the ability of the affected horse to resist modifying their basic code. The study of infection with HIV leads to a progressive loss of the immune system, then applying that killing it. This sounds difficult, and indeed it disease. CVID is a disease found both in these secondary genetic factors is known as of immune capability and eventual death Something old, something new, something knowledge to the benefit of immunodeficient is – despite many different approaches the horses and humans, though the origins of epigenetics, and this is the field in which Dr from minor secondary infections. Otherwise borrowed horses and young foals during that period of only sure-fire way to induce a robust immune the symptoms often remain mysterious, as Felippe found herself. known as immunodeficiencies, these time where they are especially susceptible to response in foals is to infect them with the Dr Felippe explains: ‘though known in human situations are also brought about by cancer, A cavalcade of complexity is thus occurring pathogens.’ microbe itself. As part of the road to better patients for the last 6 decades, only about Because CVID involves epigenetic by chemotherapy, by infections with various in a newborn, mixing new-developing with understand how the pathogen deceives the 10% of patients have been described with a mechanisms, can epigenetic factors also help pathogens, even just by being born. decaying-borrowed immune systems, all These pathogens include particularly nasty immune system, the group demonstrated genetic mutation, and the cause of disease is to provide a cure? Bone marrow transplants reacting to the colonisation of bacteria which examples such as R. equi, a dust-borne the ability to make a miniature lung segment unknown for 90% of patients.’ The lack of a are rarely used in humans with CVID to Just by being born? occurs moments after being born. Sounds bacterium which, like the agent responsible – complete with the ability to clean itself of genetic source led her group to follow other provide a fresh source of the precursor impossible to untangle? Even more complex for Tuberculosis, is able to avoid destruction inhaled dust, and then used this to watch in possibilities, with the eventual discovery that, cells which can differentiate into B-cells – Though we don’t often think about it, an when your subject is up and running around by hiding within the lungs’ own immune detail the manner in which R. equi infected in her words ‘target gene expressions were essentially overwriting the patients’ immune immune system develops – it expands in within hours of being born – as is the case cells. By hijacking these cells, known as macrophages. Knowledge of these processes downregulated in affected equine patients, system with one from a healthy donor. Dr capabilities over time. Infections trigger with those who study the immunology of macrophages, R. equi is able to grow without allows the further development of targeted and aberrant epigenetic mechanisms were Felippe’s group is studying a novel approach, expansions in antibody-producing cells horses. fear of detection and thus can rapidly treatments, and indeed Dr Felippe has associated with gene silencing, with the attempting to take the patient’s own derived which can target those pathogens, a spread throughout the lungs, causing an collaborated with other groups assessing resulting halt in B cell production.’ bone marrow and reactivate the affected memory of sorts which remains long after Untangling this complexity is the lofty often severe pneumonia. The bacterium is effective non-infectious vaccines. B-cell precursors using epigenetic modifiers. the infection is gone, protecting against the goal of Dr Julia Felippe and Dr Rebecca exclusively dangerous to newborn horses Fine words, I hear you say, but what does These cells can then be retransplanted into next infection (this, of course, is the basis of Tallmadge, both of Cornell University. Dr and foals, as (despite their loaned set of Epidemics of epigenetic this actually mean? The traditional view of the affected horse, essentially allowing them immunisation). The flip side of this, however, Julia Felippe is one of the top researchers antibodies), they have yet to develop the genetics was that each trait held by a person to be the healthy donor for themselves. is that an immune system which has not yet in the field of equine immunology, innate immunity which would otherwise Another major focus of their work is known or animal (strong legs, black hair, brown had time to develop is also far weaker than it having spent the last 27 years either protect them from infection – this same as common variable immunodeficiency eyes) was the product of one or more genes, Epigenetics are also involved in mediating could otherwise be. as a practicing equine veterinarian, effect can be seen in immunocompromised (CVID for short). One mechanism involved passed down from parents to children and the overall effect of other diseases such studying equine clinical medicine, or human or adult horse patients, who can be is the sudden halt in the production of B set in stone from the moment of conception. as equine herpesvirus-1 (EHV-1), a highly Although a large portion of the bodies’ researching equine immunodeficiencies susceptible to the same disease. cells within the bone marrow. As B-cells are This view turns out to be incomplete. There contagious virus which not only leads to immune system is developed while in and immunodevelopment. Dr Tallmadge the major source of antibodies within the are a number of ways in which DNA can neurologic damage but remains latent – WWW.SCIENTIAPUBLICATIONS.COM WWW.SCIENTIAPUBLICATIONS.COM Meet the researchers Rebecca Tallmadge, PhD Maria Julia Bevilaqua Felippe, MV, MS, PhD Department of Clinical Sciences Department of Clinical Sciences College of Veterinary Medicine College of Veterinary Medicine Cornell University Cornell University USA USA CONTACT CONTACT E: [email protected] E: [email protected] T: (+1) 607 253 3493 T: (+1) 607 253 3100 Dr Tallmadge has been in the field of equine research for many Dr Felippe is a veterinary internist and immunologist, and faculty years, beginning with her first scientific employment as a technician at Cornell University College of Veterinary Medicine. She oversees taking part in the horse genome project. This quickly led to other the Equine Clinical Immunology Laboratory, and has served as the roles in equine science: a PhD project examining immunological editor of the Equine Clinical Immunology book. Inspired by her proteins, postdoctoral work studying infectious diseases and horse patients, she has dedicated the last 27 years of her career immunodeficiencies, and her current role investigating CVID.