Why do people develop antibodies to food? While clinicians have long observed that healthy humans develop a particular type of antibody, called IgG, to the foods they eat, the reasons for this phenomenon have remained unknown. Researchers, led by investigators from Allergy and Immunology at Mass General Brigham , have identified the mechanism underlying IgG antibody development to food proteins. They discovered that humans are intrinsically predisposed to develop a particular type of IgG antibody to peanut by human antibody genes. These antibodies develop, whether or not they develop peanut allergy. Results are published in Science Translational Medicine.
"Our research not only explains why we have always found these antibodies against peanut, but why so many people, including young children, have such similar antibodies to a food so common in the world," said senior author Sarita Patil, MD, co-director of the Food Allergy Center at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham. Patil is also an assistant professor of Medicine at Harvard Medical School. "We were astonished to find highly similar antibodies. Statistically this seems improbable, since our immune system can produce as many as a quintillion different kinds of antibodies. When we found these nearly identical, public antibodies in multiple patients, we were fascinated."
The research team, including lead author Orlee Marini-Rapoport, who conducted the work at MGH, found that humans are poised to develop antibodies to peanut in highly predictable ways through multiple pathways. In fact, these antibodies can bind to peanut before they undergo further evolution. Despite the different alleles, or variations in the human genome that exist in antibody genes, most humans have gene alleles that can contribute to making these antibodies. The research team then looked for these specific antibodies by designing a new assay using blood. In peanut-allergic patients, all of them had these antibodies. The team then set out to discover whether these common, easy-to-produce antibodies might also develop at the earliest time after infants begin to eat peanut. Indeed, most young children from ages 1-3 who make IgG antibodies to these peanut proteins make these specific antibodies.
While this work begins to explain why nonallergic individuals develop antibodies to food proteins, it also has important implications to the field of allergy. The fact that individuals develop highly similar antibodies suggests that it is also possible to therapeutically target food allergy across patients.
"As we know, antibodies can be protective, but they can also cause disease in the context of allergy," said Patil. "If on a larger level, we can dissect how humans develop antibodies, and why some go on to become allergic, we may be able to intervene with targeted therapies to treat and prevent food allergies on a population level."
Authorship: In addition to Patil and Marini-Rapoport, Mass General Brigham authors include Lena Andrieux, Tarun Keswani, Timothy Sun, Victoria M. Martin, Qian Yuan, and Wayne G. Shreffler. Additional authors include Guangning Zong, Dylan Duchen, Gur Yaari, Jungki Min, Isabelle R. Lytle, Alexander F. Rosenberg, Christopher Fucile, James J. Kobie, Michael S. Piepenbrink, Antti E. Seppo, Kirsi M. Jarvinen, Johannes R. Loeffler, Andrew B. Ward, Steven H. Kleinstein, Lars C. Pedersen, Monica L. Fernandez-Quintero, and Geoffrey A. Mueller.
Disclosures: Patil has consultancy agreements with Mabylon, Bulhmann, and Seismic Therapeutics and is a site PI for a clinical trial for Regeneron. Min, Pedersen, Mueller, and Patil filed U.S. Provisional Patent 63/486,570 containing the epitope 1.1 mutant rAra h 2 allergen. Jarvinen has consultancy agreements with Janssen R&D, Harmony/Milk Care co and is a site PI for a clinical trial for Aimmune and Siolta. Duchen has a consultancy agreement with Artizan Biosciences. Kleinstein has a consultancy agreement with Peraton. Martin is a paid consultant who serves on the Scientific Advisory Board for Milk Care Co.
Funding: Funding for this work was provided by the National Institutes of Health (R01AI155630, R01AI182001, U01 131344, R01AI104739), Intramural Research Program of the National Institute of Environmental Health Sciences (1ZIAES102906, 1ZICES102645), Food Allergy Science Initiative, Gerber Foundation, Demarest Lloyd Jr. Foundation Thornhill Family Fund, NIAID (K23AI151556), and a Yale-Boehringer Ingelheim Biomedical Data Science Fellowship.
Paper cited: Marini-Rapoport, O et al. "Germline-encoded recognition of peanut underlies development of convergent antibodies in humans" Science Translational Medicine DOI: 10.1126/scitranslmed.adw4148
