Scientists led by Stephanie Eisenbarth, MD, PhD, the Roy and Elaine Patterson Professor of Medicine and director of the Center for Human Immunobiology, have discovered how critical IgA antibodies are produced through unexpected cellular pathways, findings that may help inform the design of more effective vaccines to prevent infections, according to a recent study published in Immunity.
Immunoglobulin (Ig)A is an antibody that serves as the first line of defense for mucosal tissues that comprise the inner lining of organs in the respiratory system and digestive system. IgA antibodies play a role in humoral immunity, in which IgA and other antibodies produced by B-cells fight off and prevent the spread of infection.
However, inducing an IgA-specific immune response, particularly through vaccines, has remained unsuccessful, according to Eisenbarth.
“We’re pretty good at inducing IgG antibodies, the ones that circulate in your blood, but those are not very good at protecting you when something comes in through your nose or from something you’ve eaten because those antibodies don’t penetrate mucosal tissue,” said Eisenbarth, who is also chief of the Allergy and Immunology in the Department of Medicine.
Previous work from Eisenbarth’s laboratory suggests that IgA antibody induction, or the series of cellular events that lead to the production of IgA, may follow different steps than IgG antibody induction. This process, known as class switching, occurs when activated B-cells change their production of immunoglobulin antibodies from one type to another, for example, from IgM to IgG.
“The class of antibody dictates what it can do, so understanding how this is regulated is important,” Eisenbarth said.
To better characterize this process, the scientists induced antigen-specific IgA responses in mice and then, using single-cell RNA and B-cell receptor (BCR) sequencing techniques, studied IgA activity in cells derived from tissue in the mice’s gut mucosa.
Surprisingly, the investigators found that IgA antibodies are produced through sequential class switching, where B-cells first class switch to IgG antibodies that in turn class switch again to IgA antibodies. The scientists also observed this sequential class switching in human bone marrow plasma cells and nasal swab samples, further confirming their findings.
“The way we normally think about traditional class switching is that you class switch to a particular type of antibody and then that’s it. This was an unusual process where you class switch first to one type of antibody and then you class switch again to become IgA,” Eisenbarth said.
The findings could help inform the development of new mucosal vaccines that initiate a two-in-one immune response, in which B-cells produce both IgG and IgA antibody responses in the bloodstream and mucosal tissues, Eisenbarth said.
“With this new knowledge, if we can take an IgG B-cell and promote sequential class switching, we can also get IgA, and the reason we need that is because IgGs can’t neutralize viruses at mucosal surfaces. So, this has some broader implications for how we vaccinate using mucosal vaccines, which is not our classic way of vaccinating,” Eisenbarth said.
“I have been very fortunate to have an amazing collaborative group that put this paper together, very close collaborators at Yale, the La Jolla Institute, Harvard, institutions around the country and my own lab, which I co-run with Adam Williams,” Eisenbarth added. “This work really highlights beautifully the interwoven dependence of all of us as scientists across institutions and disciplines.”
Co-authors of the study include Adam Williams, PhD, associate professor of Medicine in the Division of Allergy and Immunology, and Vipul Shukla, PhD, assistant professor of Cell and Developmental Biology and of Medicine in the Division of Hematology and Oncology.
This work was supported by National Institutes of Health (NIH) grants R01 AI136942, R01 AI168016, R37 AR40072, R01 AI152443, R01 AI170715, R01 AI158811, R01 AI104739, R00 CA248835 and R01 AI187142; the Food Allergy Science Initiative (FASI), Inc.; and the Colton Center for Autoimmunity at Yale; the Richard K. Gershon Research Fellowship; U19 AI142742 Collaborative Center for Human Immunology; T32 AI007036, A.P. Giannini Foundation fellowship award, and Burroughs Wellcome Fund Career Award for Medical Scientists; NIH P30 CA016359 (Yale Flow Cytometry Core); and the National Institute of General Medical Sciences 1S10OD030363-01A1 (Yale Center for Genome Analysis).
