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Title: B1 cell IgE impedes mast cell-mediated enhancement of parasite expulsion through B2 IgE blockade

item MARTIN, R - Virginia Commonwealth University
item DAMLE, S - Virginia Commonwealth University
item ZELLNER, M - Virginia Commonwealth University
item JAMES, B - Virginia Commonwealth University
item VALENTINE, Y - Virginia Commonwealth University
item ELKOWICH, A - Virginia Commonwealth University
item LOWNIK, J - Virginia Commonwealth University
item DEMEULES, M - Virginia Commonwealth University
item KHANDJIAN, L - Virginia Commonwealth University
item Urban, Joseph
item CONRAD, D - Virginia Commonwealth University

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/17/2018
Publication Date: 2/13/2018
Citation: Martin, R.K., Damle, S.R., Zellner, M.P., James, B.N., Valentine, Y.A., Elkowich, A.J., Lownik, J.C., Demeules, M.M., Khandjian, L.M., Urban Jr, J.F., Conrad, D.H. 2018. B1 cell IgE impedes mast cell-mediated enhancement of parasite expulsion through B2 IgE blockade. Cell Reports. 22(7):1824-1834.

Interpretive Summary: Worm parasites can infect humans and animals and stimulate production of an antibody class called IgE that can be both specific for the parasite but also of no known specificity or poly-specific. This is important because the specific IgE is thought to play a role in elimination of the parasite from the host and the poly-specific IgE has been shown to block responses to allergens by allergenic disease inducing mast cells and basophils in humans and animals. It was observed that when mice were infected with worm parasites a population of lymphocytes called B1 cells produced mainly the poly-specific IgE while another cell population called B2 cells produced the bulk of parasite specific IgE. Mice given B2 cells and infected with worms would clear the parasite from the intestine and express an allergic response to parasite proteins in the skin that was IgE and mast cell dependent. When B1 cells were given to mice, the mice were unable to eliminate the parasite and the skin allergic response to parasite proteins was blocked. These studies suggested that worm parasite may have adapted to their host by inducing B1 cells, and the poly-specific IgE antibody that they produce, to prevent elimination of the worm from the host and maintain its life cycle. This, however, may also advantage the host because it could limit the allergic response that is associated with the infection and could explain the parasite infection induced inhibition to non-parasite allergens. Further studies in this model could provide scientists and clinicians the tools to reduce the level of allergic disease in humans and animals while promoting the elimination of the worms from the host.

Technical Abstract: Helminth infection is known for generating large amounts of poly-specific IgE. Here we report that B1 cells are responsible for poly-specific IgE production during infection with the nematode parasites Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. Using two mouse models, one lacking B2 cells and the other using cell specific RAG1-/- reconstitution, we showed that B1 cells make equivalent IgE amounts to wildtype during helminth infection. In vitro analysis of factors critical for B1 cell immunoglobulin class switch recombination to IgE demonstrated a requirement for anti-CD40 and IL-4 that further enhanced IgE production when IL-5 was added to culture or when the B1 cell source was helminth infected mice. There was also IL-25-induced upregulation of IgE in B1 cells isolated from helminth infected mice. In T cell reconstituted RAG1-/- mice further reconstituted with or without B1 cells and/or B2 cells and followed by infection with N. brasiliensis only B2 cell-reconstituted mice had significantly reduced fecal egg production that was IgE dependent because there was no similar effect in mice reconstituted with B2 cells from IgE-/- mice. Parasite clearance was impeded by reconstitution with B1 cells and was also IgE dependent. Helminth-induced B1 cell IgE was not specific for N. brasiliensis because it blocked mast cell degranulation to N. brasiliensis excretory secretory antigens in infected mice. The data supports a hypothesis that B1 cell IgE secretion has evolved as a protective response used by the helminth. We also hypothesize that human poly-specific IgE production could be harnessed as potential protection against specific IgE generated in allergic disease, and may further explain the reduced atopy seen in human populations where parasitic infection is endemic.