Abstract
IgA is the most abundant immunoglobulin produced in the lamina propria (LP) of the intestine and protects the
host against microbial invasions into intestinal mucosa by coating and excluding them. Selective IgA deficiency
is the most common immunodeficiency, and more than 50% of patients are asymptomatic. However, other
patients develop various diseases such as inflammatory bowel diseases, allergies, autoimmune diseases, and
recurrent infections. Despite the essential roles of IgA, it still remains unknown what causes the different clinical
manifestations of this disease. One of the barriers to understanding the pathology of selective IgA deficiency is
a gap of knowledge about the heterogeneity of developmental origin of the IgA-secreting cells. Our long-term
goal is to fill this knowledge gap and to determine the roles of IgA+ cells of different origins in the mucosal
immunity.
There are two known pathways in producing IgA secreting cells: T-cell independent (TI) and T-cell dependent
(TD) pathways. TI-IgA is a low-affinity polyclonal antibody that coats bacteria and maintains the microbiome
homeostasis, while TD-IgA undergoes somatic hypermutation and reacts against specific antigens. The
precursors of these TI- and TD-IgA have been controversial, but it has recently been demonstrated that TI IgA+
cells are derived from peritoneal B-1b cells while TD IgA+ cells are from germinal center B-2 cells. It is generally
considered that these B-1b and B-2 cells are ultimately produced by hematopoietic stem cells (HSCs) that reside
in the bone marrow (BM). However, our and others' prior work has shown that B-1b cells are also produced by
HSC-independent fetal progenitors during embryonic development. Our lineage tracing data indicated that IgA+
cells in the lamina propria (LP) are derived from embryonic day (E) 7.5 endothelial cells (ECs), three days before
the first HSC production in the embryo. Our lineage tracing system using EC-derived (Cdh5CreERT2) and HSC-
derived (Fgd5CreERT2) enables us to segregate IgA+ cells in the LP of different origins. Thus, the central
hypothesis of this project is that IgA+ cells in the LP consists of cells with different origins: fetal (EC)- and HSC-
derived and that IgA+ cells of different origins have different roles against gut injury and infections. To test our
hypothesis, in Aim1, we will examine TI- and TD- class switching of fetal- and HSC-derived B cells. We will also
visualize these fetal- and HSC-derived TI- and TD- IgA+ cells using scRNA-sequencing and BCR repertoire-
sequencing and will display the molecular differences of these cells. In Aim 2, we will examine the protective
roles of fetal- and HSC-derived IgA+ cells against GI infection with C. rodentium.
The results obtained from this proposal will establish a new paradigm of the developmental origin of IgA+ cells
and their functions in the gut homeostasis and infections.