Throughout evolutionary time, specific immunoglobulin (Ig) isotypes have become specialized in the maintenance of MB homeostasis. In mammals, secretory IgA (sIgA), plays the predominant role in MB regulation. We have demonstrated that sIgT acts as the functional analog of sIgA in fish. Thus, the primordially conserved functions of sIgA and sIgT strongly support the use of fish as an alternative vertebrate model for the study of mucosal immunity. While the current dogma indicates that sIgA is the predominant isotype regulating MB homeostasis, it has recently been shown that sIgM recognizes and coats a large percentage of the luminal MB in humans and may assist sIgA in anchoring a highly diverse MB to mucus in the human gut. Intriguingly, sIgM does not coat gut MB in mice, thus precluding further investigation of the specific contributions of sIgA and sIgM in the maintenance of MB homeostasis in this experimental system. Critically, we have shown that as in humans, fish sIgM targets a significant portion of the gut MB. Thus, fish provide a unique tractable vertebrate model to address the role of IgM in the regulation of gut MB. Using this system, we provide the first demonstration that distinct immunoglobulins (IgT and IgM) primarily recognize different gut bacterial taxa in a non-mammalian species. This finding leads us to hypothesize unique and complementary roles for sIgT and sIgM in the recognition, regulation and control of gut MB. Several recent studies in mammals suggest that MB-specific IgA and IgG in the serum play an important role in the resolution of MB-induced sepsis. However, the involvement of serum IgM in these systemic responses, and the nature of the microbial taxa inducing such responses, are still ill-defined. Here, we show that fish serum contains very high levels of MB-specific-IgM, whereas those of IgT are negligible. These data lead us to hypothesize that serum IgM plays a critical role in the recognition and control of systemically translocated dysbiotic MB. Moreover, following colitis-induced dysbiosis, we primarily find phagocytic IgT+ B cells with internalized dysbiotic MB in the gut, while phagocytic IgM+ B cells predominate in the spleen. These results lead us to hypothesize that IgT+ and IgM+ B cells play distinct but complementary roles in the control of dysbiotic MB. To test the above mentioned hypotheses, we will use our newly developed fish models that lack IgT, IgM or both, in combination with our novel DSS-induced colitis fish model. We predict that our studies with fish will provide a unique phylogenetic dimension to the field. Thus, the aims of this proposal are:
AIM 1. Specific contributions of sIgT and sIgM in the maintenance of MB homeostasis;
AIM 2. MB taxa recognition and protective roles of sIgT and sIgM in MB-induced sepsis;
AIM 3. Contributions of IgT+ and IgM+ B cells in the recognition and control of dysbiotic MB.

Public Health Relevance

Primordially conserved principles governing mucosal immune responses to microbiota In mammals and fish, sIgA and sIgT play the predominant roles in the regulation of gut microbiota respectively. New studies in humans have highlight that in contrast to mice, sIgM plays a significant role in the recognition of the gut commensals. Here we propose to use our fish model to dissect the roles of the IgT and IgM systems in the modulation and control of homeostatic and dysbiotic microbiota.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085207-11
Application #
10070621
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Zhao, Xiaoli
Project Start
2010-09-01
Project End
2022-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
11
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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