We recently discovered that deficiency of the transmembrane activator and CAML interactor (TACI), a receptor expressed by lymphocytes, in mice, enhances production of high affinity antibodies even under conditions of limited immunodeficiency. Antibodies produced in TACI-deficient mice clear enteric pathogens that represent organisms responsible for much of the recurrent and chronic diarrhea in humans. Because human variants of TACI (C104R and A181E) that impair TACI function are relatively frequent, our observation raises the possibility that those variants might protect against common pathogens. The variants are best known because 0.002% of those who carry them have common variable immunodeficiency (CVID). However, 2% of normal individuals also carry these variants and this high frequency might well reflect protection they confer against enteric or other pathogens. This application proposes research aimed at discovering how the murine equivalents of the most frequent human TACI variants (C104R and A181E) help >99 % of those who carry them resist common debilitating and life threatening infections. The central hypothesis of the proposal is that partial deficiency in the function of TACI enhance resistance to at least one and possibly many intestinal pathogens. To test this hypothesis, we will determine whether mutant mice expressing TACI variants equivalent to C104R and A181E, like TACI-knockout mice, produce higher affinity/avidity antibodies and clear enteric infections faster than wild type mice.

Public Health Relevance

The research goal is to determine how variants of a protein (called transmembrane activator and CAML interactor, TACI) that regulates production of highly effective microbe-specific antibodies, enhances host-defense against enteric pathogens. The research will study murine models expressing the murine equivalents of human TACI variants present in 2% of normal subjects. Our studies will advance knowledge and will inspire the development of novel therapies to control (enhance or depress) enteric mucosal immunity in response to infection, immune-mediated disease or to enhance vaccination even in those with immune-deficiencies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI117561-02
Application #
9094686
Study Section
Immunity and Host Defense (IHD)
Program Officer
Hall, Robert H
Project Start
2015-07-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cascalho, M; Huynh, D; Lefferts, A R et al. (2018) Durable targeting of B-lymphocytes in living mice. Sci Rep 8:11143
Platt, Jeffrey L; Cascalho, Marilia (2018) B Cells in Transplantation of Rat, Mouse, and Man. Transplantation 102:357-358
Platt, Jeffrey L; Silva, InĂªs; Balin, Samuel J et al. (2017) C3d regulates immune checkpoint blockade and enhances antitumor immunity. JCI Insight 2:
Platt, Jeffrey L; Zhou, Xiaofeng; Lefferts, Adam R et al. (2016) Cell Fusion in the War on Cancer: A Perspective on the Inception of Malignancy. Int J Mol Sci 17:
Zeng, Melody Y; Cisalpino, Daniel; Varadarajan, Saranyaraajan et al. (2016) Gut Microbiota-Induced Immunoglobulin G Controls Systemic Infection by Symbiotic Bacteria and Pathogens. Immunity 44:647-658
Dijke, Esme I; Platt, Jeffrey L; Blair, Paul et al. (2016) B cells in transplantation. J Heart Lung Transplant 35:704-10