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.
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.
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