More than just a gut feeling: The role of IgA in the regulation of intestinal homeostasis.
intestinal microbiome has recently emerged as a multifaceted contributor to many
biological processes. However, the potential mechanisms of immune regulation of
commensal organisms and pathogens in the intestine are still poorly understood.
Immunoglobulin A (IgA) has been implicated to play a critical role in maintaining
homeostasis between intestinal microbiota and immune healt... read moreh of the host, leading to the
hypothesis that the IgA repertoire might be affected by the composition of microbiome in
the intestine and vice versa. Accumulating evidence has indicated that the IgA
repertoires in both mice and humans are composed of clones of two classes of plasma
cells. One of these classes consists of several groups of related plasma cells where
each group is clearly derived and expanded from a single precursor. These groups are
designated as "expanded". On the other hand, the second class of plasma cells is only
found once within the sequenced IgA population and completely distinct from all the
other plasma cells analyzed. Plasma cells in this group are designated as "unique".
Although previous studies have explored the general specificity of intestinal IgA in
humans, no report has yet investigated the potential differences in the reactivity of
antibodies produced by the two components of the intestinal IgA repertoire. Using a
single cell approach, we generated recombinant antibodies from both the expanded and
unique groups and compared their reactivity against various self and non-self antigens,
including intestinal microbes. Our results indicate that the IgA repertoire of wild-type
C57BL/6 mice is similar to that of MyD88 knockout mice with impaired T-independent
responses. Furthermore, polyreactivity is a common feature observed in both components
of the IgA repertoire, suggesting that IgA might contribute to the maintenance of
commensal microbes in the digestive tract by cross-linking them to other antigens such
as intestinal tissues. In addition, no obvious difference between the reactivity of
antibodies from the two components of intestinal IgA was observed, which implies that
antibodies generated through T-dependent and T-independent responses are likely to share
some antigen specificities and work collaboratively to regulate intestinal health.
Finally, the number of somatic hypermutations within the immunoglobulin genes did not
appear to affect the specificity of our recombinant antibodies, which suggests that
somatic hypermutations might serve to promote polyreactivity, rather than specificity to
one particular antigen, in intestinal IgA.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Genetics.
Advisor: Erik Selsing.
Committee: Naomi Rosenberg, Henry Wortis, and Thereza Imanishi-Kari.
Keywords: Genetics, and Immunology.read less