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@PHDTHESIS{Simons:985174,
author = {Simons, Britta},
othercontributors = {Pabst, Oliver and Wagner, Wolfgang},
title = {{T}he landscape and dynamics of plasma cells in the small
intestine during homeostasis},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2024-04504},
pages = {1 Online-Ressource : Illustrationen},
year = {2024},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2024},
abstract = {The gastrointestinal tract is the largest interface to the
external environment and thus is constantly exposed to
exogenous antigen. Consequently, a well-balanced immune
response is required to protect the host from pathogens and
ensure homeostasis. Plasma cells play a key role in this
balanced system. In fact, the gut comprises the largest
total number of plasma cells in the body. Their main
effector function is to generate and secrete antibodies that
bind to their antigens such as food or microbiota.
Antibodies, especially immunoglobulin A, contribute to host
protection and maintain homeostasis with the microbiota.
Currently, there is limited knowledge about the factors and
mechanisms that influence the generation, development and
the phenotype of plasma cells. The precise mechanism for
regulating and maintaining the B cell receptor (BCR)
repertoire of intestinal plasma cells is still unknown.
Therefore, we tracked dynamics of antibody responses in the
gut during aging in the face of different microbial
colonisation and connecting different immune compartments
such as the gut associated lymphoid tissue and the small
intestine.To investigate whether plasma cells are a
phenotypically heterogeneous population, we developed a
multi-dimensional integrated approach to analyse the
phenotype of plasma cells under various conditions. This
integrated approach enables the detection of subtle
differences that may be missed in classical non-integrated
analyses. Despite major differences in the intestinal
environment, we observed that plasma cells were remarkably
homogenous in their phenotype. However, a gradual expression
of the surface markers Ly6c and MHCII was detected. While
Ly6c expression may be associated with antibody secretion,
MHCII expression is associated with the maturation state of
B cells. Data obtained from single cell sequencing supported
this observation. MHCII expressing cells showed a
proliferating phenotype indicating them to be plasma blasts.
This observation was independent of age, microbiota
composition and location. In addition, single cell
sequencing also provided combined information on a plasma
cell’s phenotype and its BCR. Plasma cells expressing the
same BCR were evenly distributed across the unifold manifold
approximation and projection (UMAP) and did not exhibit any
specific clonal phenotype. This indicates that even clonally
related cells acquire the full range of phenotypic
states.The BCR repertoire of different aged mice was
analysed to gain a better understanding of the dynamics of
the plasma cell repertoire. We labelled active B cells in a
cell fate tracking system and followed these cells for
different time spans. In addition, we obtained gut biopsies
to describe the composition and structure of the gut plasma
cell repertoire. By comparing the clones in the biopsy and
the follow-up samples, we were able to track dynamic changes
in the BCR repertoire. Therefore, we speculate that young
mice may generate a less diverse repertoire and more
polyreactive clones, while the repertoire of adult mice may
mature towards cross-species reactive or specific antigens.
Moreover, young and adult mice were able to generate
long-lived winner clones. These clones persisted for at
least six months not only in the plasma cell pool, but also
in the memory B and germinal center B cell compartment. This
suggests the recruitment of memory B cells into germinal
centers and a continuous maturation of these clones.
However, the fraction of long-lived clones was low,
indicating that the small intestinal plasma cell pool is
maintained by long-lived clones but also by newly recruited
clones. Additionally, we have developed an approach to
analyse clonal maturation and selection by grouping clones
into clonal trees.In conclusion, the analysis of the BCR
repertoire in combination with cell tracking is a powerful
tool for understanding the dynamics of gut B cell responses.
Specific plasma cell clones can be generated and their
binding and coating characteristics can subsequently be
investigated, allow-ing for a deeper insight into the
maturation and selection processes of plasma cells. Our
results may be relevant in context of mucosal vaccination
and faecal microbiota transplants. As plasma cells displayed
a remarkably homogenous population, we speculate that routes
of antigen encounter and underlying inductive pathways do
not primarily impact plasma cell function. Nevertheless, the
clonal composition seems to slowly adapt to changes in the
gut environment during homeostasis. Such system might buffer
short-term daily changes in the antigen pool and contribute
to resilience of the microbiota. Yet eventually, continuous
gut B cell responses will diversify the repertoire of gut
plasma cells to provide balanced humoral responses to
intestinal antigens.},
cin = {526000-2 ; 922310 / 160000},
ddc = {570},
cid = {$I:(DE-82)526000-2_20140620$ / $I:(DE-82)160000_20140620$},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2024-04504},
url = {https://publications.rwth-aachen.de/record/985174},
}
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