ALLERGIC-LIKE EFFECTOR MEMORY T HELPER (TH) 2 AND AUTOIMMUNE-LIKE TH17.1 CELL POPULATIONS ARE INCREASED IN THE DUODENUM OF PATIENTS WITH FUNCTIONAL DYSPEPSIA

Background: Functional dyspepsia (FD) is characterized by chronic symptoms of postprandial distress or epigastric pain not associated with organic disease. Previous studies have
identified increased peripheral gut-homing T cells in FD patients. However, to date it is
unknown if these T cells are antigen experienced, or if a specific immunophenotype is
associated with FD. This study aimed to characterize T cell populations in the blood &
mucosa of FD patients that may be implicated in the pathophysiology of this condition.

Methods: We identified T cell populations in lamina propria lymphocytes and peripheral
blood from 13 controls (9F, 48.59±16.60y) and 39 Rome III FD patients (30F, 51.54±13.26y)
by staining of surface markers for flow cytometry. T cell populations were identified by the
expression patterns of specific surface cluster of differentiation (CD), chemokine (CCR) and
chemokine receptors (CXCR) markers. We also analysed eosinophils and tight junction
protein levels in histological sections from duodenal biopsies and investigated if subtyping
these patients based on reported symptoms identified specific immunophenotypes.

Results: Duodenal eosinophil numbers were significantly increased in biopsies from FD
patients compared to controls (n=10, 13.00±3.742/hpf vs n=36, 19.11±9.171/hpf, p=0.003)
and FD patients had lower duodenal levels of zonula occludins-1 by immunohistochemical
staining (n=12, H score=1.000±0.5957 vs n=16, H score=0.4779±0.2560, p=0.004). In
addition to increased populations of CD4+ gut-homing T cells, CD8+ gut-homing cells were
increased in FD (0.1198±0.1896 vs 0.4401±0.4683, p=0.001). FD patients have increased
proportions of Th17.1 (CD4+CD45RO+CCR6+CXCR3+, 0.6991±2.319 vs 2.248±3.292, p=
0.046) and effector memory Th2 lymphocytes (CD4+CD45RO+CCR7-CCR6-CCR4+,
13.12±10.54 vs 22.09±14.24, p=0.032) in the duodenal mucosa. We also identified proportions of Th1 (CD4+CD45RO+CCR6-CXCR3+, 1.578±2.534 vs 9.993±9.125, p<0.0001) and
Th17.1 cells (6.068±8.979, vs 10.46±8.415, p=0.022) increased in the circulation of FD
patients.

Conclusions: Our findings provide further support for the involvement of an adaptive
immune response in the etiopathogenesis of FD. This work demonstrates that FD patients
have a dual Th17.1/effector memory Th2 immune signature in the duodenum, suggesting
multiple triggers could initiate symptom onset. These results suggest that similar to asthma,
dual T cell response pathways are involved in FD symptom generation, likely in response
to infection, luminal antigens and/or autoimmune responses. In addition, the data show
that immune profile is independent of Rome III FD subtype.