Supervisors info:
Γαζούλη Μαρία, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή Αθηνών, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Crohn's disease and ulcerative colitis are chronic, inflammatory and recurrent diseases
that affect the intestinal tract, while they represent the category of idiopathic
inflammatory bowel disease (IBD). Traditionally, they are more common in the
Western world with a characteristic superiority of the North over the South in the
number of cases. However, in recent years, due to immigration, industrialization and
the adoption of a more "Western" way of life by countries that were considered "low
risk", there has been a steady increase in new cases in these areas as well. The exact
reasons that can lead to the development of such a condition are so far unknown,
including the suspicious genetic background and the disturbed immune responses to
common germs in combination with environmental factors (eg diet, smoking) and
epigenetic. The symptoms also vary according to the affected organ (for ulcerative
colitis only the large intestine, while for Crohn's disease the entire gastrointestinal
tract) and the intensity of the symptoms varies from mild to severe. In addition,
patients with IBD are characterized by periods of exacerbation and remission. For
their diagnosis, the endoscopic techniques (colonoscopy, gastroscopy) and
additionally biochemical, hematological and imaging techniques are mainly used.
Treatment is determined by the extent and severity of the disease, starting with
aminosalicylic acid and its derivatives, corticosteroids, immunosuppressive drugs and
biological agents targeting molecular pathways deregulated during the disease (eg
infliximab against TNFα, vedolizumab against α4β7 integrin). In case of non-response
to medication or dangerous symptoms, surgical methods are selected, such as
colectomy, to manage them.
In the present study, the possible difference in gene expression in groups of patients
was tested, in order to generate expression profiles to predict the response to treatment
and the upcoming mucosal healing. For this purpose, the genes IL23A, CXCL6 & 10,
CD40LG, PIGR, VCAM1, MMP9 and SAA1 were selected and tested in biopsies of
patients with ulcerative colitis before treatment for whom the future response to
vedolizumab was already known. These genes are involved in a variety of immune
functions and their expression has been found to be impaired in patients. In addition,
the expression of VCAM1, MMP9, and SAA1 before and after treatment was
monitored in a second group of IBD patients treated with infliximab. These genes are
already being used as genetic markers to predict mucosal healing in patients with
Crohn's disease, so in conjunction with the other group, conclusions can be drawn
about patients' genetic background and how this relates to the response to treatment.
The results showed a more intense inflammation in patients who did not respond to
treatment with increased expression of most of the above genes in them at both tissue
and serum levels. The IL23A, MMP9 and CXCL6 genes, which were found to be
overexpressed more than twice in patients who do not respond to vedolizumab and
may serve as predictors of mucosal healing in patients with ulcerative colitis,
provided a more distinctive picture. In addition, the results in the second group were
similar, leading to the conclusion that there are groups of genes and pathways that are
common to the response to both biological factors. In conclusion, overexpression of
genes associated with immune responses and inflammation is characteristic of patients
who do not respond to treatment, and further investigation of these in larger patient
groups may provide indicators for both prognosis and targeting as a method of
treating IBD.
Keywords:
Ulcerative colitis, Crohn's Disease, prognostic markers, IL23A, CXCL6, CXCL10, CD40LG, PIgR, VCAM1, MMP9, SAA1 mucosal healing
