Crohn's disease (CD) and Ulcerative Colitis (UC) are inflammatory bowel diseases
(IBD) of unknown etiology. In Italy, the incidence is 3.7-4.2/100.000/year,
the prevalence 50-54/100.000 (x10 in IBD families) and the mortality rate <7%,
with a mean cost/year/patient of 125.404$. No drugs are available to prevent
clinical relapse of CD. Evidences support that in genetically susceptible hosts
an inappropriate mucosal immune response towards luminal antigens, particularly
resident bacterial flora, is involved in the pathogenesis of CD. T-cell and
macrophage activation is a feature of CD, associated to a Th1 immune response
and enhanced IL-12, IFN-gamma and TNF-alpha expression, reproducing "in
vitro" most of the systemic and local alterations of CD. Activated intestinal
mononuclear cells (LPMC) expressing IL-2 receptors (CD25+) and binding IL-2
is a major component of gut inflammation in CD. Scintigraphy using 123I-labelled
IL-2 quantitates CD25+ve LPMC in the gut, showing a higher uptake in CD. In
inactive CD, the degree of gut 123I-IL2 intake and release of TNF-a and IL-1b
correlates with time to relapse, supporting that the persistence of a mucosal
immune activation is a subclinical marker of early relapse in CD. These data
lead to the development of biologic therapies specifically targeting TNF-a and
IL-12, showing a wide range of effectiveness. A persistent "biological
activity" in clinically inactive CD may therefore represent a subclinical
marker of early clinical relapse or responsive to biologic therapies. IL-18
promotes Th1 cell clone development and up-regulates the IL-12Rb2 subunit, being
upregulated in CD gut and inhibited by IL-18 antisense oligonucleotide. Differently
from CD, in UC a humoral immune response predominates, driven by IL-4, IL-5
and IL-10. Serum and mucosal IgG against organ- and non-organ-specific antigens,
as p-ANCA and anti-colon antibodies are shown in UC. Mucosal and serum IgG against
the isoform 5 of the cytoskeletal proteins tropomyosin (hTM5) in colonocytes
are shown in 2/3 of UC and in <5% of CD and C. Serum anti-Saccharomyces mannan
IgG (ASCA) are shown in 62% of ileal CD. The p-ANCA-/ASCA+ phenotype shows a
49% sensitivity, 97% specificity 96% PPV for the diagnosis of CD, while the
p-ANCA+/ASCA- phenotype a 57% sensitivity, 97% specificity, 92.5% PPV for UC.
Both phenotypes may therefore not be used for diagnostic purposes. The usefulness
of combined p-ANCA, ASCA, hTM5 IgG serology for the diagnosis, prediction of
clinical course and responsiveness to biologic therapies in CD is unknown.
To understand the molecular and cellular mechanisms involved in the immuneinflammatory
response in CD in order to elucidate the events leading to the amplification
and perpetuation of the acute inflammatory process of unknown etiology in CD
gut. Aim of the study is also to assess the association between genotypes and
host immune response, to identify genetic and immunologic subclinical markers
of responsiveness to immunomodulatory drugs and biologic therapies in CD.