Læknablaðið : fylgirit - 01.06.2002, Side 18

ÁGRIP GESTAFYRIRLESTRA / XV. ÞING FÉLAGS ÍSLENSKRA LYFLÆKNA
cannot be unlimited in somatic cells. As demonstrated by inap-
propriate shortening of telomeric sequences, T cells in patients with
RA have excessively proliferated. Based on telomeres in CD4 T
cells, the immune system in patients with RA has prematurely aged,
with T cells in 20 to 30 year old patients resembling T cells of 50 to
60 year old controls. Premature aging of T cells in patients with RA
is associated with marked changes in gene expression and function.
Due to their replicative history, T cells from patients with RA were
found to be limited in their clonal burst. Presenescent T cells lose
surface expression of CD28 and gain expression of polymorphic
receptors that recognize HLA class I molecules. Presenescent T
cells acquire cytolytic capability and produce large amounts of
interferon-y. The senescence-related shift in gene expression en-
dows these T cells with a functional capability that is proinflam-
matory in nature and may be critically involved in the chronic auto-
immune response occurring in the synovial tissue.
Cornelia M. Weyand
M.D., Departments of Medicine and Immunology, Mayo Clinic, Rochester,
MN
Inflammation and immunopathways in acute
coronary syndromes
Coronary atherosclerosis is a major contributor to global disease
burden and is the leading cause of mortality in developed countries.
Atherosclerotic disease of the coronary arteries results in a
spectrum of clinical syndromes, ranging from asymptomatic plaque
formation and stable angina to acute coronary syndromes (ACS),
including unstable angina, acute myocardial infarction, and sudden
cardiac death. It is now clear that disruption of the atherosclerotic
plaque followed by acute thrombotic occlusion of the vessel is the
main pathomechanism causing ACS. Disruption or superficial
erosions of the plaque has been closely linked to the accumulation
of inflammatory cells in the vessel wall, and the unstable coronary
plaque is beginning to be understood as an inílammatory lesion.
Predictors of plaque instability include infiltration by activated T
cells and macrophages. We have focused our studies on T cells in
the plaque and have investigated potential tissue-injurious effector
functions mediated by such T cells.
T cells infiltrating culprit lesions that have caused fatal myo-
cardial infarction are clonally expanded and derive from a unique
T-cell subset of CD4CD28™" T cells. These CD4'CD28n“" T cells can
be detected in the blood, are infrequent in healthy individuals, and
are often tenfold expanded in patients with ACS. Compared with
classic CD4 CD28' T cells, CD4'CD28nul' T cells have undergone a
series of changes in gene expression and function. We have identi-
fied two effector pathways mediated by these dysfunctional CD4 T
cells that may directly contribute to tissue damage in the plaque and
may also entertain the syndrome of systemic inflammation recently
described in patients at risk for ACS. CD4*CD28n“" T cells produce
high levels of interferon-y. As a consequence of excessive inter-
feron-y release, interferon-y-dependent transcription factors are
upregulated in the nucleus of monocytes/macrophages freshly iso-
lated from patients with unstable angina and interferon-y-depen-
dent genes are constitutively activated. Induction of the interferon-y-
dependent genes, CD64 and IP-10, is typical for patients with ACS
but not patients with stable angina. CD4*CD28”“" T cells also
acquire the ability to produce the cytolytic protein, perforin. Upon
activation, these T cells use their cytolytic machinery and kill target
cells. Endothelial cells are susceptible to this cytotoxicity and
become prime targets for activated CD4*CD28n“" T cells in the
atherosclerotic lesion. The cytolytic potential of CD4*CD28"“" T
cells is amplified in the presence of physiological concentrations of
C-reactive protein, raising the intriguing possibility that increased
concentrations of this acute phase protein accelerate the tissue-
damaging potential of plaque-infiltrating T cells.
Besides their presence in ACS, CD4*CD28n“" T cells are fre-
quently found in patients with rheumatoid arthritis, and we propose
that these T cells represent the underlying cause for increased
cardiovascular risk in patients with this autoimmune syndrome. In
rheumatoid arthritis, CD4*CD28n“" T cells participate in tissue-
destructive, chronic inflammatory lesions. Their presence in the
immune system signals fundamental defects in controlling the
composition of the T-cell pool. We propose the model that abnor-
malities in regulating T-cell generation, turnover, and selection con-
tribute to the risk for acute complications of otherwise asympto-
matic atherosclerotic disease, with tissue-damaging T cells occu-
pying center stage in the disease process.
Peter J. Kahrilas
M.D., Marquardt Professor of Medicine, Northwestem University, Chicago,
USA
Update on the management of gastroesophageal
reflux disease
It is now well accepted that proton pump inhibitor (PPI) therapy is
very effective in resolving esophagitis and that, given appropriate
PPI dose adjustments, virtually every case can be healed from an
endoscopic vantage point. Direct comparative trials have shown that
the most potent PPI (esomeprazole) can achieve higher healing
rates for esophagitis than either omeprazole or lansoprazole. In fact,
from a clinical perspective, the problem of esophagitis was essen-
tially solved with the PPIs. However, the same cannot be said for
gastroesophageal reflux disease (GERD) symptom control, the
problem of esophageal adenocarcinoma or the issue of treatment
complications. These have now emerged as the dominant issues in
GERD management. As esophagitis has become less of a problem,
the issue of symptom control has become a more substantial one.
Thus, whether it be in cases of healed esophagitis or in cases of
endoscopy negative reflux disease (ENRD) the frontier has shifted
to symptom control. In considering the ENRD picture it has become
clear that this is a heterogeneous group no longer bound by the
common denominator of endoscopic findings, as is the case with
esophagitis. In fact, three distinct patient subgroups emerge: 1) indi-
viduals who in essence have esophagitis, but are either in remission
or simply fail to meet the endoscopic criteria being employed, 2)
patients with hypersensitivity to esophageal stimuli exhibiting both
acid and mechano-sensitivity to stimuli below the sensory threshold
of a normal population, and 3) patients with “functional heartbum”
whose symptoms are not clearly related to reflux despite being
18 Læknablaðið/Fylgirit 44 2002/88