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(Circulation. 1999;100:2124.)
© 1999 American Heart Association, Inc.
Editorial |
A Tale of Two Diseases
Atherosclerosis and Rheumatoid Arthritis
From the Department of Internal Medicine and Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center, Houston, and the Texas Heart Institute, St Luke’s Episcopal Hospital, Houston.
Correspondence to Edward T.H. Yeh, MD, Department of Internal Medicine, 6431 Fannin St, Suite 4200, UT-Houston HSC, Houston, TX 77030.
Key Words: Editorials • atherosclerosis • immune system • lymphocytes
Acute coronary
syndromes are responsible for most of the morbidity and mortality
caused by coronary atherosclerosis. Both
unstable angina and acute myocardial infarction are characterized by
coronary thrombosis, usually caused by rupture or fissuring of
a coronary plaque. Yet the occurrence of plaque rupture and
coronary thrombosis is not related to severity of
coronary plaques, and functional factors other than the mere
presence of atherosclerotic lesions play an important
role.1 2 Recent studies have focused on the inflammatory
component of atherosclerosis, trying to highlight the
differences between stable and unstable coronary plaques. An
increasing body of evidence supports the hypothesis that
atherosclerosis shares many similarities with
other inflammatory/autoimmune diseases. Indeed, there are surprising
similarities in the inflammatory/immunologic response observed in
atherosclerosis, in unstable angina, and in rheumatoid
arthritis, the prototype of autoimmune disease
(Table
). However, although our understanding of
the molecular and immunological mechanisms of rheumatoid arthritis has
greatly progressed, due to the relatively easy access to the
diseased tissue (synovium) and to the availability of animal models,
the study of the inflammatory and immunological components of
atherosclerosis is still in its initial stages.
Unfortunately, it is more difficult for cardiologists to follow the
evolution of inflammatory response in plaques or make correlations with
the clinical course. Furthermore, although mice models of
atherosclerosis have been developed in the last
few years, there are still no animal models able to reproduce
the events occurring in acute coronary syndromes. Thus, the
study of the molecular mechanisms of rheumatoid arthritis may give
valuable hints for research on the inflammatory/immunological
mechanisms of atherosclerosis and acute
coronary syndromes.
|
Activation of inflammatory cells (in particular macrophages and mast cells), releasing many collagen-breaking enzymes within atherosclerotic plaques is likely to play an important role in destabilization of plaques.3 Collagen degradation is also an essential element in the pathogenesis of rheumatoid arthritis. Local expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and of endothelin have been described in both diseases.4 5 Similarly, recent studies found that neoangiogenesis, known to be an important factor in the pathogenesis of rheumatoid arthritis,6 can also contribute to development of atherosclerosis.7 Activated T cells are also present in atherosclerotic plaques, as well as in rheumatoid synovium, and unstable plaques have an increased percentage of activated T cells expressing the IL2 receptor.8 It can be argued that these similarities are merely a consequence of chronic persistent inflammation. In this issue of Circulation, however, Liuzzo et al reported another important analogy, suggesting that the similarities between these 2 diseases may be more than a scientific curiosity.9
In this study, Liuzzo et al found increased levels of an unusual subset
of T cells, CD4+CD28-, in
65% of patients with unstable angina, but not in patients with
stable angina. This lymphocyte subpopulation was originally described
in patients with rheumatoid arthritis and has been associated with
presence of extra-articular disease and, in particular, vasculitis.
Increased levels of T cells (both CD4+ and
CD8+) producing IFN-
and lower levels of T
cells producing IL2 and IL4, suggesting an imbalance between Th1 and
Th2 response, were also found in patients with unstable angina compared
with patients with stable angina.9
The identification in the mouse of 2 populations of T helper
(CD4+) cells (namely Th1 and Th2 cells) producing
2 different pattern of cytokines has allowed a better
understanding of the mechanisms of immune response in
vivo.10 Th1 cells produce IFN- and activate
monocyte/macrophage cells, whereas Th2 cells release
cytokines (IL4, IL5, and IL10) which stimulate immunoglobulin
production and eosinophil and mast-cell proliferation. Although
in humans the distinction of Th1 and Th2 clones is more ambiguous, the
distinction between Th1-like cells (IFN-+) and
Th2-like cells (IL4+) can be useful for practical
purposes. Th1 and Th2 responses are often mutually
antagonistic, and the Th1/Th2 balance may be involved in
the pathogenesis of several autoimmune diseases, including rheumatoid
arthritis. The CD28 receptor is an important component of the T-cell
activation. T-cell activation usually requires 2 signals: the first
results from the interaction of the antigen-specific T-cell receptor
with the antigenic peptide bound to major histocompatibility complex
molecules on the antigen presenting cells; the second costimulatory
signal is provided by the interaction of costimulatory receptors on the
T cell with surface molecules expressed by the antigen presenting
cell. The interaction of the CD28 receptor on the lymphocyte with
receptors of the B7 family on the antigen presenting cell is one of
the most important of these costimulatory pathways. This signal induces
T-cell activation, clonal expansion, and inhibits T-cell
apoptosis. Activation of the T-cell receptor without
costimulation of the CD28 receptor does not induce activation but
anergy or cell death.11 Inhibition of the CD28 pathway by
blocking the B7 receptor is a possible treatment for autoimmune
diseases. However, presence of CD28- T-cell
clones is not associated with a reduced immune response.
CD4+CD28- cells are rare
in normal individuals (usually 1%), although they tend to increase
with advanced age. Higher levels of
CD4+CD28- cells are
present in a subset of patients with rheumatoid
arthritis,12 in particular in those patients with
extra-articular disease or with vasculitis, but not in those with
rheumatoid arthritis restricted only to joints.13
CD4+CD28- cells have
several peculiar features differentiating them from the classic T
helper cells: they do not depend on the B7/CD28 pathway for activation,
do not express the CD40 receptor, are incapable of activating B cells,
have significant cytolytic activity, and express high levels of IFN-
(which induces monocyte activation). Thus, presence of a significant
amount of CD4+CD28- cells
could shift immune response from B-cell activation and
production of immunoglobulins toward Th1-cell activation, with
production of IFN- (which inhibits collagen synthesis by
smooth muscle cells) and activate macrophage to
release several matrix-degrading proteases.2 The
importance of this pathway in the evolution of
atherosclerosis is supported by the marked inhibition
of atherosclerosis in Apo-E–deficient mice lacking the
IFN- receptor.14 Interestingly, selective recruitment
of Th1 cells into tissues depends on the expression of adhesion
molecules, in particular E- and P-selectin15 and,
possibly, ICAM-1 and VCAM-1,4 which are also highly
expressed in atherosclerotic plaques. Although no study has
specifically assessed the presence of
CD4+CD28- T cells in
atherosclerotic plaques, an immunohistochemical study found that only a
very low percentage (10%) of T cells in human plaques express the
CD28 antigen,16 suggesting that many of the
CD4+ cells would result in
CD28-.
In rheumatoid arthritis, levels of
CD4+CD28- are usually
stable for years and are not related to waxing and waning of symptoms.
Indeed, Liuzzo et al found persistently increased levels of
CD4+CD28- and
IFN-+ T cells even at 2 to 6 months after the
end of the unstable phase. It is possible to speculate that increased
levels of CD4+CD28- and
the long-term shift of immune activation toward a Th1-like response
could be present before the onset of unstable angina. This could
identify a subgroup of patients with an inflammatory/immunologic
response facilitating plaque instability because Th1-like
cytokines (IFN-) can induce macrophage activation
and cytolysis and inhibit collagen synthesis. However, it should be
underscored that about one third of the patients with unstable angina
had levels of CD28- similar to that of stable
patients, and only 9% of all CD4+ lymphocytes
were CD28-, a percentage lower than that found
in patients with rheumatoid vasculitis. Furthermore, it is not clear
whether the long-term increase in
CD4+CD28- population is
related to the presence of lymphocyte activation during the acute phase
of unstable angina.
The presence of systemic immune activation in unstable angina has been assessed by previous clinical studies17 18 19 20 that have focused mainly on markers of T-cell activation, such as soluble IL2 receptor (sIL2R) and presence of activated T cells, expressing both the T-cell–specific surface molecule CD3 and the activation marker HLA-DR (CD3+DR+ cells). Although 2 studies found evidence of T-cell activation in patients with unstable angina,18 19 other studies reported negative results.17 20 These contradictory findings may be explained in part by the differences in the inclusion criteria. However, immunologic response is a time-dependent phenomenon not easily assessed by an analysis limited to a single time point. The 2 studies that assessed markers of T-cell activation in a time period compatible with the physiological immunologic response found significant signs of T-cell activation in unstable angina compared with stable angina.18 19
Liuzzo et al found a marked increase of both CD4+
and CD8+ lymphocytes producing IFN- in the
early phase of unstable angina, whereas the percentage of lymphocytes
releasing IL2 or IL4 was reduced. During waning of symptoms 2 weeks
after discharge, there was a significant shift in the T-cell response,
with increased levels of IL4+ lymphocytes. These
findings suggest that resolution of unstable angina may be associated
with a shift of immune response from a Th1-like cytolytic response to a
Th2 response associated with immunoglobulin production and
inhibition of macrophage activation. Indeed, in a previous
study an increase of activated T cells
(CD3+/DR+) and IgM in the 2
weeks after discharge was associated with lower levels of C-reactive
protein at admission and with an uncomplicated clinical
outcome.19 These findings suggest the presence of specific
antigenic stimuli in unstable angina. However, these intriguing
findings come from 2 very small groups of patients and may be explained
in part by several confounding factors. In particular, myocardial
revascularization, which presumably was performed
in most of these patients, was found to decrease levels of sIL2R
in patients with stable angina,21 and it might have
similar effects in patients with unstable angina. Lymphocyte activation
may be due in part to the release of myocardial antigens during
episodes of small myocardial necrosis, common in severe unstable
angina.22 Thus, the significance of the transient change
of immune markers observed in the subacute phase of unstable angina
is unclear; further studies, including a larger number of patients,
should address this issue.
The increasing knowledge of the inflammatory and immunological mechanisms of rheumatoid arthritis is leading to the development of new and effective strategies for the treatment of this disease, in particular anti-cytokine strategies, immunological interventions, and modulation of the Th1/Th2 response. The knowledge of the inflammatory and immunological mechanisms of coronary heart disease is still at its beginning and is raising more questions than answers. However, this innovative approach may lead to new discoveries that could improve our understanding of the basic mechanisms of this disease and, possibly, lead to innovative, fascinating strategies for prevention and treatment of atherosclerosis and its complications.
Acknowledgments
This work was supported in part by the DREAM project (to E.T.H.Y.). Dr. Yeh is an Established Investigator of the American Heart Association.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Buja LM, Willerson JT. Role of inflammation in
coronary plaque disruption. Circulation. 1994;89:503–505.
2.
Libby P. Molecular bases of the acute coronary
syndromes. Circulation. 1995;91:2844–2850.
3.
van der Wal AC, Becker AE, van der Loos CM, Das PK.
Site of intimal rupture or erosion of thrombosed coronary
atherosclerotic plaques is characterized by an inflammatory process
irrespective of the dominant plaque morphology. Circulation. 1994;89:36–44.
4. Oppenheimer-Marks N, Lipsky PE. Adhesion molecules in rheumatoid arthritis. Springer Semin Immunopathol. 1998;20:95–114.[Medline] [Order article via Infotrieve]
5.
Ross R. Atherosclerosis–an
inflammatory disease. N Engl J Med. 1999;340:115–126.
6. Firestein GS. Starving the synovium: angiogenesis and inflammation in rheumatoid arthritis. J Clin Invest. 1999;103:3–4.[Medline] [Order article via Infotrieve]
7.
Moulton KS, Heller E, Konerding MA, Flynn E, Palinski
W, Folkman J. Angiogenesis inhibitors endostatin or TNP-470
reduce intimal neovascularization and plaque growth in apolipoprotein
E-deficient mice. Circulation. 1999;99:1726–1732.
8.
van der Wal AC, Piek JJ, de Boer OJ, Koch KT,
Teeling P, van der Loos CM, Becker AE. Recent activation of the plaque
immune response in coronary lesions underlying acute
coronary syndromes. Heart. 1998;80:14–18.
9.
Liuzzo G, Kopecky SL, Frye RL, O’Fallon WM, Maseri A,
Goronzy JJ, Weyand CM. Perturbation of the T cell repertoire in
patients with unstable angina. Circulation. 1999;100:2135–2139.
10. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787–793.[Medline] [Order article via Infotrieve]
11. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233–258.[Medline] [Order article via Infotrieve]
12. Schmidt D, Goronzy JJ, Weyand CM. CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest. 1996;97:2027–2037.[Medline] [Order article via Infotrieve]
13. Weyand CM, Klimiuk PA, Goronzy JJ. Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes. Springer Semin Immunopathol. 1998;20:5–22.[Medline] [Order article via Infotrieve]
14. Gupta S, Pablo AM, Jiang X, Wang N, Tall AR, Schindler C. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997;99:2752–61.[Medline] [Order article via Infotrieve]
15. Austrup F, Vestweber D, Borges E, Lohning M, Brauer R, Herz U, Renz H, Hallmann R, Scheffold A, Radbruch A, Hamann A. P-, and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature. 1997;385:81–83.[Medline] [Order article via Infotrieve]
16. de Boer OJ, Hirsch F, van der Wal AC, van der Loos CM, Das PK, Becker AE. Costimulatory molecules in human atherosclerotic plaques: an indication of antigen specific T lymphocyte activation. Atherosclerosis. 1997;133:227–234.[Medline] [Order article via Infotrieve]
17. De Servi S, Mazzone A, Ricevuti G, Mazzucchelli I, Fossati G, Gritti D, Angoli L, Specchia G. Clinical and angiographic correlates of leukocyte activation in unstable angina. J Am Coll Cardiol. 1995;26:1146–1150.[Abstract]
18.
Neri Serneri GG, Prisco D, Martini F, Gori AM, Brunelli
T, Poggesi L, Rostagno C, Gensini GF, Abbate R. Acute T-cell activation
is detectable in unstable angina. Circulation. 1997;95:1806–1812.
19.
Caligiuri G, Liuzzo G, Biasucci LM, Maseri A. Immune
system activation follows inflammation in unstable angina: pathogenetic
implications. J Am Coll Cardiol. 1998;32:1295–1304.
20. Takeshita S, Isshiki T, Ochiai M, Ishikawa T, Nishiyama Y, Fusano T, Toyoizumi H, Kondo K, Ono Y, Sato T. Systemic inflammatory responses in acute coronary syndrome: increased activity observed in polymorphonuclear leukocytes but not T lymphocytes. Atherosclerosis. 1997;135:187–192.[Medline] [Order article via Infotrieve]
21.
Blum A, Sclarovsky S, Shohat B. T lymphocyte activation
in stable angina pectoris and after percutaneous
transluminal coronary angioplasty. Circulation. 1995;91:20–22.
22.
Willerson JT, Parkey RW, Bonte FJ, Meyer SL,
Atkins JM, Stokley EM. Technetium stannous pyrophosphate myocardial
scintigrams in patients with chest pain of varying etiology.
Circulation. 1975;51:1046–1052.
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V. Pasceri, J. T. Willerson, and E. T. H. Yeh Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells Circulation, October 31, 2000; 102(18): 2165 - 2168. [Abstract] [Full Text] [PDF]
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K. Raza, J. Thambyrajah, J. N. Townend, A. R. Exley, C. Hortas, A. Filer, D. M. Carruthers, and P. A. Bacon Suppression of Inflammation in Primary Systemic Vasculitis Restores Vascular Endothelial Function: Lessons for Atherosclerotic Disease? Circulation, September 26, 2000; 102(13): 1470 - 1472. [Abstract] [Full Text] [PDF]
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G. Caligiuri, G. Paulsson, A. Nicoletti, A. Maseri, and G. K. Hansson Evidence for Antigen-Driven T-Cell Response in Unstable Angina Circulation, September 5, 2000; 102(10): 1114 - 1119. [Abstract] [Full Text] [PDF]
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S. MANZI, M. C. M WASKO, and S. MANZI Inflammation-mediated rheumatic diseases and atherosclerosis Ann Rheum Dis, May 1, 2000; 59(5): 321 - 325. [Full Text]
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