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Editorial
The B Cell
A Good Guy in Vascular Disease?
Göran K. Hansson
I
nflammatory cells and molecules have largely been
considered bad guys in the pathogenesis of atherosclerosis and other vascular diseases. This is particularly true
for macrophages, T cells, and mast cells. In contrast, the role
of B cells has remained unclear.1 Recent studies suggest that
this cell type may inhibit the development of vascular
pathology in models of atherosclerosis and restenosis.2,3 The
Table summarizes some experiments addressing the effect on
atherosclerosis of cells involved in adaptive immunity.
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been identified as a key promotor of transplant vascular
sclerosis (transplant arteriosclerosis, chronic vascular
rejection).9
All these data point to a proatherogenic role for cellmediated, inflammatory immunity that involves macrophages
and T cells at its core. Paradoxically, activation of the
immune system with the athero-antigen, oxidized LDL,
reduces rather than aggravates the disease process. Such an
effect was first demonstrated by Palinski et al10 using oxidized LDL (Ox-LDL) immunization of Watanabe LDL receptor– deficient rabbits. Protective effects of immunization
with modified LDL has been demonstrated in several models
including apoE and LDL receptor knockout (KO) mice and
suggest that the immune system can mount protective as well
as detrimental activities during the course of atherosclerosis.
Protective immunity seems to correlate with development of
IgG antibodies to Ox-LDL, although this remains controversial.11 A role for antibodies in atheroprotective immunity was
also suggested by a study showing that infusions of immunoglobulins (ivIg preparations) could reduce atherosclerosis
in apoE KO mice.12
A report in the March 15 issue of the Journal of Clinical
Investigation has provided more direct evidence for an
atheroprotective role of B cells. In it, Caligiuri et al2 demonstrate that transfer of B cells from atherosclerotic apoE KO
mice to young, disease-prone apoE KO mice could protect the
latter from developing advanced disease. Protection to a
lesser extent was observed when B cells from young apoEdeficient donors were transferred, implying a role for development of adaptive immunity in the protective response. The
reduction in atherosclerosis was paralleled by an increase in
the titers of IgG–anti-Ox-LDL, but it remains to be formally
demonstrated whether transfer of antibodies can actually
protect recipients from disease. Alternatively, protection may
depend on cell-cell interactions involving B cells.
In the current issue of Arteriosclerosis, Thrombosis, and
Vascular Biology, Dimayuga et al3 present further evidence
for a protective role of B cells in vascular disease. They have
used a periadventitial cuff to induce intimal hyperplasia in the
carotid artery of mice and assessed the role of adaptive
immunity by comparing immunodeficient Rag-1 KO mice
with immunocompetent C57BL/6⫻129/S controls. Interestingly, lesions were approximately 3- to 5-fold larger in the
Rag-1 KO mice, which lack T and B cells. This is in line with
previous studies that we have performed in T cell– deficient
nude rats, which also exhibit enhanced lesion formation after
mechanical injury.13 In the latter model, injection of the T cell
cytokine interferon-␥ reduced smooth muscle proliferation
and lesion formation. Therefore, T cells may inhibit restenotic lesions. By inference, one would assume that T cells could
See page 644
The case for the monocyte-derived macrophage is particularly strong. It can oxidize lipoproteins, express scavenger
receptors, and accumulate cholesteryl esters. It is also capable
of producing tissue factor, and it is a major source of matrix
metalloproteinases and proinflammatory cytokines. All of
these factors and phenomena are considered proatherogenic.
Direct support for the conclusion that macrophages promote
atherosclerosis was obtained in studies of mice deficient in
functional macrophage-colony stimulating factor.4 When
such mice were crossed with atherosclerosis-prone apolipoprotein E– deficient (apoE⫺/⫺) mice, the offspring developed little, if any, atherosclerosis. This implies that monocyte
differentiation into macrophages is a necessary step in the
development of atherosclerosis.
T cells as well as B cells can respond to athero-antigens
such as oxidized LDL and heat shock proteins. The predominant T cell subtype in atherosclerotic lesions, the CD4⫹ Th1
cell, responds to antigenic challenge by releasing proinflammatory cytokines including interferon-␥, tumor necrosis factor–␣ and lymphotoxin.1 ApoE⫺/⫺ mice that lack adaptive
immunity, ie, T and B cells, develop significantly less
atherosclerosis than immunocompetent apoE⫺/⫺ mice (Table 1).5,6 Reconstitution of such apoE⫺/⫺⫻SCID (severe
combined immunodeficiency) mice with CD4⫹ T cells increases atherosclerosis dramatically.6 This indicates that the
CD4⫹ T cell subset contains proatherogenic immunity.
Additional evidence suggests that such proatherogenic activity is exerted at least partly through secretion of the cytokine,
interferon-␥. ApoE⫺/⫺ mice that lack interferon-␥ or its
receptor develop significantly smaller lesions, implying a
proatherogenic role for this cytokine.7,8 Interferon-␥ has also
From the Center for Molecular Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Correspondence to Göran K. Hansson, Center for Molecular Medicine,
Karolinska Institute, Building 8:03, Karolinska Hospital, SE-17176
Stockholm, Sweden. E-mail [email protected]
(Arterioscler Thromb Vasc Biol. 2002;22:523-524.)
© 2002 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
DOI: 10.1161/01.ATV.0000015098.68671.1C
523
524
Arterioscler Thromb Vasc Biol.
April 2002
Effect of Immune Defects and Immune Cell Transfer on Lesion Development in Vascular
Disease Models
Model
Balloon injury in rats
Immunophenotype
Cell
Transfer
T cell–deficient (nude)
T cell–deficient (nude)
T cells
Effect on
Lesions
Reference
1
13
2
13
ApoE⫻Rag-1 mice, atherosclerosis
T⫹B cell–deficient
2
5
ApoE⫻SCID mice, atherosclerosis
T⫹B cell–deficient
2
6
ApoE⫻SCID mice, atherosclerosis
T⫹B cell–deficient
CD4⫹ T cells
1
6
ApoE mice, atherosclerosis
Immunocompetent
B cells
2
2
Rag-1 mice, cuff injury
T⫹B cell–deficient
1
3
Rag-1 mice, cuff injury
T⫹B cell–deficient
2
3
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destabilize atherosclerotic plaques by inhibiting the formation
of smooth muscle caps.
In their study, Dimayuga et al3 attempted to protect the
immunodeficient mice by infusing B cells from immunocompetent mice 48 hours before injury. This procedure had a
remarkable effect on the lesions, which did not develop
beyond the size of those in immunocompetent animals. In
other words, B cell transfer reduced lesions ⬇3- to 4-fold.
The protective effect could be demonstrated even under
conditions when lesion formation was accelerated by a
high-fat diet.
The mechanism by which B cells reduce neointimal formation remains unclear. The authors speculate that IgM
antibodies might mediate the protective effect. A previous
study from the same group showed a protective effect on
neointimal hyperplasia by immunization with Ox-LDL14 and
it could be speculated that antibodies to this antigen may
inhibit neointimal formation. However, the mechanism by
which such protection might operate is unknown. One can
envisage how antibodies to Ox-LDL could protect against
atherosclerosis by eliminating oxidized lipoprotein particles
from the circulation or preventing their uptake by macrophages. In contrast, it is difficult to see how anti–Ox-LDL
antibodies might prevent neointimal hyperplasia. Because the
antigens are not known in this condition, it is unclear how
antibodies could protect against neointimal post-injury hyperplasia. The alternative possibility should also be considered
that B cells themselves can inhibit lesion formation either by
cell-cell contact or by secreting a factor other than an
immunoglobulin. It will obviously be important to test
whether immunoglobulin preparations or specific antibodies
can affect neointimal proliferation. Similarly, they should be
tested in models of atherosclerosis to follow up the report of
B cell protection in this disease.
Although several questions remain, the two articles by
Caligiuri et al2 and Dimayuga et al3 put B cells in the
limelight of vascular research for the first time. And after the
identification of one bad guy after another, it is about time for
a good guy to appear on the scene.
B cells
References
1. Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler
Thromb Vasc Biol. 2001;21:1876 –90.
2. Caligiuri G, Nicoletti A, Poirier B, Hansson GK. Protective immunity
carried by B cells of hypercholesterolemic mice. J Clin Invest. 2002;
109:745–753.
3. Dimayuga P, Cercek B, Oguchi S, Nordin Fredriksson G, Yano J, Shah
PK, Jovinge S, Nilsson J. Inhibitory effect on arterial injury-induced
neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice.
Arterioscler Thromb Vasc Biol. 2002;22:644 – 649.
4. Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata M.
Decreased atherosclerosis in mice deficient in both macrophage colonystimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A.
1995;92:8264 – 8268.
5. Dansky HM, Charlton SA, Harper MM, Smith JD. T and B lymphocytes
play a minor role in atherosclerotic plaque formation in the apolipoprotein
E-deficient mouse. Proc Natl Acad Sci U S A. 1997;94:4642– 4646.
6. Zhou X, Nicoletti A, Elhage R, Hansson GK. Transfer of CD4(⫹) T cells
aggravates atherosclerosis in immunodeficient apolipoprotein E knockout
mice. Circulation. 2000;102:2919 –2922.
7. Gupta S, Pablo AM, Jiang X-C, Wang N, Tall AR, Schindler C. IFN-␥
potentiates atherosclerosis in apoE knock-out mice. J Clin Invest. 1997;
99:2752–2561.
8. Whitman SC, Ravisankar P, Elam H, Daugherty A. Exogenous
interferon-gamma enhances atherosclerosis in apolipoprotein E⫺/⫺
mice. Am J Pathol. 2000;157:1819 –1824.
9. Tellides G, Tereb DA, Kirkiles-Smith NC, Kim RW, Wilson JH,
Schechner JS, Lorber MI, Prober JS. Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature. 2000;403:207–211.
10. Palinski W, Miller E, Witztum JL. Immunization of low density
lipoprotein (LDL) receptor-deficient rabbits with homologous
malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad
Sci U S A. 1995;92:821– 825.
11. Zhou X, Caligiuri G, Hamsten A, Lefvert AK, Hansson GK. Protection
against atherosclerosis by LDL immunization is associated with T cell
dependent IgG antibodies in apoE-deficient mice. Arterioscler Thromb
Vasc Biol. 2001;21:108 –114.
12. Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK. Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin
Invest. 1998;102:910 –918.
13. Hansson GK, Holm J, Holm S, Fotev Z, Hedrich HJ, Fingerle J. T
lymphocytes inhibit the vascular response to injury. Proc Natl Acad Sci
U S A. 1991;88:10530 –10534.
14. Nilsson J, Calara F, Regnström J, Hultgårdh-Nilsson A, Ameli S, Cercek
B, Shah PK. Immunization with homologous oxidized low density
lipoprotein reduces neointimal formation after balloon injury in hypercholesterolemic rabbits. J Am Coll Cardiol. 1997;30:1886 –1891.
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The B Cell: A Good Guy in Vascular Disease?
Göran K. Hansson
Arterioscler Thromb Vasc Biol. 2002;22:523-524
doi: 10.1161/01.ATV.0000015098.68671.1C
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