Académique Documents
Professionnel Documents
Culture Documents
review article
Mechanisms of Disease
T
o the clinician, systemic lupus erythematosus is important be- From the Centre for Rheumatology Re-
cause it is a potentially fatal disease that is easily confused with many other search, Division of Medicine, University
College London, London. Address reprint
disorders. To the immunologist, lupus is intriguing because all the key com- requests to Dr. Isenberg at the Centre for
ponents of the immune system are involved in the underlying mechanisms of the Rheumatology Research, Division of Med-
disease. This review describes these mechanisms and shows how knowledge of the icine, University College London, Rm. 331,
3rd Fl., 46 Cleveland St., London W1T 4JF,
pathogenesis of lupus facilitates its treatment. United Kingdom, or at d.isenberg@ucl.
The prevalence of lupus ranges from approximately 40 cases per 100,000 persons ac.uk.
among Northern Europeans to more than 200 per 100,000 persons among blacks.1
N Engl J Med 2008;358:929-39.
In the United States, the number of patients with lupus exceeds 250,000. The life ex- Copyright © 2008 Massachusetts Medical Society.
pectancy of such patients has improved from an approximate 4-year survival rate of
50% in the 1950s2 to a 15-year survival rate of 80% today.3 Even so, a patient in whom
lupus is diagnosed at 20 years of age still has a 1 in 6 chance of dying by 35 years of
age, most often from lupus or infection.4 Later, myocardial infarction and stroke be-
come important causes of death.4 This bimodal pattern of mortality in lupus was
recognized more than 30 years ago.5
The diverse presentations of lupus range from rash and arthritis through anemia
and thrombocytopenia to serositis, nephritis, seizures, and psychosis. Lupus should
be part of the differential diagnosis in virtually any patient presenting with one of
these clinical problems, especially in female patients between 15 and 50 years
of age.
Since 90% of patients with lupus are female, an important role for female hormones6
seems likely, but a protective role for male hormones or an effect of genes on the
X chromosome is also possible. In a blinded, randomized, controlled trial, menopausal
women with lupus who received hormone-replacement therapy containing conjugated
estrogens and progesterone had a risk of a mild-to-moderate disease flare that was
1.34 times the risk among women who received placebo (P = 0.01).7 However, trials
of hormonal treatments for lupus, such as dehydroepiandrosterone, have been dis-
appointing.8 It is unclear how sex hormones could promote lupus.
Many drugs cause a variant of lupus called drug-induced lupus. The best known
of these drugs are procainamide, hydralazine, and quinidine. Patients with drug-
induced lupus usually present with skin and joint manifestations; renal and neuro-
logic features are very rare.9 An antecedent viral-like illness may occur at the onset
of lupus or immediately before a flare. Identifying a particular causative virus has
proved challenging. Epstein–Barr virus (EBV) may be important, since a temporal as-
sociation between the onset of lupus and the occurrence of EBV infection has been
reported. A case–control study involving children and young adults showed that anti-
EBV antibodies were present in 99% and EBV DNA was present in 100% of patients
clinically quiescent disease, 80% have disease that tions, particularly in autoimmune hemolytic ane-
becomes clinically active within 5 years after the mia, thrombocytopenia, skin disease, and neona-
detection of elevated levels of these antibodies.24 tal lupus. Table 2 lists common autoantibodies in
In a study of renal-biopsy specimens obtained lupus and the evidence that they are pathogenic;
from patients with lupus at autopsy,25 Mannik some are described in more detail below.
et al. detected IgG that bound to a number of non- The presence of anti-Ro antibodies, anti-La an-
DNA antigens, including Ro (a ribonucleopro- tibodies, or both in pregnancy confers a 1 to 2%
tein complex), La (an RNA-binding protein), C1q risk of fetal heart block. Ro antigens are exposed
(a subunit of the C1 complement component), and on the surface of fetal (but not maternal) cardiac
Sm (nuclear particles consisting of several differ- myocytes as the heart undergoes remodeling by
ent polypeptides). The detection of antibodies to apoptosis, and maternal anti-Ro antibodies that
these antigens in autopsy specimens does not cross the placenta interact with these antigens.
prove that they play a role in the development of The maternal autoantibodies damage the conduct-
lupus nephritis. Rather than cause the inflamma- ing tissues of the fetal heart.41,43 The absence of
tion, these autoantibodies may establish them- an effect on the mother’s heart shows the impor-
selves in tissue only after the apoptosis of cells in tance of both the autoantibody and exposure of
inflamed kidney tissue exposes nuclear antigens. the antigen on cardiac tissue.
The strongest evidence concerning the mechanism Antibodies against the N-methyl-d-aspartate
of lupus nephritis relates to anti–double-stranded (NMDA) receptor may be important in central ner-
DNA, anti-nucleosome, and anti–α-actinin anti- vous system lupus.27 NMDA is an excitatory amino
bodies (see below). acid released by neurons. Kawal and colleagues
Although anti–double-stranded DNA antibod- showed that in patients with lupus, the serum with
ies are the most extensively studied autoantibodies antibodies against DNA and NMDA receptors
in lupus, others play a role in clinical manifesta- caused cognitive impairment and hippocampal
damage when given intravenously to mice. They both cross-react with proteins in the kidney; thus,
also showed that anti–NMDA-receptor antibodies they have a direct pathogenic effect on renal cells.
are present in the brain tissue of patients with ce-This is an example of polyreactivity, whereby the
rebral lupus.27 same antibody can bind to antigens with different
Both anti-Ro and anti-nucleosome antibodies structures because they have similar surface shapes
may play a role in cutaneous lupus. Anti-Ro an- (so-called shared epitopes) or areas of similar
tibodies are associated with an increased risk of charge. Among possible target antigens in the
the development of a photosensitive rash.42 Anti- kidney, attention is currently focused on α-actinin.
nucleosome antibodies have been detected in skin- This protein is critical for maintaining the func-
biopsy specimens obtained from a minority of tion of renal podocytes, which are constituents of
patients with active renal lupus, and these pa- the glomerular filtration barrier.57 Two studies
tients had no rash.36 have shown that mouse monoclonal anti-DNA an-
Autoantibody-mediated destruction of red cells tibodies that cross-reacted with α-actinin (a pro-
and platelets is important in the hemolytic anemia tein that cross-links actin, a component of the
and thrombocytopenia that can occur in patients cytoskeleton) were pathogenic, whereas monoclo-
with lupus.54 Pujol et al.55 detected antiplatelet nal anti-DNA antibodies that did not cross-react
antibodies in the serum of 56 of 90 patients with with α-actinin were nonpathogenic.52,53 Pathoge-
lupus. A total of 29 of 90 patients had thrombo- nicity was judged according to whether the anti-
cytopenia, and in these patients there was a strong bodies caused proteinuria and histologic changes
correlation between thrombocytopenia and the of glomerulonephritis after passive transfer into
presence of antiplatelet antibodies.55 recipient mice.52,58 Although anti–α-actinin anti-
bodies are not specific for lupus, these antibodies,
when present in the serum of patients with lupus,
T is sue Da m age
by Au t oa n t ibodie s in Lupus can serve as a marker of renal involvement.28,51
The detection of anti-α-actinin antibodies has not
Most studies of autoantibody-mediated tissue dam- been reported in specimens obtained from renal
age in patients with lupus have focused on the role biopsies in patients with lupus.
of anti–double-stranded DNA antibodies in pa-
tients with lupus nephritis. There are two main The Rol e of T Cel l s
theories; both stress that the binding of antibod-
ies to double-stranded DNA itself is probably not Autoantibodies can occur in healthy people with-
the most critical determinant of tissue damage. out causing harm, and they may play a protective
Extracellular double-stranded DNA occurs mainly role.59 Pathogenic autoantibodies in patients with
in the form of nucleosomes, which are fragments lupus have particular properties that enable them
of chromatin that cells release when they under- to cause disease. Clinical investigations and stud-
go apoptosis. Berden and colleagues have proposed ies in laboratory mice have shown that IgG anti-
that pathogenic anti–double-stranded DNA auto- bodies with high-affinity binding to double-strand-
antibodies in patients with lupus bind to nucleo- ed DNA tend to be more strongly associated with
somes that have entered the bloodstream; in turn, tissue damage than IgM or lower-affinity IgG
these antibody–nucleosome complexes settle in the antibodies.33,34,60 Production of these high-affin-
renal glomerular basement membrane.56 These im- ity IgG antibodies is “driven” by antigen. The term
mune complexes activate complement, which initi- “antigen-driven” refers to a process in which an-
ates the glomerulonephritis. This series of events tigen binds immunoglobulin on the surface of
has been demonstrated in animal models.39,40 Fur- B lymphocytes, thereby stimulating the cells to pro-
thermore, IgG antibodies have been shown, by liferate. The higher the affinity of the surface im-
means of electron microscopy, to colocalize with munoglobulin for the antigen, the more strongly
extracellular chromatin in lupus nephritis in hu- the cells are stimulated and the more they prolif-
mans and mice.37,38 Also relevant is the detection erate. In the presence of the stimulating antigen,
of anti-nucleosome antibodies in the blood and there is a continuous selective pressure favoring
inflamed tissues of patients with lupus.26,36 B cells that display on their surface and secrete
The second model proposes that anti–double- immunoglobulins with high affinity for that an-
stranded DNA, anti-nucleosome antibodies, or tigen. In general, this antigen-driven process can
Stimulation
CD28 B7
T cell APC
TCR MHC
Antigen
CTLA-4 B7
Inhibition
T cell B cell
TNF-α
Interferon-γ
Interleukin-10
Antibodies
Ultraviolet light
Keratinocytes
Apoptotic
cells
the surface of these blebs (Fig. 3), and they may C y t ok ine s in Lupus
trigger an immune response. These exposed an-
tigens include nucleosomes, Ro 62, Ro 50, La, and The role of tumor necrosis factor α (TNF-α) in lu-
anionic phospholipids.72 Antibodies to these L O R Fpus
C Oan- IGUR isE controversial. This cytokine may be protec-
tigens occur commonly in patients with Draft lupus. 2 tive in
01/31/08patients with lupus, since giving TNF-α to
The removal of apoptotic debris isAuthor
abnormal in lupus-prone NZB/W F1 mice delayed the develop-
Isenberg
patients with lupus.73 In vitro, phagocytes
Fig # 3from ment of lupus.77 The protective effect is specific
Title
patients with lupus were shown to engulf
ME
far less to that mouse strain, and the mechanism is un-
apoptotic material than phagocytesDE from healthy known. In some patients with rheumatoid arthri-
people during a 7-day culture period. 74 C1q SBL
Artist plays tis who were treated with anti–TNF-α antibodies,
a role in phagocytosis by binding to cell debris, anti–double-stranded DNA antibodies developed,78
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
which can then be engulfed by macrophages that and lupus developed in a few of these patients.79
Please check carefully
Issue date
have surface C1q receptors. Thus, a deficiency of One group has shown that the balance between
complement may be an important reason for the TNF-α and the soluble inhibitors (TNF-soluble re-
poor “waste disposal” seen in lupus. Homozygous ceptor 75kDa and TNF-soluble receptor 55kDa) is
deficiencies of C1q, C2, and C4 are rare disorders, altered in favor of the inhibitors in active lupus;
but the presence of any of these genetic conditions this provides support for the idea that low TNF-α
is a strong predisposing factor for lupus.17 In C1q activity is associated with increased disease activ-
knockout mice, a lupuslike renal disease develops; ity in lupus.80 By contrast, the level of TNF-α mes-
kidney-biopsy specimens from mice with this con- senger RNA was high in kidney-biopsy specimens
dition reveal multiple apoptotic fragments.75 Da- from patients with lupus nephritis.81 Aringer et
vies and colleagues reported reduced clearance of al. reported that giving the anti–TNF-α antibody
immune complexes through the spleen in a pa- agent infliximab to six patients with lupus led to
tient with C2 deficiency and lupus; this was cor- resolution of joint swelling in three patients with
rected by restoring the C2 levels with the use of arthritis and the reduction of urinary protein loss
transfusions of fresh-frozen plasma.76 by 60% in four patients with renal lupus.82
Anti-BlyS Anti-interleukin-10
TACI-Ig
Anti-CD20
Interleukin-10
B stimulating
including BlyS Peptide
B-cell
CTLA-4–Ig Peptide Anti-CD22 tolerogan
Draft 3 02/02/08
Author Isenberg
Fig # 4
Serum levels of interleukin-10
Title are consistently in several other conditions, including rheumatoid
high in patients with lupus, and they correlate with arthritis and Sjögren’s syndrome, as well as in lu-
ME
DE
83 Interleukin-10 has a pus. The overexpression of B-lymphocyte stimula-
the activity of the disease.Artist SBL
number of biologic effects, including AUTHOR stimulation
PLEASE NOTE: tor has been detected in both humans with lupus
Figure has been redrawn and type has been reset
of polyclonal populations of B lymphocytes. Block- and lupus-prone mice. Stohl et al. reported elevat-
Please check carefully
DNA antibodies leads to lower mean levels of such sodium was not superior to placebo in an analysis
antibodies and reduced frequency of severe flares of the primary outcome measure (time to renal
of disease, but one study indicated that the side flare) for the whole study group, but in post hoc
effects of corticosteroids were a problem.31 Ritux- analyses, the drug was superior to placebo in a
imab89 and abetimus sodium90 have been used as subgroup analysis of patients who had serum an-
specific methods of reducing levels of anti–double- tibodies with high affinity for the drug.90
stranded DNA. Rituximab is nonspecific; that is, Anti-CD40 ligand61 and CTLA-4–Ig62 directly
it is an antibody against CD20, which is found on target the interaction between T cells and anti-
the surface of all mature B cells. Abetimus sodium gen-presenting cells by inhibiting costimulation.
is designed to deplete only B lymphocytes that pro- Peptides derived from pathogenic anti-DNA anti-
duce anti–double-stranded DNA antibodies be- bodies may be useful in generating anti-idiotypic
cause its four surface oligonucleotides can engage responses to autoantibodies and thus suppress-
surface anti–double-stranded DNA antibodies on ing their pathogenic effects.95 Trials of anti–TNF-α
those cells, but it has no epitopes to allow bind- antibody82 and anti–interleukin-10 antibody84 are
ing of helper T cells. The B cells therefore undergo described above.
apoptosis rather than proliferation, but it is not
clear whether this depleting mechanism occurs in Sum m a r y
patients. Abetimus sodium may also work by form-
ing complexes with anti–double-stranded DNA an- Pathogenic autoantibodies are the primary cause
tibodies, which are then cleared from the circu- of tissue damage in patients with lupus. The pro-
lation.91 duction of these antibodies arises by means of
Several case series suggest that rituximab is complex mechanisms involving every key facet
helpful in treating lupus.89,92 The use of a mono- of the immune system. Many different elements of
clonal anti-CD22 antibody (which also targets the system are potential targets for therapeutic
B cells)93 is being studied in a clinical trial, and drugs in patients with lupus.
the survival and proliferation of B cells can also No potential conflict of interest relevant to this article was
reported.
be modulated with the use of anti–B-lymphocyte We thank Dr. Betty Tsao for her help with defining the ge-
stimulator.88,94 A large trial showed that abetimus netic aspects of lupus.
References
1. Johnson AE, Gordon C, Palmer RG, phrology. Oxford, England: Oxford Univer- teria for the classification of systemic lu-
Bacon PA. The prevalence and incidence of sity Press, 2005:809-29. pus erythematosus. Arthritis Rheum 1997;
systemic lupus erythematosus in Birming- 7. Buyon JP, Petri MA, Kim MY, et al. The 40:1725.
ham, England: relationship to ethnicity and effect of combined estrogen and proges- 13. Sullivan KE. Genetics of systemic lu-
country of birth. Arthritis Rheum 1995;38: terone hormone replacement therapy on pus erythematosus: clinical implications.
551-8. disease activity in systemic lupus erythe- Rheum Dis Clin North Am 2000;26:229-
2. Merrell M, Shulman LE. Determina- matosus: a randomized trial. Ann Intern 56.
tion of prognosis in chronic disease, illus- Med 2005;142:953-62. 14. Wakeland EK, Liu K, Graham RR,
trated by systemic lupus erythematosus. 8. Chang DM, Lan JL, Lin HY, Luo SF. Behrens TW. Delineating the genetic ba-
J Chronic Dis 1955;1:12-32. Dehydroepiandrosterone treatment of sis of systemic lupus erythematosus. Im-
3. Abu-Shakra M, Urowitz MB, Gladman women with mild-to-moderate systemic munity 2001;15:397-408.
DD, Gough J. Mortality studies in systemic lupus erythematosus: a multicenter ran- 15. Namjou B, Kelly JA, Harley JB. The ge-
lupus erythematosus: results from a sin- domized, double-blind, placebo-controlled netics of lupus. In: Tsokos GC, Gordon C,
gle center. II. Predictor variables for mor- trial. Arthritis Rheum 2002;46:2924-7. Smolen JS, eds. Systemic lupus erythema-
tality. J Rheumatol 1995;22:1265-70. 9. Rubin R. Drug induced lupus. In: Wal- tosus. Philadelphia: Mosby Elsevier, 2007:
4. Gladman DD, Urowitz MB. Prognosis, lace DJ, Hahn BH, eds. Dubois’ lupus ery- 74-80.
mortality and morbidity in systemic lupus thematosus. 6th ed. Philadelphia: Lippin- 16. Walport MJ, Black CM, Batchelor JR.
erythematosus. In: Wallace DJ, Hahn BH, cott Williams & Wilkins, 2002:885-916. The immunogenetics of SLE. Clin Rheum
eds. Dubois’ lupus erythematosus. 7th 10. James JA, Kaufman KM, Farris AD, Dis 1982;8:3-21.
ed. Philadelphia: Lippincott Williams & Taylor-Albert E, Lehman TJ, Harley JB. An 17. Walport MJ. Complement and system-
Wilkins, 2007:1333-53. increased prevalence of Epstein-Barr virus ic lupus erythematosus. Arthritis Res 2002;
5. Urowitz MB, Bookman AA, Koehler infection in young patients suggests a pos- 4:Suppl 3:S279-S293.
BE, Gordon DA, Smythe HA, Ogryzlo MA. sible etiology for systemic lupus erythema- 18. Sigurdsson S, Nordmark G, Göring
The bimodal mortality pattern of systemic tosus. J Clin Invest 1997;100:3019-26. HH, et al. Polymorphisms in the tyrosine
lupus erythematosus. Am J Med 1976;60: 11. Tan EM, Cohen AS, Fries JF, et al. The kinase 2 and interferon regulatory factor 5
221-5. 1982 revised criteria for the classification genes are associated with systemic lupus
6. Mason LJ, Isenberg D. The pathogen- of systemic lupus erythematosus. Arthri- erythematosus. Am J Hum Genet 2005;
esis of systemic lupus erythematosus. In: tis Rheum 1982;25:1271-7. 76:528-37.
Davidson AM, Cameron JS, Grunfeld JP, et 12. Hochberg MC. Updating the Ameri- 19. Morel L, Croker BP, Blenman KR, et al.
al., eds. Oxford textbook of clinical ne- can College of Rheumatology revised cri- Genetic reconstitution of systemic lupus
erythematosus immunopathology with pus erythematosus. Lancet 1995;345:1595- Askanase AD, Buyon JP. Immunohistologic
polycongenic murine strains. Proc Natl 9. [Erratum, Lancet 1995;346:516.] evidence supports apoptosis, IgG deposi-
Acad Sci U S A 2000;97:6670-5. 32. Tseng CE, Buyon JP, Kim M, et al. The tion, and novel macrophage/fibroblast
20. Koffler D, Schur PH, Kunkel HG. Im- effect of moderate-dose corticosteroids in crosstalk in the pathologic cascade lead-
munological studies concerning the ne- preventing severe flares in patients with ing to congenital heart block. Arthritis
phritis of systemic lupus erythematosus. serologically active, but clinically stable, Rheum 2004;50:173-82.
J Exp Med 1967;126:607-24. systemic lupus erythematosus: findings of 44. Maddison PJ, Reichlin M. Deposition
21. Isenberg DA, Manson JJ, Ehrenstein a prospective, randomized, double-blind, of antibodies to a soluble cytoplasmic
MR, Rahman A. Fifty years of anti-ds placebo-controlled trial. Arthritis Rheum antigen in the kidneys of patients with
DNA antibodies: are we approaching jour- 2006;54:3623-32. systemic lupus erythematosus. Arthritis
ney’s end? Rheumatology (Oxford) 2007; 33. Ravirajan CT, Rahman MA, Papadaki Rheum 1979;22:858-63.
46:1052-6. L, et al. Genetic, structural and functional 45. McCarty GA, Harley JB, Reichlin M.
22. Isenberg DA, Shoenfeld Y, Walport M, properties of an IgG DNA-binding mono- A distinctive autoantibody profile in black
et al. Detection of cross-reactive anti-DNA clonal antibody from a lupus patient with female patients with lupus nephritis. Ar-
antibody idiotypes in the serum of sys- nephritis. Eur J Immunol 1998;28:339-50. thritis Rheum 1993;36:1560-5.
temic lupus erythematosus patients and [Erratum, Eur J Immunol 1999;29:3052.] 46. Yoshio T, Onda K, Nara H, Minota S.
of their relatives. Arthritis Rheum 1985; 34. Ehrenstein MR, Katz DR, Griffiths Association of IgG anti-NR2 glutamate
28:999-1007. MH, et al. Human IgG anti-DNA antibod- receptor antibodies in cerebrospinal fluid
23. ter Borg EJ, Horst G, Hummel EJ, Lim- ies deposit in kidneys and induce protein- with neuropsychiatric systemic lupus ery-
burg PC, Kallenberg CG. Measurement of uria in SCID mice. Kidney Int 1995;48:705- thematosus. Arthritis Rheum 2006;54:
increases in anti-double-stranded DNA an- 11. 675-8.
tibody levels as a predictor of disease exac- 35. Madaio MP, Carlson J, Cataldo J, Ucci 47. Lapteva L, Nowak M, Yarboro CH, et
erbation in systemic lupus erythematosus: A, Migliorini P, Pankewycz O. Murine al. Anti-N-methyl-D-aspartate receptor an-
a long-term, prospective study. Arthritis monoclonal anti-DNA antibodies bind di- tibodies, cognitive dysfunction, and de-
Rheum 1990;33:634-43. rectly to glomerular antigens and form pression in systemic lupus erythematosus.
24. Ng KP, Manson JJ, Rahman A, Isen- immune deposits. J Immunol 1987;138: Arthritis Rheum 2006;54:2505-14.
berg DA. Association of antinucleosome 2883-9. 48. Alarcón-Segovia D, Delezé M, Oria CV,
antibodies with disease flare in serologi- 36. Grootscholten C, van Bruggen MC, et al. Antiphospholipid antibodies and the
cally active clinically quiescent patients van der Pijl JW, et al. Deposition of nu- antiphospholipid syndrome in systemic lu-
with systemic lupus erythematosus. Ar- cleosomal antigens (histones and DNA) pus erythematosus: a prospective analysis
thritis Rheum 2006;55:900-4. in the epidermal basement membrane in of 500 consecutive patients. Medicine (Bal-
25. Mannik M, Merrill CE, Stamps LD, human lupus nephritis. Arthritis Rheum timore) 1989;68:353-65.
Wener MH. Multiple autoantibodies form 2003;48:1355-62. 49. Girardi G, Redecha P, Salmon JE. Hep-
the glomerular immune deposits in pa- 37. Kalaaji M, Fenton KA, Mortensen ES, arin prevents antiphospholipid antibody-
tients with systemic lupus erythematosus. et al. Glomerular apoptotic nucleosomes induced fetal loss by inhibiting comple-
J Rheumatol 2003;30:1495-504. are central target structures for nephrito- ment activation. Nat Med 2004;10:1222-6.
26. Amoura Z, Koutouzov S, Chabre H, et genic antibodies in human SLE nephritis. 50. Pierangeli SS, Liu X, Espinola R, et al.
al. Presence of antinucleosome autoanti- Kidney Int 2007;71:664-72. Functional analyses of patient-derived IgG
bodies in a restricted set of connective tis- 38. Kalaaji M, Mortensen E, Jørgensen L, monoclonal anticardiolipin antibodies us-
sue diseases: antinucleosome antibodies Olsen R, Rekvig OP. Nephritogenic lupus ing in vivo thrombosis and in vivo micro-
of the IgG3 subclass are markers of renal antibodies recognize glomerular basement circulation models. Thromb Haemost 2000;
pathogenicity in systemic lupus erythema- membrane-associated chromatin frag- 84:388-95.
tosus. Arthritis Rheum 2000;43:76-84. ments released from apoptotic intraglo- 51. Mason LJ, Ravirajan CT, Rahman A,
27. Kowal C, Degiorgio LA, Lee JY, et al. merular cells. Am J Pathol 2006;168:1779- Putterman C, Isenberg DA. Is alpha-actinin
Human lupus autoantibodies against 92. a target for pathogenic anti-DNA antibodies
NMDA receptors mediate cognitive impair- 39. Kramers C, Hylkema MN, van Brug- in lupus nephritis? Arthritis Rheum 2004;
ment. Proc Natl Acad Sci U S A 2006; gen MC, et al. Anti-nucleosome antibod- 50:866-70.
103:19854-9. ies complexed to nucleosomal antigens 52. Mostoslavsky G, Fischel R, Yachimov-
28. Becker-Merok A, Kalaaji M, Haugbro show anti-DNA reactivity and bind to rat ich N, et al. Lupus anti-DNA autoantibod-
K, et al. Alpha-actinin-binding antibodies glomerular basement membrane in vivo. ies cross-react with a glomerular struc-
in relation to systemic lupus erythematosus J Clin Invest 1994;94:568-77. tural protein: a case for tissue injury by
and lupus nephritis. Arthritis Res Ther 40. van Bruggen MC, Walgreen B, Rijke molecular mimicry. Eur J Immunol 2001;
2006;8:R162. TP, et al. Antigen specificity of anti-nucle- 31:1221-7.
29. Siegert CE, Daha MR, Swaak AJ, van ar antibodies complexed to nucleosomes 53. Deocharan B, Qing X, Lichauco J, Put-
der Voort EA, Breedveld FC. The relation- determines glomerular basement mem- terman C. Alpha-actinin is a cross-reac-
ship between serum titers of autoantibod- brane binding in vivo. Eur J Immunol tive renal target for pathogenic anti-DNA
ies to C1q and age in the general popula- 1997;27:1564-9. antibodies. J Immunol 2002;168:3072-8.
tion and in patients with systemic lupus 41. Buyon JP, Clancy RM. Maternal auto- 54. Quismorio FP. Other serologic abnor-
erythematosus. Clin Immunol Immuno- antibodies and congenital heart block: malities in systemic lupus erythematosus.
pathol 1993;67:204-9. mediators, markers, and therapeutic ap- In: Wallace DJ, Hahn BH, eds. Dubois’ lu-
30. Ehrenstein M, Isenberg DA. Systemic proach. Semin Arthritis Rheum 2003;33: pus erythematosus. 7th ed. Philadelphia:
lupus erythematosus in adults — clinical 140-54. Lippincott Williams & Wilkins, 2007:527-
features and aetiopathogenesis. In: Isen- 42. Sontheimer RD, Maddison PJ, Reich- 50.
berg DA, Maddison PJ, Woo P, Klars D, lin M, Jordon RE, Stastny P, Gilliam JN. 55. Pujol M, Ribera A, Vilardell M, Ordi J,
Breedveld FC, eds. Oxford textbook of Serologic and HLA associations in sub- Feliu E. High prevalence of platelet auto-
rheumatology. 3rd ed. Oxford, England: acute cutaneous lupus erythematosus, antibodies in patients with systemic lupus
Oxford University Press, 2004:819-41. a clinical subset of lupus erythematosus. erythematosus. Br J Haematol 1995;89:137-
31. Bootsma H, Spronk P, Derksen R, et Ann Intern Med 1982;97:664-71. 41.
al. Prevention of relapses in systemic lu- 43. Clancy RM, Kapur RP, Molad Y, 56. Berden JH, Licht R, van Bruggen MC,
Tax WJ. Role of nucleosomes for induc- Datta SK. Very low-dose tolerance with nauld JC. Serum interleukin 10 titers in
tion and glomerular binding of autoanti- nucleosomal peptides controls lupus and systemic lupus erythematosus reflect dis-
bodies in lupus nephritis. Curr Opin induces potent regulatory T-cell subsets. ease activity. Lupus 1995;4:393-5.
Nephrol Hypertens 1999;8:299-306. J Immunol 2005;174:3247-55. 84. Llorente L, Richaud-Patin Y, García-
57. Michaud JL, Lemieux LI, Dubé M, 72. Casciola-Rosen LA, Anhalt G, Rosen Padilla C, et al. Clinical and biologic ef-
Vanderhyden BC, Robertson SJ, Kennedy A. Autoantigens targeted in systemic lu- fects of anti-interleukin-10 monoclonal an-
CR. Focal and segmental glomeruloscle- pus erythematosus are clustered in two tibody administration in systemic lupus
rosis in mice with podocyte-specific ex- populations of surface structures on apop- erythematosus. Arthritis Rheum 2000;43:
pression of mutant alpha-actinin-4. J Am totic keratinocytes. J Exp Med 1994;179: 1790-800.
Soc Nephrol 2003;14:1200-11. 1317-30. 85. Rönnblom L, Alm GV. Systemic lupus
58. Katz JB, Limpanasithikul W, Diamond 73. Munoz LE, Gaipl US, Franz S, et al. erythematosus and the type I interferon
B. Mutational analysis of an autoantibody: SLE — a disease of clearance deficiency? system. Arthritis Res Ther 2003;5:68-75.
differential binding and pathogenicity. Rheumatology (Oxford) 2005;44:1101-7. 86. Baechler EC, Batliwalla FM, Karypis
J Exp Med 1994;180:925-32. 74. Herrmann M, Voll RE, Zoller OM, G, et al. Interferon-inducible gene expres-
59. Avrameas S. Natural autoantibodies: Hagenhofer M, Ponner BB, Kalden JR. Im- sion signature in peripheral blood cells of
from ‘horror autotoxicus’ to ‘gnothi seau- paired phagocytosis of apoptotic cell ma- patients with severe lupus. Proc Natl Acad
ton.’ Immunol Today 1991;12:154-9. terial by monocyte-derived macrophages Sci U S A 2003;100:2610-5.
60. Okamura M, Kanayama Y, Amastu K, from patients with systemic lupus erythe- 87. Mathian A, Weinberg A, Gallegos M,
et al. Significance of enzyme linked im- matosus. Arthritis Rheum 1998;41:1241- Banchereau J, Koutouzov S. IFN-alpha in-
munosorbent assay (ELISA) for antibodies 50. duces early lethal lupus in preautoim-
to double stranded and single stranded 75. Botto M, Dell’Agnola C, Bygrave AE, mune (New Zealand Black x New Zealand
DNA in patients with lupus nephritis: cor- et al. Homozygous C1q deficiency causes White) F1 but not in BALB/c mice. J Im-
relation with severity of renal histology. glomerulonephritis associated with mul- munol 2005;174:2499-506.
Ann Rheum Dis 1993;52:14-20. tiple apoptotic bodies. Nat Genet 1998; 88. Stohl W, Metyas S, Tan SM, et al.
61. Sidiropoulos PI, Boumpas DT. Les- 19:56-9. B lymphocyte stimulator overexpression
sons learned from anti-CD40L treatment 76. Davies KA, Erlendsson K, Beynon HL, in patients with systemic lupus erythema-
in systemic lupus erythematosus patients. et al. Splenic uptake of immune complex- tosus: longitudinal observations. Arthri-
Lupus 2004;13:391-7. es in man is complement-dependent. J Im- tis Rheum 2003;48:3475-86.
62. Davidson A, Diamond B, Wofsy D, munol 1993;151:3866-73. 89. Leandro MJ, Edwards JC, Cambridge
Daikh D. Block and tackle: CTLA4Ig takes 77. Jacob CO, McDevitt HO. Tumour ne- G, Ehrenstein MR, Isenberg DA. An open
on lupus. Lupus 2005;14:197-203. crosis factor-alpha in murine autoimmune study of B lymphocyte depletion in systemic
63. Isenberg D, Rahman A. Systemic lu- ‘lupus’ nephritis. Nature 1988;331:356-8. lupus erythematosus. Arthritis Rheum
pus erythematosus — 2005 annus mirabi- 78. Charles PJ, Smeenk RJ, De Jong J, Feld- 2002;46:2673-7.
lis? Nat Clin Pract Rheumatol 2006;2:145- mann M, Maini RN. Assessment of anti- 90. Alarcón-Segovia D, Tumlin JA, Furie
52. bodies to double-stranded DNA induced in RA, et al. LJP 394 for the prevention of
64. Coffman RL, Lebman DA, Rothman rheumatoid arthritis patients following renal flare in patients with systemic lupus
P. Mechanism and regulation of immuno- treatment with infliximab, a monoclonal erythematosus: results from a randomized,
globulin isotype switching. Adv Immunol antibody to tumor necrosis factor alpha: double-blind, placebo-controlled study. Ar-
1993;54:229-70. findings in open-label and randomized thritis Rheum 2003;48:442-54.
65. Shlomchik MJ, Marshak-Rothstein A, placebo-controlled trials. Arthritis Rheum 91. Weisman MH, Bluestein HG, Berner
Wolfowicz CB, Rothstein TL, Weigert 2000;43:2383-90. CM, de Haan HA. Reduction in circulat-
MG. The role of clonal selection and so- 79. Mohan AK, Edwards ET, Coté TR, ing dsDNA antibody titer after adminis-
matic mutation in autoimmunity. Nature Siegel JN, Braun MM. Drug-induced sys- tration of LJP 394. J Rheumatol 1997;24:
1987;328:805-11. temic lupus erythematosus and TNF-alpha 314-8.
66. Rahman A. Autoantibodies, lupus and blockers. Lancet 2002;360:646. 92. Chambers SA, Isenberg D. Anti-B cell
the science of sabotage. Rheumatology 80. Gabay C, Cakir N, Moral F, et al. Cir- therapy (rituximab) in the treatment of
(Oxford) 2004;43:1326-36. culating levels of tumor necrosis factor autoimmune diseases. Lupus 2005;14:
67. Dörner T, Lipsky PE. Immunoglobu- soluble receptors in systemic lupus ery- 210-4.
lin variable-region gene usage in systemic thematosus are significantly higher than 93. Dörner T, Kaufmann J, Wegener WA,
autoimmune diseases. Arthritis Rheum in other rheumatic diseases and correlate Teoh N, Goldenberg DM, Burmester GR.
2001;44:2715-27. with disease activity. J Rheumatol 1997;24: Initial clinical trial of epratuzumab (hu-
68. Lu L, Kaliyaperumal A, Boumpas DT, 303-8. manized anti-CD22 antibody) for immu-
Datta SK. Major peptide autoepitopes for 81. Herrera-Esparza R, Barbosa-Cisneros notherapy of systemic lupus erythemato-
nucleosome-specific T cells of human lu- O, Villalobos-Hurtado R, Avalos-Díaz E. sus. Arthritis Res Ther 2006;8:R74.
pus. J Clin Invest 1999;104:345-55. Renal expression of IL-6 and TNFalpha 94. Baker KP, Edwards BM, Main SH, et
69. Mudd PA, Teague BN, Farris AD. Reg- genes in lupus nephritis. Lupus 1998;7: al. Generation and characterization of
ulatory T cells and systemic lupus erythe- 154-8. LymphoStat-B, a human monoclonal anti-
matosus. Scand J Immunol 2006;64:211-8. 82. Aringer M, Graninger WB, Steiner G, body that antagonizes the bioactivities of
70. Valencia X, Yarboro C, Illei G, Lipsky Smolen JS. Safety and efficacy of tumor B lymphocyte stimulator. Arthritis Rheum
PE. Deficient CD4+CD25(high) T regula- necrosis factor alpha blockade in systemic 2003;48:3253-65.
tory cell function in patients with active lupus erythematosus: an open-label study. 95. Merrill JT. BLyS antagonists and pep-
systemic lupus erythematosus. J Immunol Arthritis Rheum 2004;50:3161-9. tide tolerance induction. Lupus 2005;14:
2007;178:2579-88. 83. Houssiau FA, Lefebvre C, Vanden 204-9.
71. Kang H-K, Michaels MA, Berner BR, Berghe M, Lambert M, Devogelaer JP, Re- Copyright © 2008 Massachusetts Medical Society.