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Protective autoantibodiesRole in homeostasis clinical importance and therapeutic potential.

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Vol. 52, No. 9, September 2005, pp 2599–2606
DOI 10.1002/art.21252
© 2005, American College of Rheumatology
Protective Autoantibodies
Role in Homeostasis, Clinical Importance, and Therapeutic Potential
Yehuda Shoenfeld1 and Elias Toubi2
antigens by masking their antigenic determinants. Humoral autoimmune protection is a growing field of study
in which protective autoantibodies are thought to play a
role in preventing many autoimmune diseases, such as
systemic lupus erythematosus (SLE). IgM anti–doublestranded DNA (anti-dsDNA) antibodies have a negative
correlation with the severity of glomerulonephritis (GN)
in SLE. The administration of IgM anti-dsDNA antibodies into SLE-prone mice prevented the development of
nephritis, suggesting a protective role for these antibodies. In addition, the presence of rheumatoid factor (RF)
in SLE was suggested by many investigators to be
protective against the development of lupus nephritis.
Beneficial autoimmunity against proinflammatory cytokines has also been reported to play a role in
the immunomodulation of autoimmune diseases, such as
rheumatoid arthritis (RA). Autoantibodies to various
oxidation-specific neoepitopes on oxidized low-density
lipoprotein (oxLDL) have been demonstrated to attenuate inflammation and plaque formation in atherosclerosis. Thus, protective autoantibodies may be utilized for
therapeutic purposes, e.g., IgM anti-dsDNA and antioxLDL antibodies might serve as useful treatments for
patients with SLE and patients with atherosclerosis,
Thus, it seems that the protective role of autoimmunity is not limited to the cellular processes of the
immune system, since the humoral process (autoantibodies) has also been found to be involved. In the
present report, we summarize the current knowledge on
protective autoantibodies, the existence of which seems
to lead to their application for therapeutic purposes.
Paul Eherlich, a Nobel prize laureate, believed
that the existence of autoantibodies is always associated
with fatal conditions, referring to the idea as the horror
autotoxicus. However, this notion of fatal autoimmunity
was later refuted by him when he suggested that antiautotoxin antibodies may exist. The dogma that autoimmunity leads to continuous damage of organisms has
since been challenged by a mass of data in which
autoimmunity is demonstrated to be protective in many
Previous studies have shown that central nervous
system (CNS) trauma spontaneously evokes a beneficial
T cell–dependent immune response that reduces neuronal loss. Injuries to the CNS induce self-destructive
processes, leading to the degeneration of initially spared
neurons. This destruction is mediated by increased
amounts of glutamate, a neurotransmitter that becomes
cytotoxic when presented in excessive amounts but
which can recruit and activate a T cell–dependent
self-protective immune mechanism (1–3). This protective autoimmunity was shown to be a Th1-mediated
response that could be experimentally achieved by passive transfer of autoreactive Th1 cells (4–6).
Natural autoantibodies are found in the sera of
healthy individuals. They are polyreactive, mostly of the
IgM isotype, and react with both self and non-self
antigens. Nonspecific and low-affinity binding of these
natural autoantibodies to self antigens may prevent
autoreactive clones from reacting vigorously with self
Yehuda Shoenfeld, MD, FRCP (Hon): Sheba Medical Center, Tel-Aviv University, Tel-Hashomer, Israel; 2Elias Toubi, MD:
Bnai Zion Medical Center, Haifa, Israel.
Address correspondence and reprint requests to Yehuda
Shoenfeld, MD, FRCP (Hon), Department of Medicine “B,” Sheba
Medical Center, Tel-Hashomer 52621, Israel. E-mail:
Submitted for publication January 19, 2005; accepted in
revised form May 24, 2005.
Natural autoantibodies as protective immunoglobulins
Natural autoantibodies derive their name from
the fact that they are generated in the absence of specific
immunization and exist independent of exposure to
foreign antigens (i.e., belong to the innate immune
system) (7). Although natural autoantibodies may belong to all isotypes, IgM antibodies constitute the major
component. Moreover, natural autoantibodies are primarily polyreactive, encoded by germline V-gene segments, and have low affinities but broad specificities to
both foreign and self structures (8). Depending on the
conditions encountered, natural autoantibodies are able
to exert either a physiologic (beneficial, protective) or a
pathologic (harmful) role. When they transform into a
higher affinity, become self specific, and are produced in
excess, natural autoantibodies might participate in the
formation of pathogenic immune complexes (9).
Natural autoantibodies are characterized by their
reactivity against well-conserved public epitopes. They
fulfill the definition of autoantibodies, since they are self
reactive but not self specific. The nonspecific and lowaffinity binding of natural autoantibodies to self antigens
may prevent autoreactive clones from reacting vigorously with self antigens by binding and masking their
antigenic determinants (10). Early studies shared the
concept that natural autoantibodies act to remove circulating products, some of which are immunogenic
autoantigens, before they can elicit a damaging autoimmune response (11). This is consistent with their
reported participation in the clearance of altered self
constituents, such as aged erythrocytes and keratinocytes, by enabling multivalent binding of natural IgG
antikeratin antibodies and the subsequent phagocytosis
of the immune complexes formed (12).
The recent availability of secreted IgM–deficient
(sIgM⫺/⫺) mice has provided a model to test the importance of natural IgM in autoimmune diseases. In this
model, mice bear a deletion of the coding sequence for
sIgM; therefore, IgM is expressed, but not secreted, on
the surface of B cells. When MRL/lpr mice were crossed
with sIgM⫺/⫺ mice, they developed a more severe form
of disease, suggesting that deficiency of natural IgM
antibodies could be the predisposing factor for accelerated SLE (13).
Natural IgM antibodies pooled from the normal
circulating IgM repertoire have recently been shown to
induce apoptosis of lymphoblastoid cell lines and human
peripheral blood mononuclear cells. The IgM-induced
cell death involved classic features of apoptosis, such as
nuclear fragmentation and activation of caspases (14).
Soluble Fas molecules inhibited this natural
autoantibody–induced apoptosis, suggesting that the Fas
pathway is involved. These results allude to a role for
normal IgM antibodies in controlling cell death and
proliferation, and imply a possible therapeutic role for
IgM antibodies in autoimmune and lymphoproliferative
In some autoimmune situations, the inhibition of
certain IgG autoreactive responses to histone or dsDNA
by natural polyreactive IgM monoclonal antibodies
(mAb) does not function, leading to the expression or
expansion of autoreactive IgG-producing clones. The
inhibitory effect of IgM mAb is mediated by V-region–
dependent interactions with the autoreactive IgG, as
shown by the ability of these antibodies to block the
binding of F(ab⬘)2 fragments of autoreactive IgG to their
respective autoantigens (15). The blocking activity was
found to be dose-dependent, with maximal inhibition
occurring at a specific molar ratio between the patient’s
IgG and a given mAb, supporting the concept of a
functional idiotypic network regulating autoimmune responses.
The interaction between IgM mAb and F(ab⬘)2
fragments of autoreactive IgG might involve several sites
and could be dependent on 3-dimensional configurations (16). Nevertheless, it is conceivable that many of
the natural autoantibodies may act protectively by being
immunoregulatory. Observed qualitative differences
would imply that there are modifications in the mechanisms of natural autoantibody synthesis, leading to the
development of monospecific autoantibodies that possess high affinities for self structures. Autoimmunity
after infections by parasites or viruses could lead to
permanent immune activation, due to dysregulation of
natural autoantibody production. Anti–single-stranded
DNA, antithyroglobulin, and anti-IgG antibodies are
demonstrated after stimulation of CD5⫹ B lymphocytes
from healthy humans by viruses such as the Epstein-Barr
virus (17). Thus, natural autoantibodies act as a filter,
preventing autoantigens from inducing autoimmunity by
cross-reaction with antigens on infectious organisms.
Natural autoantibodies may also act by blocking the
receptors on autoreactive CD5⫹ cells and by downregulating their own synthesis (18).
It has been demonstrated that 10–20% of the
total IgG molecules isolated from immune and nonimmune sera are asymmetrically glycosylated, in such a way
that they fail to trigger immune effector mechanisms and
to form insoluble complexes with antigens (19). In
contrast to symmetrically glycosylated IgG autoantibodies, asymmetric IgG antibodies are self specific but have
no deleterious effect in normal individuals, and therefore may act as autoprotective antibodies. Asymmetric
IgG antibodies act in a competitive way when they are
mixed with precipitating or symmetric antibodies of the
same specificity, and the action of these antibodies
therefore depends on their respective proportion in the
mixture (20). The increased ratio of asymmetric to
symmetric IgG in sera from older rats suggests that
asymmetric antibodies may exert a beneficial effect by
protecting self antigens from inducing severe immune
responses (21).
Protective antibodies in autoimmune diseases
It seems that natural autoantibodies are not the
only molecules that entail protective characteristics.
Protective autoantibodies may also be detected among
the regular repertoire of autoantibodies in a disease
IgM anti-dsDNA antibodies. Anti-dsDNA antibodies differ with respect to their avidity, isotype, antigen specificity, charge, idiotypes, and V-region sequences. The IgM class of anti-dsDNA antibodies
appears in disease states other than SLE, such as RA,
Sjögren’s syndrome, and autoimmune liver disease (22).
The presence of IgM anti-dsDNA antibodies in SLE was
found to be significantly associated with milder disease
activity, namely, a negative correlation with lupus nephritis (23). In contrast, immune complexes containing
IgG autoantibodies against dsDNA are deposited in the
renal vasculature, which results in organ damage, and
this has been correlated with the severity of GN in SLE
In a recent study, absence of lupus nephritis was
suggested to be a consequence of a predominance of the
IgM isotype of anti-dsDNA antibodies (25). SLE patients with a permanent ratio of IgG to IgM of ⬍0.8 did
not develop lupus nephritis, despite high levels of antidsDNA antibodies. The greater ability of antibodies of
the IgM class to bind more circulating antigen could
explain the phenomenon of a decrease in the formation
of IgG-class immune complexes via competitive inhibition. It is also possible that IgM anti-dsDNA antibodies
may down-regulate autoreactive B cells and decrease the
production of pathogenic IgG anti-dsDNA antibodies.
Thus, higher titers of IgM compared with IgG antidsDNA antibodies, as well as the impaired switchover of
IgM to IgG, might indicate a protective effect against
lupus nephritis.
In addition, it has been suggested that IgM
anti-dsDNA–dsDNA complexes are cleared more effectively by phagocytes and are therefore minimally deposited in the glomerular basement membrane (Figure 1).
Thus, it was logical to investigate whether IgM antidsDNA antibodies can be used to prevent immune
complex–mediated organ damage. In a group of un-
Figure 1. Protective and pathogenic roles of anti–double-stranded
DNA (anti-dsDNA) antibodies. A, IgM anti-dsDNA are efficent in
binding and neutralizing dsDNA. In addition, IgM–dsDNA immune
complexes undergo efficient phagocytosis instead of being deposited
on the glomerular basement membrane. B, Pathogenic IgG antidsDNA antibodies remain soluble and therefore escape efficient
phagocytosis and are deposited on the glomerular basement membrane. Color figure can be viewed in the online issue, which is available
treated NZB ⫻ NZW mice, which are prone to develop
SLE, typical signs of GN, including glomerular IgG
deposits and infiltration of mononuclear cells, were
evident; in contrast, when age-matched mice were
treated with IgM anti-dsDNA antibodies, absence or
only mild signs of GN and only a minimal glomerular
deposition of IgG could be determined (26). These
results demonstrate that IgM anti-dsDNA antibodies
may protect against immune complex–mediated organ
damage in murine lupus and may explain why human
SLE patients with higher titers of IgM anti-dsDNA are
partially protected against GN.
Protective RF. There is no agreement on whether
the presence of RF exerts protection, induces injury, or
is an epiphenomenon with regard to kidney disease in
SLE. The presence and isotype distribution of RF in
SLE patients in relation to some clinical parameters,
including renal function, was not found to be protective
(27). However, many other studies demonstrated RF to
be protective against the development of lupus nephritis.
In one study, a highly significant correlation between the
presence of IgM-RF and the absence of kidney disease
was noted (28). In that same study, elevated levels of
IgG-RF indicated active SLE disease, suggesting that
there is the potential for various RF isotypes to interact
differently with immune complexes in vitro and in vivo.
In another study, it was shown that IgM-RF could
block attachment of C3b, which is capable of reacting
with glomeruli receptors, indicating that IgM-RF can
inhibit binding of immune complexes to human glomer-
uli (29). This in vitro phenomenon may represent a
possible protective mechanism of RF in vivo in immune
complex diseases. Furthermore, it was shown that the
presence of only IgA-RF defined a subgroup of SLE
patients in whom high disease activity, but a lower
incidence of SLE nephropathy, was present (30). It is
speculated that immune complexes are enlarged by the
presence of RF and are therefore more efficiently
phagocytosed, or cannot penetrate the glomerular basement membrane, thereby decreasing their nephritogenic
An interesting negative association between
IgG-RF and IgG–anticardiolipin (aCL) antibodies has
been reported, suggesting that the presence of IgG-RF
in SLE may lower the risk of developing the clinical
manifestations of the antiphospholipid syndrome (APS)
(31). Further confirmatory studies are needed to establish the above observations.
Protective anticytokine antibodies. Anticytokine
antibodies have been shown to play an important role in
the regulation of the immune response, both under
normal conditions and in several autoimmune disorders.
It has recently been demonstrated that the immune
system, which can attack self components, also generates
beneficial autoimmunity against proinflammatory mediators. A well-defined model of RA was used to elaborate
the contribution of beneficial autoimmunity to the regulation of the disease, demonstrating that during the
disease, autoantibody production is elicited against a few
inflammatory, but not regulatory, mediators. Epitope
mapping has revealed that anti–tumor necrosis factor ␣
(anti-TNF␣) immunity is highly restricted and shows no
cross-reactivity to other known gene products (32).
The occurrence and clinical significance of natural neutralizing antibodies against interferons (IFNs)
has been investigated in patients with myasthenia gravis
(MG). Natural antibodies against any of the IFNs were
not detected in healthy subjects, whereas 21% of patients with MG had natural antibodies against IFN␣ and
9% had natural antibodies against IFN␤ (33). The role
of these natural antibodies in MG needs to be further
Protective anti–T cell receptor (anti-TCR) antibodies. The nonresponsiveness of T cells to self antigens
is controlled by several mechanisms, including clonal
deletion, T cell ignorance, and existence of specific
regulatory T cells. Anti-TCR antibodies may constitute
another significant level of regulation, but their occurrence and regulatory role have been poorly investigated.
Natural autoantibodies specific for the TCR are produced spontaneously at low levels in some healthy
human sera, and at higher levels in patients with RA and
SLE (34).
There are also variations in isotype and in the
particular variable region that is recognized. IgM autoantibodies directed against a few peptide-defined determinants were elevated in RA, whereas SLE patients’
sera showed higher IgG binding to a broad spectrum of
TCR peptides. Naturally occurring, circulating regulatory anti-TCR antibodies have also been detected in
patients with MG (35). These antibodies were reactive
against a dominant T cell population expressing the
V␤5.1 TCR gene, which is responsible for the production
of the pathogenic anti–acetylcholine receptor antibodies
in HLA–DR3–positive patients with early-onset MG.
Anti-TCR antibodies specifically bound the native TCR
on intact V␤5.1-expressing cells and specifically inhibited
the proliferation and IFN␥ production of purified
V␤5.1-expressing cells to alloantigens in the mixed lymphocyte reaction, indicating regulatory functions for
these antibodies. The occurrence of anti-TCR antibodies has been associated with less severe disease, but the
effects are not sufficient to prevent a chronic exacerbated autoimmune process.
Protective autoantibodies in atherosclerosis.
Anti-oxLDL antibodies. Atherosclerosis is a chronic inflammatory disease whose pathogenesis involves disrupted lipoprotein metabolism and the formation of
proinflammatory lipid perioxidation products. The oxidation of LDL generates a variety of oxidatively modified lipids and proteins that represent highly immunogenic neodeterminants of the immune system (36). In
murine models of atherosclerosis, such as apolipoprotein E–deficient (ApoE⫺/⫺) mice, atherosclerosis is correlated with the development of high titers of autoantibodies to various oxidation-specific neoepitopes of
oxLDL (37). IgG-oxLDL immune complexes facilitate
increased uptake of oxLDL via Fc␥ receptors on macrophages, the formation of foam cells, and the release of
IFN␥ and TNF␣, thus contributing to endothelial cell
dysfunction and the development of atherosclerosis
(38,39). In contrast, IgM anti-oxLDL antibodies were
suggested, in many studies, to play a protective role
against the development of atherosclerosis.
In ApoE⫺/⫺ mice, a panel of oxLDL-specific B
cell lines that secrete IgM antibodies were defined as
natural autoantibodies with a protective role against
atherosclerosis (40). All were IgM antibodies that bound
strongly to malondialdehyde (MDA)–modified LDL or
to LDL previously oxidized by exposure to copper.
These antibodies have been shown to bind to the
phosphorylcholine (PC) head group of oxidized phos-
pholipids (oxPLs) and to be structurally and functionally
identical to the natural T15/EO6 IgM anti-PC antibodies
(of B-1 cell origin and reported to provide optimal
protection from virulent pneumococcal infection) (41).
Immunization of mice with MDA-modified LDL induced the expansion of innate B-1 cells and the secretion
of IgM antibodies that bind the PC of oxPLs, thus
reducing atherogenesis (42).
Anti-oxLDL antibodies have been shown to be
inversely related to intima-media thickening (IMT) of
the carotid arteries when studied in a healthy population
with no clinical signs of atherosclerosis (43). In a
population-based cohort of 1,022 middle-age men and
women, the relationship between different isotypes of
autoantibodies to copper-oxidized LDL and MDAmodified LDL and the development of carotid artery
IMT was investigated (44). Circulating IgM autoantibodies to MDA-modified LDL had a stronger, inverse
correlation with subclinical atherosclerosis (determined
by IMT of the carotid artery) than that of autoantibodies
to copper-oxidized LDL.
In a recent study, a significant inverse correlation
between the presence of anti-oxLDL autoantibodies and
the degree of LDL or LDL oxidation was demonstrated
(45), suggesting that the increase in anti-oxLDL antibodies and the extent of the LDL oxidation ratio is protective against atherosclerosis. The findings are indeed
conflicting, since some anti-oxLDL autoantibodies seem
to be protective, whereas many others are found to be
correlated with the extent of atherosclerosis; thus, antioxLDL can be characterized as either predictive or
pathogenic. This contradiction is explained by the possibility that there are, in fact, at least 2 different types of
antibodies produced in vivo. One is a protective antibody that is induced by active immunization and is able
to clear oxLDL cholesterol from the circulation, whereas
the other types of antibody are pathogenic and play a
role in the formation of foam cells. This could be due to
the heterogeneous nature of these antibodies, which
differ both in Ig subclass and in their epitope specificity
and affinity (46).
A number of protective mechanisms of IgM
anti-oxLDL antibodies have been proposed. 1) Natural
IgM antibodies can inhibit the scavenger receptor–
mediated binding and uptake of oxLDL by macrophages
in a dose-dependent manner. 2) The ability of apoptotic
cells and blebs to induce monocyte adhesion by endothelial cells was inhibited by protective IgM anti-oxLDL
antibodies, indicating that apoptotic and oxidized membrane blebs contain the same biologically active oxPLs
present in oxLDL (47). By binding to these proathero-
Figure 2. Protective role of anti–oxidized low-density lipoprotein
(anti-oxLDL) antibodies (Abs) against atherosclerosis. A, Uptake of
oxLDL by phagocytes increases the formation of foam cells and
atherosclerotic plaques. B, Protective IgM anti-oxLDL antibodies bind
oxidation-specific epitopes on apoptotic cells, preventing their uptake
by macrophages and decreasing the formation of foam cells.
genic epitopes, natural IgM antibodies promote their
clearance away from vascular sites to distant sites, such
as the spleen. 3) Anti-oxLDL antibodies may retain
potentially proatherogenic oxLDL particles that are
largely intravascular, which prevents their interaction
with the vessel wall (Figure 2).
Interleukin-5 (IL-5). IL-5 has been shown to be
stimulatory on innate B-1 cells, leading to increased
secretion of T15/EO6 IgM antibodies, whereas IL-5
deficiency leads to decreased titers of these antibodies
and accelerated atherosclerosis. Thus, IL-5 links adaptive and natural immunity specifically to epitopes of
oxLDL and protects from atherosclerosis, in part by the
expansion of atheroprotective natural IgM antibodies
specific for oxLDL (48). Naturally occurring antibodies
to cholesterol in normal human plasma also contribute
to turnover of LDL cholesterol by opsonizing LDL and
other lipoproteins containing bad cholesterol, thus enabling removal by complement receptors (49).
Antiphospholipid antibodies (aPL). Patients with
APS are at a higher risk of developing atherosclerosis,
and individuals with primary atherosclerosis have an
increased prevalence of both aPL and anti-oxLDL (50).
Several studies indicate that some aPL can cross-react
with oxLDL, indicating that similar antigenic determinants can be created by the oxidation of PLs and LDLs.
It has been assumed that aPL, similar to antioxLDL, may play a protective role against atherosclerosis. To further investigate this theory, the CL-reactive
mAb FB1 was obtained from an (NZW ⫻ BXSB)F1
mouse (a strain with features of SLE and APS) and
passively administered to atherosclerosis-prone mice
(51). The antibody was found to cross-react with both
native LDL and oxLDL and significantly reduced plaque
formation in these mice, indicating that some aPL may
play a protective role in atherogenesis. In addition to its
possible effect on cleaning oxLDL from the circulation
and preventing its uptake by macrophages, it has been
proposed that the FB1 mAb could modify lipoproteins
and inhibit expression of adhesion molecules in the
aortic vasa vasorum. In addition, the presence of aPL
that cross-react with oxLDL immune complexes can
crosslink Fc receptors on macrophages and induce IL-10
production, a protective factor against atherosclerosis
Protective autoimmunity as a future therapy
Among the many immunomodulatory therapeutic regimens in autoimmune diseases, high-dose intravenous immunoglobulin (IVIG) has been shown to be
beneficial, without being immunosuppressive or toxic
(53). IVIG contains a wide range of natural autoantibodies that reflect the exposure of the donor population
to different immunopathogens. These natural autoantibodies are directed against the constant heavy- and
light-chain domains of autoantibodies. Natural antiidiotype autoantibodies may also bind to variable regions of
antigen receptors, rendering cell activation by autoantigens impossible (54). Natural anti–hinge region autoantibodies may also block autoreactive B cell proliferation,
especially when autoantigen is bound to the B cell
antigen receptor (55) (Figure 3).
Natural anti-CD4 and anti–class I major histocompatibility complex autoantibodies have been
affinity-purified from IVIG preparations, inhibiting
CD4 T cell proliferation in a mixed lymphocyte culture
and hindering the function of CD8 T cells. These data
suggest that IVIG might modulate T cell–mediated
autoimmune diseases (56). IVIG has been shown to
contain agonistic anti–Fas receptor autoantibodies that
mediate antiinflammatory effects by inducing apoptosis
of inflammatory cells such as activated CD4⫹ T cells
and autoreactive B cells. Natural antiidiotype autoantibodies were also found to block Fas ligand–Fas receptor
interactions, thus preventing apoptosis of some immunomodulatory cells. Therefore, both mechanisms are
relevant in IVIG-induced immunomodulation in SLE
In order to evaluate the clinical response of SLE
patients to IVIG, 20 patients were treated with highdose (2 gm/kg) IVIG monthly, in a 5-day schedule for
Figure 3. Protective role of natural autoantibodies in intravenous
immunoglobulin (IVIG). A, Natural autoantibodies in IVIG prevent
autoimmunity by binding apoptotic cells and increasing their efficient
phagocytosis. B, Natural antibodies may bind self antigens expressed in
blebs on apoptotic cells and prevent their recognition by autoreactive
cells. C, Natural autoantibodies have also been shown to downregulate autoreactive B cells, especially when autoantigens are bound
to the B cell antigen receptor. Color figure can be viewed in the online
issue, which is available at
1–8 treatment courses (58). A beneficial clinical response was seen in 17 of 20 patients (85%). Mainly
manifestations such as arthritis, fever, thrombocytopenia, and neuropsychiatric lupus responded to the treatment. Responders tended to have a significant normalization of their abnormal C4 and anti-SSA/Ro antibody
levels following IVIG treatment. Assuming that the
idiotype network is an important mechanism for maintaining self tolerance, we investigated the effects of
modulation by antiidiotype antibodies by using concentrated, specific natural polyclonal anti-dsDNA antiidiotype antibodies (IVIG-Id) that were obtained from
commercial IVIG in (NZB ⫻ NZW)F1 mice (59). The
IVIG-Id–treated mice showed a decline in the titer of
anti-dsDNA antibodies during the treatment. Improvement in the renal immunohistologic condition was significant and the survival time was much longer in the
IVIG-Id–treated mice compared with controls (59).
The protective role of IgM anti-dsDNA antibodies in ameliorating renal involvement in murine lupus
and the protective effects of the naturally existing antibodies to proinflammatory cytokines support the idea
that natural autoantibodies could become one of the
future therapies in several autoimmune diseases. These
antibodies could be boosted either by specific immuni-
zation or by utilizing hybridoma techniques with selection for specific protective IgM antibodies. As we have
discussed, there is the potential to harness this knowledge for therapeutic purposes, utilizing active immunization with the relevant autoantigens as a means to
stimulate the immune therapeutic response (e.g., active
immunization with oxLDL to protect against atherosclerosis) or utilizing passive transfer of protective antibodies (e.g., IVIG or specific protective autoantibodies such
as IgM anti-dsDNA, aCL, and anti-TCR) (60,61). Defining the characteristics of these protective autoantibodies and the conditions of their generation brings us
closer to the potential for prevention of autoimmune
diseases such as RA and SLE.
1. Nevo U, Kipnis J, Golding I, Shaked I, Neumann A, Akselrod S,
Schwartz M. Autoimmunity as a special case of immunity: aiding
to remove threats from within. Trends Mol Med 2003;9:88–93.
2. Schori H, Yoles E, Schwartz M. T-cell-based immunity counteracts the potential toxicity of glutamate in the central nervous
system. J Neuroimmunol 2001;119:199–204.
3. Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A, et
al. Protective autoimmunity is a physiological response to CNS
trauma [published erratum in J Neurosci 2001;21:1A]. J Neurosci
4. Kipnis J, Mizrahi T, Yoles E, Ben-Nun A, Schwartz M, Ben-Nur
A. Myelin specific Th1 cells are necessary for post-traumatic
protective autoimmunity. J Neuroimmunol 2002;130:78–85.
5. Shaked I, Portal Z, Gersner R, Kipnis J, Schwartz M. Early
activation of microglia as antigen-presenting cells correlates with T
cell-mediated protection and repair of the injured central nervous
system. J Neuroimmunol 2004;146:84–93.
6. Schwartz M, Kipnis J. Autoimmunity on alert: naturally occurring
regulatory CD4⫹CD25⫹ T cells as part of the evolutionary
compromise between a “need” and a “risk.” Trends Immunol
7. Shoenfeld Y, Isenberg DA. Natural autoimmunity. In: The mosaic
of autoimmunity. Amsterdam: Elsevier; 1989. p. 53–74.
8. Boes M. Role of natural and immune IgM antibodies in immune
responses. Mol Immunol 2000;37:1141–9.
9. Stahl D, Sibrowski W. Regulation of the immune response by
natural IgM: lessons from warm autoimmune hemolytic anemia.
Curr Pharm Des 2003;9:1871–80.
10. Oppezzo P, Dighiero G. Autoantibodies, tolerance and autoimmunity. Pathol Biol (Paris) 2003;51:297–304.
11. Graber P. The “globulines-transporteurs” theory and autosensitization. Med Hypotheses 1975;5:172–5.
12. Hinter H, Romani N, Stanzl U, Grubauer G, Fritsch P, Lawley TJ.
Phagocytosis of keratin filament aggregates following opsonization
with IgG anti-keratin antibodies. J Invest Dermatol 1987;88:
13. Boes M, Schmidt T, Linkemann K, Beaudette BC, MarshakRothstein A, Chen J. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM.
Proc Natl Acad Sci U S A 2000;97:1184–9.
14. Varambally S, Bar-Dayan Y, Bayry J, Lacroix-Desmazes S, Horn
M, Sorel M, et al. Natural human polyreactive IgM induce
apoptosis of lymphoid cell lines and human peripheral blood
mononuclear cells. Int Immunol 2004;16:517–24.
15. Melero J, Tarrago D, Nunez-Roldan A, Sanchez B. Human
polyreactive IgM monoclonal antibodies with blocking activity
against self-reactive IgG. Scand J Immunol 1997;45:393–400.
Vakil M, Kearney JF. Functional characterization of monoclonal
auto-anti-idiotypic antibodies isolated from the early B cell repertoire of BALB/c mice. Eur J Immunol 1986;16:1151–8.
Mockridge CI, Rahman A, Bacham S, Hamblin T, Isenberg DA,
Stevenson FK, et al. Common patterns of B cell perturbation and
expanded V4-34 immunoglobulin gene usage in autoimmunity and
infection. Autoimmunity 2004;37:9–15.
Kohler H, Bayry J, Nicoletti A, Kaveri SV. Natural autoantibodies
as tools to predict the outcome of immune response? Scand
J Immunol 2003;58:285–9.
Mathov I, Plotkin LI, Squiquera L, Fossati CA, Margni RA, Leoni
J. N-glycanase treatment of F(ab⬘)2 derived from asymmetric
murine IgG3 mAb determines the acquisition of precipitating
activity. Mol Immunol 1995;32:1123–30.
Canellada A, Gentile T, Dokmetjian J, Margni RA. Occurrence
properties and function of asymmetric IgG molecules isolated
from non-immune sera. Immunol Invest 2002;31:107–20.
Margni RA, Malan Borel I. Paradoxical behavior of asymmetric
IgG antibodies. Immunol Rev 1998;163:77–87.
Hahn BH. Antibodies to DNA. N Engl J Med 1998;338:1359–68.
Bootsma H, Spronk PE, Hummel EJ, de Boer G, ter Borg EJ,
Limburg PC, et al. Anti-dsDNA antibodies in SLE: detection and
clinical relevance of IgM-class antibodies. Scand J Rheumatol
Witte T, Hartung K, Sachse C, Matthias T, Fricke M, Deicher H,
et al, and the SLE Study Group. IgM anti-dsDNA antibodies in
SLE: negative association with nephritis. Rheumatol Int 1998;18:
Forger F, Matthias T, Oppermann M, Becker H, Helmke K.
Clinical significance of anti-ds DNA antibody isotypes: IgG/IgM
ratio of anti-dsDNA antibodies as a prognostic marker for lupus
nephritis. Lupus 2004;13:36–44.
Werwitzke S, Trick D, Kamino K, Matthias T, Kniesch K,
Schlegelberger B. Treatment of murine SLE with IgM antidsDNA autoantibodies: from animal models to human genetics.
In: Conrad K, Bachman P, Chan EK, Fritzler MJ, Humbel RL,
Shoenfeld Y, editors. Research on the induction and pathogenicity
of autoantibodies. Berlin: PABST Science Publ; 2004. p. 107–9.
Turner-Stokes L, Jones M, Addison I, Mansell M, Isenberg D.
Does rheumatoid factor protect lupus patients from the development of nephritis? Ann Rheum Dis 1989;48:14–6.
Tarkowski A, Westberg G. Rheumatoid factor isotypes and renal
disease in SLE. Scand J Rheumatol 1987;16:309–12.
Bolton WK, Schrock JH, Davis JS IV. Rheumatoid factor inhibition of in vitro binding of IgG complex in the human glomerulus.
Arthritis Rheum 1982;25:297–303.
Witte T, Hartung K, Sachse C, Matthias T, Fricke M, Kalden JR,
et al, and the SLE Study Group. Rheumatoid factor in SLE:
association with clinical and laboratory parameters. Rheumatol Int
Spadaro A, Riccieri V, Terracina S, Rinaldi T, Taccari E, Zoppini
A. Class specific rheumatoid factor and antiphospholipid syndrome in SLE. Lupus 2000;9:56–60.
Wildbaum G, Nahir MA, Karin N. Beneficial autoimmunity to
proinflammatory mediators restrains the consequences of selfdestructive immunity. Immunity 2003;19:679–88.
Bagnato F, Clemenzi A, Scagnolari C, Strizzi L, di Pasquale A,
Bellomi F, et al. Neutralizing antibodies against endogenous
interferon in myasthenia gravis patients. Eur Cytokine Netw
Robey IF, Schluter SF, Akporiaye E, Yocum DE, Marchalonis JJ.
Human monoclonal natural autoantibodies against the T-cell
receptor inhibit interleukin-2 production in murine T cells. Immunology 2002;105:419–29.
Jambou F, Zhang W, Menestrier M, Klingel-Schmitt I, Michel O,
Caillat-Zucman S, et al. Circulating regulatory anti-T cell receptor
antibodies in patients with myasthenia gravis. J Clin Invest 2003;
Palinski W, Horkko S, Miller E, Steinbrecher UP, Powell HC,
Curtiss LK, et al. Cloning of monoclonal autoantibodies to
epitopes of oxidized lipoproteins from apolipoprotein E-deficient
mice: demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest 1996;98:800–14.
Shoenfeld Y, Harats D, Wick G, editors. Atherosclerosis and
autoimmunity. Amsterdam: Elsevier; 2001. p. 1–370.
Khoo JC, Miller E, Pio F, Steinberg D, Witztum JL. Monoclonal
antibodies against LDL further enhance macrophage uptake of
LDL aggregates. Arterioscler Thromb 1992;12:1258–60.
Vonder Thusen JH, Kniper J, van Berkel TJ, Diessen EA.
Interleukins in atherosclerosis: molecular pathways and therapeutic potential. Pharmacol Rev 2003;55:133–66.
Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Wiztum
JL. ApoE-deficient mice are a model of lipoprotein oxidation in
atherogenesis: demonstration of oxidation-specific epitopes in
lesion and high titers of autoantibodies to malondialdehyde-lysine
in serum. Arterioscler Thromb 1994;14:605–16.
Shaw PX, Horkko S, Chang MK, Curtiss LK, Palinski W, Silverman GJ, et al. Natural antibodies with the T15 idiotype may act in
atherosclerosis, apoptotic clearance, and protective immunity.
J Clin Invest 2000;105:1731–40.
George J, Afek A, Gilburd B, Levkovitz H, Shaish A, Goldberg I,
et al. Hyperimmunization of apo-E-deficient mice with homologous malondialdehyde LDL suppresses early atherogenesis. Atherosclerosis 1998;138:147–52.
Fukumoto M, Shoji T, Emoto M, Kawagishi T, Okuno Y, Nishizawa Y. Antibodies against ox-LDL and carotid artery intimamedia thickness in a healthy population. Atheroscler Thromb Vasc
Biol 2000;20:703–7.
Karvonen J, Paivansalo M, Kesaniemi YA, Horkko S. Immunoglobulin M type of autoantibodies to ox-LDL has an inverse
relation to carotid artery atherosclerosis. Circulation 2003;108:
Brizzi P, Tonolo G, Bertrand G, Carusillo F, Severino C, Maioli
M, et al. Auto-antibodies against ox-LDL and LDL oxidation
status. Clin Chem Lab Med 2004;42:164–70.
Shoenfeld Y, Wu R, Dearing L, Matsuura E. Are anti-oxidized
low-density lipoprotein antibodies pathogenic or protective? Circulation 2004;110:2552–8.
Chang MK, Bergmark C, Laurila A, Horkko S, Han KH, Friedman
P, et al. Monoclonal antibodies against oxLDL bind to apoptotic
cells and inhibit their phagocytosis by elicited macrophages:
evidence that oxidation-specific epitopes mediate macrophage
recognition. Proc Natl Acad Sci U S A 1999;96:6353–8.
48. Binder CJ, Hartvigsen K, Chang MK, Miller M, Broide D, Palinski
W, et al. IL-5 links adaptive and natural immunity specific for
epitopes of oxLDL and protects from atherosclerosis. J Clin Invest
49. Alving CR, Wassef N. Naturally occurring antibodies to cholesterol: a new theory of LDL cholesterol metabolism. Immunol
Today 1999;20:362–6.
50. Sherer Y, Shoenfeld Y. Antiphospholipid antibodies: are they
pro-atherogenic or an epiphenomenon of atherosclerosis? Immunobiology 2003;207:13–6.
51. Nicolo D, Goldman BI, Monestier M. Reduction of atherosclerosis in low-density lipoprotein receptor–deficient mice by passive
administration of antiphospholipid antibody. Arthritis Rheum
52. Nicolo D, Monestier M. Antiphospholipid antibodies and atherosclerosis. Clin Immunol 2004;112:183–9.
53. Lane C, Leitch J, Tan X, Hadjati J, Bramson JL, Wan Y.
Vaccination-induced autoimmune vitiligo is a consequence of
secondary trauma to the skin. Cancer Res 2004;64:1509–14.
54. Lacroix-Desmazes S, Mouthon L, Spalter SH, Kaveri S, Kazatchkine MD. Immunoglobulins and the regulation of autoimmunity
through the immune network [review]. Clin Exp Rheumatol
1996;14 Suppl 1:S9–15.
55. Coggeshall KM. Inhibitory signaling by B cell Fc␥RIIb. Curr Opin
Immunol 1998;10:306–12.
56. Bayry J, Misra N, Latry V, Prost F, Delignat S, Lacroix-Desmazes
S, et al. Mechanisms of action of intravenous immunoglobulin in
autoimmune and inflammatory diseases [review]. Transfus Clin
Biol 2003;10:165–9.
57. Altznauer F, von Gunter S, Spath P, Simon HU. Concurrent
presence of agonistic and antagonistic anti-CD95 auto-Abs in IVIg
preparations. J Allergy Clin Immunol 2003;112:1185–90.
58. Levy Y, Sherer Y, Ahmed A, Langevitz P, George J, Fabbrizzi F,
et al. A study of 20 SLE patients with IVIG: clinical and serological
response. Lupus 1999;8:705–12.
59. Shoenfeld Y, Rauva L, Gilburd B, Kvapil F, Goldberg I, Koplovic
J, et al. Efficacy of IVIG affinity-purified anti-dsDNA antiidiotypic antibodies in the treatment of an experimental murine
model of SLE. Int Immunol 2002;14:1303–11.
60. Krause I, Blank M, Levi I, Koike T, Barak V, Shoenfeld Y.
Anti-idiotype immunomodulation of experimental antiphospholipid syndrome via effect on Th1/Th2 expression. Clin Exp
Immunol 1999;117:190–7.
61. Wu R, Shoenfeld Y, Sherer Y, Patnaik M, Matsuura E, Gilburd B,
et al. Anti-idiotypes to oxidized LDL antibodies in intravenous
immunoglobulin preparations: possible immunomodulation of
atherosclerosis. Autoimmunity 2003;36:91–7.
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potential, clinical, protection, therapeutic, autoantibodiesrole, importance, homeostasis
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