Systemic Lupus Erythematosus

224 Pages·1995·14.55 MB·English

by  Professor Dr. Peter A. Miescher (auth.), Professor Dr. Peter A. Miescher (eds.)

Springer-Verlag Berlin Heidelberg New York
London Paris Tokyo HongKong
Peter A. Miescher (Ed.)
Systemic Lupus
Erythematosus
With 21 Figures and 24 Tables
Springer
Professor Dr. Peter A. Miescher
Division d'Hematologie
Centre de Transfusion Sanguine
Hopital Cantonal Universitaire
25, rue Micheli-du-Crest
CH-1211 Geneva 4, Switzerland
ISBN-13: 978-3-642-79624-1 e-ISBN: 978-3-642-79622-7
DOT: 10.1007/978-3-642-79622-7
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Contents
Introduction
P. A. Miescher . .... .... .... ........ .... .... .... .... .... ........ ........ .... .... .... .... .... .... ........ .... .... .... .... ... 1
Mechanisms of genetic control of murine systemic lupus erythematosus
S. Izui, R. Merino, M. Iwamoto, L. Fossati ............................................................... 3
The role of cytokines in the immunopathogenesis of lupus
B. S. Handwerger, V. Rus, L. daSilva, C. S. Via ..................................................... 23
The cytokine network in the pathogenesis of systemic lupus erythematosus
and possible therapeutic implications
D. A. Horwitz, C. O. Jacob ....................................................................................... 51
Antibodies to CD45 and other cell membrane antigens in systemic lupus
erythematosus
J. B. Winfield, P. Fernsten, J. Czyzyk, E. Wang, J. MarchaIonis ............................. 71
Antigenic specificities of "antiphospholipid" autoantibodies
R. A. S. Roubey .......................................................................................................... 81
Antiphospholipid antibodies and the antiphospholipid syndrome
E. N.Harries, S. S. Pierangeli .................................................................................... 93
Lupus pregnancies and neonatal lupus
M. D. Lockshin ........................................................................................................ 117
Systemic lupus erythematosus in children
A. M. Rosenberg ...................................................................................................... 131
Systemic lupus erythematosus - disease management
M. F. Gourley ........................................................................................................... 151
Contents VI
Drug combination therapy of systemic lupus erythematosus
P. A. Miescher, H. Favre, R. Lemoine, Y.-P. Huang .............................................. 165
Central nervous system involvement in systemic lupus erythematosus:
a new therapeutic approach with intrathecal dexamethasone
and methotrexate
G. Valesini, R. Priori, A. Francia, G. Balestrieri, A. Tincani, P. Airo,
R. Cattaneo, A. Zambruni, B. Troianello, M. Chofflon, P. A. Miescher ................ 183
Extracorporeal photochemotherapy for the treatment of lupus erythematosus:
preliminary observations
R. M. Knobler .......................................................................................................... 193
Immunological intervention reveals reciprocal roles for tumor necrosis factor-a
and interleukin-l0 in rheumatoid arthritis and systemic lupus erythematosus
R. N. Maini, M. J. Elliott, P. J. Charles, M. Feldmann ........................................... 197
Prognosis in systemic lupus erythematosus
J. M. Esdaile ............................................................................................................. 207
Introduction
Peter A. Miescher
Division d'Hematologie, Centre de Transfusion Sanguine, Hopital Cantonal Universitaire,
25, rue Micheli-du-Crest, CH-1211 Geneve 4, Suisse
During the past 50 years, systemic lupus erythematosus (SLE) has been the main
subject in the field of immunopathology. Each individual discovery was followed by
the discovery of a multitude of related immune phenomena. Thus, the false-positive
VDR reaction opened the door to additional antibodies leading to the concept of the
anti-phospholipid syndrome. The demonstration of anti-nuclear antibodies led to the
discovery of a cascade of antibodies against various constituents of the cell nucleus.
Today's concept of a genetic predisposition emerged with the discovery of the H2
system in mice by Snell and subsequently of the immune response genes by Benacerraf
and McDevitt.
This book reflects the present status of our understanding of this protean dis-
ease. Izui covers the various animal models which clearly show that different gene
combinations can lead to the final clinical expression of SLE, with HLA class II
genes probably responsible for the targeting of the autoimmune response. Similarly,
research on cytokines in SLE patients has shown that SLE is a syndrome depending
on different pathways. Handwerger stresses the possible co-involvement of lympho-
cyte tropic viruses which may lead, depending on the genetic predisposition, to the
clinical picture of SLE. Horwitz describes different cytokine constellations depending
on whether we are dealing with the initiation or perpetuation of autoimmunity. We,
thus, are no longer focusing on single cytokines but rather on the entire cytokine
network.
Apoptosis may play an important role in the initiation process. Furthermore, ge-
netically based alterations of cell metabolism may also be of importance, stressing
the participation of non-immune parameters in the genetic predisposition to SLE.
Antibodies to cell membrane antigens are a frequent finding in SLE. Autoimmune
haemolytic anaemia and severe thrombocytopenia are readily acknowledged as being
due to the respective antibodies against cell membrane antigens. More complex are
the cold reacting antibodies against CD45 and other lymphocyte membrane antigens,
a subject which is well covered by Winfield and associates. Are these antibodies
a consequence of SLE or are they directly implicated in the lymphopenia or other
pathological events? Or do they represent a physiogenetic attempt by the immune
system to restore homeostasis in response to aggressive autoimmune stimulation?
2 P.A. Miescher
Anti-phospholipid antibodies discussed in the chapters by Roubey and Harris represent
another hot subject in lupus research. Do these antibodies cause thrombosis, CNS
damage and thrombocytopenia, etc., or are they a consequence of an autoaggression
against various endothelial targets? With regard to pregnancy, they certainly appear
to be directly involved in miscarriage. Whatever the mechanism, the physician has to
offer help to his patients. In the case of serious problems of deep vein thrombosis, life-
long anti-coagulation becomes mandatory whether or not antiphospholipid antibodies
are present. The same measures are necessary for the treatment of haemorrhagic
processes within the brain. Even after one single cerebral vascular accident, anti-
coagulation becomes advisable since a second serious accident may occur even years
after the first.
Lockshin covers the important subject of lupus pregnancies and neonatal SLE.
Again, with or without antiphospholipid antibodies, ASA is probably advisable for
all patients with SLE to prevent placental infarction. A more complex problem con-
cerns antibodies to RO-SSA and LA-SSP. Neonatal lupus, a rare condition, appears
to be clearly linked to maternal antibodies to these antigenic targets. Rosenberg em-
phasises that a child with SLE presents a special challenge to the physician. Indeed,
the disease activity must be controlled rapidly with as little cortisone as possible. In
our experience, cyclosporin is very helpful in this regard if given in association with
methotrexate and, if necessary, the more toxic cyclophosphamide.
The remaining papers deal with the treatment of patients with SLE. Gourley speaks
of disease management since so many factors have to be taken into consideration in
the attempt to control disease activity while permitting a good quality of life. To try to
reach this goal, my own group has developed a drug combination therapy. With regard
to CNS involvement, Valesini reports on the possibility of offering a local treatment
by intrathecal injection of dexamethasone and methotrexate. Knobler gives a short
summary of extracorporeal photochemotherapy where one hopes that lymphocytes
active in the disease process will preferentially assimilate the photo-sensitive drug
8-methoxypsoralen. It is assumed that subsequent ultraviolet radiation will kill those
lymphocytes which then would serve to immunise patients against the idiotypes of
the pathogenic lymphocyte clones.
Another experimental approach is discussed by Maini. However, while anti-TNF
therapy has been shown to be effective for remission induction in rheumatoid arthritis
(RA), conditions in lupus are different. In particular, in RA we are dealing with a
real concentration of the cells of the immune system which are ready to attack the
putative autoantigen target (collagen II?). In the case of SLE, we do not have such
a concentration; Maini, thus, does not expect anti-TNF to be of much use in the
treatment of lupus.
Finally, the question of prognosis is discussed by Esdaile. Fortunately, with every
passing decade, the prognosis for patients with SLE gets better and better, both with
regard to control of disease activity and quality of life.
Mechanisms of genetic control
of murine systemic lupus erythematosus
Shozo Izui, Ramon Merino, Masahiro Iwamoto, Liliane Fossati
Department of Pathology, Centre Medical Universitaire, University of Geneva, CH-121l Geneva 4, Switzer-
land
Introduction
The pathogenesis of systemic lupus erythematosus (SLE) is a complex process in
which many genetic factors apparently play essential roles in determining the inci-
dence, onset and nature of SLE. The involvement of genetic factors in SLE was
initially suggested by the fact that there is a familial tendency for SLE. Since a num-
ber of different immunopathological manifestations are found in members of the same
family, it is likely that the expression of SLE is controlled by multiple genes and a
number of secondary factors. Although the conclusion from family studies have to
be considered as preliminary, these studies have led to the concept that a special ge-
netic background is necessary for contracting SLE. A sophisticated genetic analysis is
only possible by using animal models of SLE with well-defined genetic backgrounds,
preferably congenic strains of mice differing at defined genetic loci. The availability
of several SLE-prone mice such as (NZB x NZW)FJ, MRL-lprllpr and BXSB with
different genetic backgrounds (reviewed in [112]) offers an invaluable opportunity for
elucidating the mechanisms by which genetic factors participate in the pathogenesis
of SLE. In this article, we will review the current understanding for the role of various
genetic factors and abnormalities involved in different strains of lupus-prone mice.
Multigenic features of murine SLE
Since Helyer and Howie [30] first reported the development of an SLE-like syn-
drome in the FJ progeny of the NZB and NZW strains, the genetic basis for SLE
in (NZB x NZW)FJ hybrids (NZB x W) has been investigated in a number of lab-
oratories. Early genetic studies on New Zealand mice have demonstrated that many
individual autoimmune traits segregate independently of each other in (NZBxW) x
NZW backcross mice [102], in the F2 generation of NZBxW [40] mice and in the
Correspondence to: s. Izui
4 S. Izui et aI.
Table 1. Possible genetic factors involved in murine systemic lupus erythematosus (SLE)
I. Immunoglobulin variable region genes
2. T cell receptor genes
3. MHC class II genes
4. Genes regulating apoptosis
- the Fas apoptosis gene: the lpr mutation
- the gld gene: the Fas ligand
5. The Yaa gene: intercellular adhesion molecule (7)
6. Genes for expression of nephritogenic autoantigens
- genes encoding and/or regulating
the expression of serum retroviral gp70 antigen
7. Genes regulating the immunoglobulin class switching
- genes for cytokines and/or their receptors
- the xid gene: Bruton's tyrosine kinase (?)
lpr, Iymphoproliferation; gld, generalized lymphoproliferative disease; Yaa, Y chromosome-linked autoim-
mune acceleration; xid, X chromosome-linked immunodeficiency
recombinant inbred strains derived from the NZB strain crossed with normal strains
[8, 88]. This suggests that there is no common genetic defect causing overall autoim-
mune responses, but each of the autoimmune traits is under the control of separate
genetic mechanisms, at least in the New Zealand strain. Multiple, unlinked genes
are apparently responsible for the production of a variety of autoantibodies and the
expression of various disease manifestations.
Since the major features of NZBxW autoimmune disease are not present in the
parental strains, genes from each parent most likely act in concert to produce the FI
phenotype. Although the precise nature and number of genes involved in the develop-
ment of SLE remain unclear, several genes have been investigated as candidate genes
to be implicated in SLE in the last decades (Table 1). They include immunoglobulin
(Ig) variable (V) region genes encoding autoantibodies with pathogenic specificity, T
cell receptor genes and the major histocompatibility complex (MHC) genes. In ad-
dition, in view of the complexity of the immune network, there can be a number of
other different kinds of genes, which may play an active role in the regulation of au-
toimmune responses, such as genes for cytokines or their receptors, genes regulating
apoptosis, and genes regulating the expression of nephritogenic autoantigens, etc.
The immunoglobulin variable region genes
In an attempt to gain a better understanding of the genetic ongm of autoantibod-
ies characteristic in SLE, the V gene usage in autoantibodies has been extensively
analyzed to determine whether lupus autoantibodies are encoded by unique Ig gene
segments present in the normal germ-line repertoire, but not expressed in immune
responses against exogenous antigens, and whether the autoantibody response is ge-
netically and structurally restricted. Nucleic acid sequence studies on the V regions of
various autoantibodies derived from lupus-prone mice have clearly demonstrated that
these lupus autoantibodies use the same germ-line repertoire as anti-foreign antibodies
(reviewed in [11, 55]). In addition, it has been shown that autoantibody responses in
lupus-prone mice are quite heterogeneous in terms of V region gene usage, indicating
that a la):ge variety of Ig gene segments are capable of encoding lupus autoantibod-
ies. All these results strongly argue against the idea that spontaneous development of
autoantibodies in lupus-prone mice is related to the abnormality in the Ig V region
genes.
Mechanisms of genetic control of murine systemic lupus erythematosus 5
The T cell receptor genes
Based on the fact that the NZW strain contributes to the switch from IgM autoantibod-
ies (an NZB trait) to IgG autoantibodies in NZBxW mice [56], which is dependent on
the presence of CD4+ T cells [99, 121], it is conceivable that the influence of the NZW
strain can be on the T cell function. The analysis of the T cell receptor (TCR) gene
complex has revealed an unusual TCR ,8-chain allele in NZW mice, characterized by
the deletion of C/31, D/32 and J/32 gene segments [57, 81]. An attractive hypothesis
is that a deletion of these elements could result in the unusual joining of J /31 to C/32,
which may lead to the generation of a harmful autoreactive T cell repertoire. In fact,
studies on (NZBxW) x NZB backcross and TCR congenic NZBxW mice by Shirai
and his co-workers [33, 124] have shown a statistically significant association of the
NZW TCR ,8 chain allele with autoimmune manifestations characteristic of NZBxW
mice. However, two other studies failed to show any association of disease expression
with the presence of the NZW allele in (NZBxW) x NZB backcross mice [58] and in
NZBxW F2 mice [82]. This discrepancy can be in part due to the fact that the effect
of the NZW TCR allele was incomplete in the study by the former group [33, 124].
Nevertheless, it should be stressed that autoreactive T cells responsible for SLE are
apparently well developed in T cells bearing the non-NZW TCR allele in the thymic
microenvironment of the appropriate autoimmune genetic background, as observed in
NZB mice carrying the H_2bm12 haplotype [13] as well as in two other SLE strains
of mice (MRL and BXSB). Apparently, the NZW TCR ,8-chain deletion is not an
indispensable genetic defect for the development of typical murine SLE.
The demonstrations that specific TCR V /3 genes are required for responses to
certain autoantigens in the case of experimental allergic encephalomyelitis, collagen-
induced arthritis and insulin-dependent diabetes (reviewed in [2]) have prompted the
exploration of a possible association of particular TCR V /3 gene(s) with SLE. Relative
over-representation of T cells expressing TCR V /38 family genes has been reported
in MRL-Iprllpr mice [28, 98, 103]. Furthermore, it has been claimed that the V /38 T
cells may playa critical role in the development of a lupus-like syndrome in MRL-
lprllpr mice, since the selective diminution of V /38+ T cells by treating them with
either staphylococcal enterotoxin B (SEB) or anti-V /38 monoclonal antibody resulted
in an inhibition of autoimmune disease in MRL-Iprllpr mice [18, 52]. However, the
interpretation of these results should be cautious, since repeated injections of SEB
or anti-V /38 monoclonal antibody could lead to a persistent activation of T cells,
resulting in a massive production of cytokines such as tumor necrosis factor-a (TNF-
a). This would cause a profound effect on the immune system, thereby preventing
the excessive stimulation of autoimmune responses. In fact, repeated injections of
recombinant TNF-a have been shown to delay the development of SLE in NZBxW
mice [45] and of autoimmune diabetes in non-obese diabetic (NOD) mice [48, 95].
Further experiments are awaited to clarify to what extent the V /38+ T cells indeed
contribute to the development of lupus-like autoimmune syndrome in MRL-lpr/lpr
mice. It should be mentioned, however, that the development of a severe form of
SLE in (NZB x BXSB)FI hybrid mice despite clonal deletion of V /38+ T cells due
to the expression of endogenous superantigens strongly argues against the idea that
V /38+T cells are an essential element for the development of autoimmune responses
in murine SLE.