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Natural history of murine lupus. Modulation by sex hormones

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NATURAL HISTORY OF MURINE LUPUS
MODULATION BY SEX HORMONES
NORMAN TALAL
Pathologic and immunologic features of the spontaneous autoimmune disease of NZB and NZB/NZW F,
(B/W) mice resemble human SLE in three major respects: formation of antibodies to nucleic acids, deposition
of immune complexes containing DNA in the kidney, and
earlier onset of severe disease in females. Genetic, viral,
and hormonal factors are involved in a pathogenetic mechanism that is manifest primarily as a disturbance in immunologic regulation. Recent studies on the sequential development of IgM and then IgC antibodies to DNA and RNA
suggest that the thymus, spleen, and gonads exert important regulatory influences. We have found that sex hormones modulate the expression of autoimmunity in B/W
mice, with androgens suppressing and estrogens accelerating disease. The hormones may act by restoring immunologic control.
Animal models for human illness provide an unusual opportunity to study preclinical disease that is
only rarely possible in human medicine. Such studies
can lead to valuable insights into pathogenetic mechanisms underlying early events in disease and offer the
hope of finding more specific and effective modes of
prophylaxis or therapy.
There are now several animal models for human
lupus, including a new mouse strain called MRL, and a
Supported by the Medical Research Service of the Veterans
Administration and by USPHS Grant AM16140.
Norman Talal, M.D.: Professor of Medicine, University of
California, Chief, Clinical Immunology and Arthritis Section, Veterans Administration Hospital, 41 50 Clement Street, San Francisco,
California 94121.
Address reprint requests to Dr. Talal.
Arthritis and Rheumatism, Vol. 21, No. 5 Supplement (June 1978)
lupus-like illness in dogs. The best known and most
widely studied animal model for lupus is the NZB/
NZW F, (B/W) mouse, a hybrid of NZB and NZW.
This mouse spontaneously develops an autoimmune disease that resembles the human disorder in three major
respects: 1) the formation of antibodies to nucleic acids,
particularly to double-stranded DNA; 2) the deposition
of DNA-containing immune complexes in the kidney
leading t o renal insufficiency and death; and 3) a sex
factor that is manifest as an earlier onset of disease in
females who generally die before 1 year of age (1).
The parent NZB mouse also develops a spontaneous autoimmune disease characterized predominantly
by Coombs’ positive hemolytic anemia. The parent
NZW mouse is clinically normal for most of its life.
Autoantibodies and mild nephritis appear in aged NZW
mice, as they do in old mice of several normal strains.
Genetic, viral, and immunologic factors are all involved
in the pathogenesis of autoimmunity in the NZB and
B/W strains (2-4).
The various strains of New Zealand mice derive
from random bred animals brought to New Zealand
from Mill Hill over 40 years ago and subsequently bred
for coat color. The genetic predisposition of NZB mice
to develop autoimmune hemolytic anemia was appreciated 20 years ago. Despite fairly extensive genetic analysis in several laboratories, we still lack precise information as to the number of genes involved and how they
might function. NZB mice have the allele H2d. With
regard to experimental antigens under the control of
specific immune response genes, NZB mice make levels
of antibody generally comparable to other H2d strains.
There is evidence for modifying genes. For example, the
NATURAL HISTORY OF MURINE LUPUS
Table 1. Immunologic Abnormalities in N Z B and
Finding
Premature development of immune competence
Excessive antibody responses to many antigens
Relative resistance t o immune tolerance
Impaired cellular immunity
Production of thymocytotoxic antibody
Decreased suppressor function
Decreased thymic humoral factor
B l W Mice
References
73
9-12
9,13,14
8,15,16
17
19-21
22
mating of NZB with nonautoimmune strains often results in suppression of autoimmunity in the F, offspring.
There is a variable expression of autoimmunity in the F2
and backcross mice which is compatible with the action
of modifying genes influencing a dominant pattern of
inheritance.
With regard to viral factors, NZB and B/W mice
contain abundant type C viral particles. High concentrations of gp70, the major envelope glycoprotein of’this
virus, are present in serum and tissues ( 5 ) . Immune
complexes containing gp70 are found in the glomerular
deposits of B/W mice along with the DNA-anti-DNA
immune complexes. The possible role of type C viruses
in normal processes of growth and differentiation, as
well as in autoimmunity and neoplasia, is a subject of
current biological interest (3).
Much evidence suggests that normal mechanisms
of immunologic regulation are disordered in NZB and
B/W mice. Genetic and possibly viral factors may contribute to this regulatory disturbance. Abnormalities of
B cells, T cells, and macrophages, as well as abnormalities of thymic epithelial function, have been described.
Major interest has focused on a loss of suppressor T
cells with consequent escape of autoantibody producing
B-cell clones. A defect of splenic macrophages has been
observed by using in vitro immunization to foreign
erythrocytes.
Our own recent studies on the sequential development of IgM and IgG antibodies to DNA and RNA
suggest that the thymus, spleen, and gonads exert major
regulatory influences (6). In general, these seem to reflect physiologic control mechanisms expressed on aberrant autoantibody responses.
Investigative work on these New Zealand strains
evolved in several phases. The first 10 years (from 19581968) were largely concerned with clinical and experimental pathology and detailed histologic descriptions of
various tissue lesions (1). Studies performed in different
areas of the world indicated a general uniformity of
disease expression. The development of splenomegaly
s59
and hemolytic anemia in the NZB, of LE cells and
immune complex nephritis in the B/W, and of general.
ized lymphoid hyperplasia progressing at times to lymphoid neoplasia in both strains, was well described. Also
documented were the ability of spleen cells from older
Coombs’ positive mice to transfer autoantibody production into young Coombs’ negative syngeneic recipients
and the acceleration of disease that ensued following
neonatal thymectomy.
The next phase of investigation (from 1968 to the
present) was strongly influenced by a rapid burst of new
knowledge in cellular immunology and lymphocyte biology. Experiments were performed measuring various
immunologic responses in these autoimmune strains in
the hope that comparisons with nonautoimmune strains
would bring insight into pathogenetic mechanisms. The
major observations are listed in’Table 1. The New Zealand strains develop immunologic competence prematurely compared t o normal strains (7). Within the
first week of life, they make antibody responses to sheep
erythrocytes equivalent to that seen in adult NZB mice.
Other strains require several weeks to achieve such immunologic maturity. This premature maturation of the
immune system may also extend to cellular responses,
because very young New Zealand mice can regress tumors more rapidly than age-matched control strain animals (8).
NZB and B/W mice make excessive antibody
responses to many but not all experimental antigens,
including foreign proteins, sheep erythrocytes, and synthetic nucleic acids (9-1 1). This hyperactivity is seen in
young adult mice and is selective, because some antigens
elicit responses that fall within the normal range (12).
Antibody responses tend to decline in older animals.
Adult New Zealand mice are relatively resistant
to the induction and maintenance of immunologic tolerance to soluble deaggregated foreign proteins such as
bovine gammaglobulin (9,13,14). Their ability to become tolerant declines at 1-2 months of age, in contrast
to many control strains that manifest long-lasting tolerance. This resistance to tolerance is associated with T
rather than B cells. A relative resistance to tolerance is
also seen in other strains such as SJL and Balb/c mice
where it is under genetic control.
Older New Zealand mice have marked impairment of cellular immunity which is demonstrated by
decreased response to mitogens (15), and decreased ability to induce graft-vs-host disease (16) or to reject tumors and skin grafts. At this age, they show a decline in
recirculating lymphocytes and in theta-positive lymphocytes. These alterations may be related in part to the
TALAL
S60
aging process itself, and to the spontaneous appearance
of an autoantibody cytotoxic to thymocytes and T lymphocytes (17). This anti-T cell antibody occurs in virtually all NZB mice and in the majority of B/W mice.
The importance of suppressor T cells in immunologic regulation and tolerance has become increasingly
apparent (18). NZB and B/W mice lose suppressor T
cells (19-21) between 1 and 2 months of age, corresponding to the time when they become resistant t o the
development of immunologic tolerance. Moreover, neonatal thymectomy can result in an accelerated development of autoimmunity, a possibility suggesting that the
thymus exerts a suppressing influence on disease expression (1).
The cause of the suppressor T-cell deficiency is
unknown. NZB and B/W mice demonstrate a premature decline in a thymic humoral factor which may
function as a thymic differentiation hormone (22). The
administration of thymosin to these mice can restore
some aspects of thymocyte and T-cell function but has
no significant therapeutic effect (23).
The sequence of immunologic changes and disease manifestations in these mice evolves in a manner
that suggests a causal relationship (Figure 1). The early
decline in thymic epithelial cell function, suppressor T
cells, and T-cell tolerance precedes the development of
autoantibodies, tissue lymphocytic infiltrates, immune
complex nephritis, and hemolytic anemia. The more
:>
severe defects in cell-mediated immunity occur at an age
when malignant lymphomas and monoclonal macroglobulins may appear (24,25).
Several modes of therapy have been tried in NZB
and B/W mice, some of which are new and highly
promising (Table 2). Conventional forms of treatment,
such as corticosteroids and immunosuppressive drugs,
have been used for many years. Cyclophosphamide is
particularly effective but, as in humans, the development
of lymphoid malignancy is enhanced by immunosuppression (26-28). Various attempts to restore or to
maintain suppressor function have been tried. These
have included repeated injection of spleen or thymus
lymphocytes from young mice presumed to contain suppressor cells (29,30), thymus grafts from young mice
(3 1 ), or various thymic humoral factors representing
putative thymic hormones (23,32,33). In general, treated
mice have shown a delayed onset of autoantibodies and
nephritis, consistent with the transfer of a suppressor
mechanism. However, treated mice succumb to their
disease with often little or no significant prolongation of
survival. Results are best if treatment is started very
early in life.
Protein or calorie restriction delayed the onset of
hemolytic anemia in NZB mice (34), and prolonged
survival in B/W mice. An immunologic mechanism was
suggested. The technique of hapten-specific carrier-determined tolerance, using nucleosides of DNA cova-
MONTHS
BIRTH
-I
4 THYMIC
HORMONE
T SUPPRESSOR CELLS
+T-CELL TOLERANCE
+
+ CELL-MEDIATED
IMMUNITY
r
-
c
-
-’
NUCLEIC ACIDS
LYMPHOCYTE SURFACE
ANTIGENS
TISSUE LYMPHOCYTIC INFILTRATION
IMMUNE COMPLEX NEPhRITIS
HAEMOLYTIC ANAEMIA
AUTOANTI BODIES
{
-9
-
- II
-I2
13
-
MALIGNANT LYMPHOMA
MONOCLONAL I g M
DEATH
Figure 1. Immunopaihology in N Z B and N Z B I N Z W mice.
N A T U R A L HISTORY OF M U R I N E LUPUS
Table 2. Models of Therapy in NZB and NZBlNZW F, Mice
Treatment
Corticosteroids
Immunosuppression
“Suppressor” lymphoid cells
Thymus grafts
Thymic humoral factors
Protein or calorie restriction
Nucleoside-isologous IgG tolerance
SIRS (Con A-induced suppression)
Prostaglandin E
Ribavirin
Androgens
References
1
26-28
29,30
31
23,32.33
34
35
36
37
38
6.39
lently bound to isologous NZB IgG, has been shown to
delay nephritis in B/W mice (35).
The ability of concanavalin A (Con A ) to induce
a soluble immune response suppressor (SIRS) has been
employed successfully to decrease autoimmunity and
nephritis and prolong survival in B/W mice ( 3 6 ) . The
New Zealand mice lose the ability to produce SIRS
themselves but can respond when this soluble suppressor factor is administered to them. Prostaglandin E,
administered once or twice daily to B/W mice (37) and
ribavirin (38) (an antiviral agent) will also prolong survival.
Our laboratory has been interested in why the
disease develops earlier and with greater severity in females. We have found that androgens are protective in
B/W mice, and we have used androgen therapy to reduce immune complex nephritis and to prolong survival
in female animals (6,39).
Several laboratories, in studying the influence of
sex hormones on immune responses in conventional
strains, have found a greater activity in females compared to males (40,41). Thus, female mice have higher
antibody responses to several experimental antigens and
have greater cell-mediated immunity. Castration of male
mice increases thymic and lymph node weight and augments immune reactivity. Most investigators attribute
these effects to an action of sex hormones on a thymic
mechanism.
I n clinical medicine, the greater incidence of several different autoimmune diseases in females is well
recognized. In lupus, the female: male ratio is approximately 9 : 1 . Furthermore, autoimmunity is associated
with Klinefelter’s syndrome, a disorder of males in
which masculine features fail to develop. A recent study
S6 1
reported 2 patients with lupus and Klinefelter’s syndrome w h o had an abnormality of estradiol metabolism, a finding that suggested that they were subject to
persistent estrogenic stimulation (42).
My laboratory reported last year that prepubertal castration of male B/W mice performed at 2
weeks of age resulted in accelerated formation of antibodies to DNA and increased mortality (43). This apparent protective effect of androgen has been investigated further by subjecting prepubertally castrated male
and female mice to sustained concentrations of either
androgen or estrogen. Each experimental group was
composed of 15-25 mice. The hormones were administered in small silastic tubes implanted subcutaneously at
3 weeks of age. Mice were followed monthly for autoantibodies, proteinuria, and renal status. Selected animals were sacrificed for microscopic examination of
their kidneys (performed by Dr. John S. Greenspan).
Male mice given estrogen showed a greatly enhanced
mortality compared to sham-operated or androgentreated controls. Estrogen also accelerated mortality in
female mice, whereas androgen treatment prolonged
survival. Mice of either sex given androgen had less
antibody to DNA and milder nephritis as determined by
light, immunofluorescent, and electron microscopy.
These results suggest that sex hormones modulate autoimmunity and disease expression in B/W mice.
Androgens suppress disease and estrogens accelerate it.
This hormonal influence is in agreement with the experimental and clinical observations already mentioned.
Our results were anticipated by Howie and Helyer ( l ) ,
who made the following comment in a review paper
published 9 years ago: “Variations in the hormonal
environment, resulting from differences in sex and
breeding activity, influence the pattern of disease, probably by exerting some control over the disordered immunological activity.”
How the sex hormones act, whether on immunologic or viral mechanisms, is currently under investigation in our laboratory. The expression of viral antigens
(such as gp70) on the lymphocyte membrane raises the
possibility that immunologic and viral mechanisms are
not mutually exclusive. The effect of sex hormones on
lymphocyte subpopulations and on T-cell regulation
needs to be studied by modern immunologic techniques.
I hope that the deliberations of this conference will offer
new insights into these and other highly relevant questions so that future research on this murine model will
bring us closer to understanding the biological complexities of lupus.
TALAL
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