The role of the immunoendocrine interaction via the hypothalamo-pituitary-adrenal axis in autoimmune disease

the OS model it seems that the presence of a single recessive gene determines

The Role of the Immunoendocrine Interaction via the HypothalamoPituitary-Adrenal Axis in Autoimmune Disease Emphasis on the Obese Strain Chicken Model Georg Wick, Yan-Hua Hu, and Johann Gruber

The key to the molecular basis of the pathogenesis of autoimmune disease (AID) certainly lies in the identification of genes coding for the altered immune response and those responsible for the susceptibility of the target organ to the autoimmune attack. The elucidation of nonessential modulatory factors is, however, also of great importance, because it is via these routes that an effective AID therapy is practical at the present time. Hormones in general, and those affecting the hypothalamo-pituitary-adrenal (HPA) axis in particular, are among the best candidates for more rational new therapeutic approaches. Studies of immune-endocrine communication in animal models with spontaneously occurring organ-specific or systemic autoimmune diseases are ideal for this kind of investigation, since immunologic studies commencing prior to onset of the AID in question can be performed. (Trends Endocrlnol Metab 1992;3:141-146)

Autoimmune

diseases

multifactorial

pathogenesis

(AIDS)

have

a

(Shoenfeld

and Schwartz

1984; Wick et al. 1987). Most

of the work

in this field

genetic factors underlying

deals with the inappxo-

priate reactivity of the immune system, such as the lack or insufficient deletion and/or inactivation

of

autoreactive

T

cells in the thymus or the periphery, preferential gens

by

presentation

molecules

histocompatibility

of

of

autoanti-

certain

(MIX)

major

class II hap-

lotypes, the possibility of restricted usage of

distinct

autoantibody

or

T-cell-

receptor variable (V) gene segments, the

Georg Wick, Yan-Hua Hu, and Johann Gruber are at the Institute for General and Experimental Pathology, University of Innsbruck, Medical School: and the Institute for Biomedical Aging Research of the Austrian Academy of Sciences, A-6020 Innsbruck, Austria. TEM Vol. 3, No. 4, 1992

intrinsic overproduction of various cytokines, such as interleukin-2 (L2), and so forth. Very little, if any, attention has been paid to the possible role of the target organ (or autoantigenic structures, respectively, in systemic autoimmune diseases) in the emergence of an AID. Based on studies of different animal models with spontaneously occurring AID, particularly obese strain (OS) chickens that spontaneously develop a Hashimoto-like autoimmune thyroiditis (Wick et al. 1989), we put forth a new concept of AIB pathogenesis (Figure 1). As was done in previous concepts, we postulate the existence of essential and modulatory genes that influence the development and severity of a given AID. However, among the essential genes, we distinguish between those that relate to the abnormally autoreactive immune system and those that code for a primary alteration of the target organ that makes it susceptible to autoimmune attack. In

81992. Elsevier Science Publishing Co., 1043-2760/92/$5.00

whether autoimmune thyroiditis develops (Kroemer et al. 1990). An AIB can emerge only if an individual possesses both the essential genes responsible for abnormal immune reactivity and those coding for target organ susceptibility. In addition to these essential genes, there are modulatory genetic or environmental factors that determine the final outcome of a given AD, such as viral infections, diet, sex hormones, and other hormones. The elucidation of the function of these modulatory factors is of special clinical interest because this is the only route by which therapeutic intervention is currently possible. 0 Interaction Between the Immune and the Endocrine Systems Mediated by Steroid Hormones Interactions between the immune and the neuroendocrine systems can be considered at physiologic, pharmacologic, and pathologic levels. Perhaps the best example, which is also the most frequently employed therapy, of the immunomodulatory role of hormones is that of steroids, notably sex hormones and glucocorticoids. Estrogens increase humoral and cellular immune reactions, whereas male sex steroids (for example, testosterone) have an immunosuppressive effect. In chickens, the development of the B-dependent limb of the immune system can be inhibited by in ovo or early posthatching treatment with testosterone. This is due to the abolition of the epithelial bursal microenvironment rather than to an effect on the lymphoid cells themselves. It is, however, important to emphasize that the immunomodulatory effects of sex hormones are not identical with their endocrinologic activity. As a matter of fact, considerable efforts have been made to synthesize androgen analogues that are immunosuppressive, but lack the unwanted endocrinologic side effects. Such analogues have already been successfully applied to the treatment of various animal models with AD (murine lupus erythematosus, OS chickens, and so on) (Verheul et al. 1981; Wick et al. 1989) and are now being scrutinized for their suitability in human patients. The most intensively studied hormonal actions on immunity are those of the

141

Immunesystem a - restricteduse of TCR V genes?

c

- IL-2 hypersecretion - T-cell mitogen hyperresponse

Sex hormones Glucocorticoid hormones Diet (e.g. iodine, lipids)

Virus (endogenous, /T exogenous)

Target organ b

- lower threshold for +N

induced aberrant MHC class II antigen expression

- thyrotropic virus infection - increased iodination of thyroglobulin? d Figure 1. Example of candidates for essential and modulating factors in the development of spontaneous autoimmune thyroiditis in OS chickens. (a) Essential genes possibly affecting immune function. (b) Essential genes that may modify target organ susceptibility. (c) No data available for OS model, but good correlation of severity of thyroiditis with presence and titer of autoantibodies to tbyroglobulin (a T-dependent antigen). T cells are the first effector cells in tbyroiditis; tbymglobulin autoantibodies play an accelerating role. (d) Iodination of thyroglobulin is increased in C-strain (CS) chickens, the ancestor strain of the OS. The situation in the OS itself is still unresolved. yZFN, y-interferon.

glucocorticoids and ACTH. Although very little is known about the immunomodulatory mode of action of physiologic levels of glucocorticoids, a vast amount of data is available on the effects of pharmacologic doses, such as those applied to patients for antiinflammatory or immunosuppressive purposes. Glucocorticoids exert their action mainly on immature and naive T cells (Cupps and Fauci 1982). The mechanisms of glucocorticoid-regulated gene expression are under intensive study in many laboratories and are schematically depicted in Figure 2. Briefly, glucocorticoids bind to cytosolic receptors and lead to a conformational change of the receptor molecule. This complex is then translocated to the nucleus and binds to glucocorticoid-

142

sensitive DNA sequences (steroid-responsive elements, SREs). The binding of a glucocorticoid to the E domain of the receptor entails the exposure of the two zinc fingers on the C domain; zinc finger II mediates anchorage of the complex to the DNA so that zinc finger I can interact with the specific glucocorticoid-responsive elements (GREs). GREs are located upstream of a TATA box in close proximity to a promoter sequence (in case it leads to enhanced gene expression) or to as-yet-unidentified silencer sequences (in case it leads to downregulation of gene expression). Up- or downregulation of gene expression is brought about by upor downregulation, respectively, of RNA polymerase activity. The exact molecular biologic basis of these mechanisms still remains to be elucidated. Examples of

glucocorticoid-regulated genes that may be relevant in the present context are the antiinflammatory lipocortins (upregulated), the retroviral-immunosuppressive transmembrane-murine leukemia retroviral envelope protein p 15 E (upregulated), and the rate-limiting enzyme of intracellular cholesterol biosynthesis, hydroxymethyl-glutaryl coenzyme A reductase (downregulated) (Helmberg et al. 199 1). The last of these may be of special interest because the function of lymphocytes, like that of all other cells, crucially depends on the state of their finely tuned cholesterol homeostasis (Trail1 et al. 1990). The practical relevance of such studies is obvious: if glucocorticoidregulated immunosuppressive gene products could be identified, these proteins, or peptides thereof, could be applied therapeutically, thus circumventing the often deleterious endocrinologic side effects of steroids. In addition to these molecular regulatory mechanisms of glucocorticoid-regulated gene expression, other modes of DNA-targeted action have been described. Thus, in vitro or in vivo treatment of thymocytes with glucocorticoids leads to the fragmentation of DNA, resulting in a “ladder-“-like appearance in gel electrophoresis (Figure 3). The size of the fragments (ladder steps) is -200 base pairs or multiples thereof, that is, corresponding to the loops extending from the DNA wound around the core histones in the nucleosomes (see also Figure 2). Compton and Cidlowski (1987) have postulated that this fragmentation is due to the glucocorticoidinduced activation of endonucleases, although this explanation is still controversial (Alnemri and Litwack 1989). We have recently shown that this phenomenon can also be induced by maximal induction of endogenous glucocorticoid production via an immunoendocrine feedback loop (J. Gruber and G. Wick, manuscript submitted).

??

Immune-Endocrine Modulation Autoimmune Disease

in

The Role of Sex Hormones Most AIDS show a clear-cut female preponderance; the female-male ratio is -10: 1 for Hashimoto thyroiditis and -20: 1 for systemic lupus erythematosus (SLE). This association is, however, not absolute: although female predilection is

01992, Elsevier Science Publishing Co., 1043-2760/92/$5.00

TEA4 Vol. 3, No. 4, 1992

steroid

Figure 2. Mechanisms of steroid action. Steroid receptor (SR) complex with different domains (A, B, C, D, and E) binds to steroid-responsive elements (SRE). SRE are located upstreamof promoter sequences(TATA and CATA boxes). Cup site, start of transcription.

clear-cut in some models of murine lupus, for example, the (NZBxNZW) Fl and the MRL/lpr strains, mice of the BxSB strain show a significantly higher incidence of male disease. Castration or treatment with estrogens of male (NZBxNZW) Fl mice leads to increased anti-DNA autoantibody

for-

Figure 3. Four-week-old BALB/c mice were treated for 6 h with different doses of the glucocorticoid super-agonist dexamethasone (0.05 mg/kg, 0.1 mg/kg, and 1 mg/kg body weight, intraperitoneally). The steroid was soiubilized in PBUEDTA. The control animal (C) received the appropriate vehicle only. DNA was electrophoretically separated on a 1.8% agarose gel and stained with ethidium bromide. SM, size marker expressed in kilobases.

mation and clinical signs of SLE approaching those found in females. Conversely, treatment of females from AIDprone strains with testosterone or testosterone analogues (see Table 1) prevents the disease (Roubinian et al. 1977; Verheul et al. 198 1). The exact molecular mechanism of the immunosuppressive effect of androgens is not yet known. We have analyzed the possible role of testosterone in the development of spontaneous autoimmune thyroiditis (SAT) in the OS chicken model developed by R.K. Cole from a closed-bred colony of white leghorn chickens, the so-called Cornell C strain (CS) (Cole et al. 1968). In this strain, Cole originally observed a low

percentage (~1%) of female birds with phenotypical signs of hypothyroidism. By selective breeding of affected hens with clinically normal CS roosters, the incidence and severity of SAT was gradually increased, and in our present OS colony nearly 100% of males and females are affected to the same degree (Wick et al. 1989). Together with the demonstration of a beneficial effect of testosterone and synthetic testosterone analogues in the prevention or therapy of SAT and thyroglobulin autoantibody (TgAAb) formation (Wick et al. 1989) this is a good indication for the nonessential modulatory effect of sex hormones in the pathogenesis of AID. The role of testosterone in the OS was then scrutinized in detail. We first showed that the characteristics (affinity, specificity, association and dissociation rate, and sedimentation behavior) of androgen, estrogen, progestin, and glucocorticoid receptors in the bursa of Fabricius did not differ between OS and age- and sex-matched normal white leghorn (NWL) controls (Faessler et al. 1986a). Furthermore, an ontogenetic study of bursal steroidreceptor characteristics did not show any difference between OS and NWL embryos even before the time of lymphoid precursor cell immigration, that is, embryonic day 7. In contrast to bursal epithelial cells, immature bursal lymphocytes and mature spleen cells, as well as thyroid epithelial cells, lack androgen receptors. Thus, any effect of testosterone on SAT in the OS cannot be allocated to a direct action on lymphocytes or the thyroid itself. Furthermore, in contrast to mammals, birds do not possess a sex-hormone-binding globulin (SHBG), so that the serum

Table 1. Effect of testosterone treatment of SAT, Tg-AAb production, and CBG in OS chickens Wtosterone ireuimenp None 1000 l.tg IO0 Pg IOlJg

myroicf No. inffltratkm (%P 9 6 5 7

81.3 + 27.7 f 48.5 + 77.5 f

7.8 15.6c 17.6 20.9

Tg-AAb (ng/WOplJ

L3ursa we&&t (mg)

133.5 f 22.7 28.5 + 7.oC 129.0 f 29.5 117.7 + 32.8

903.3 0.0 386.0 640.7

f 60.9 + o.oc f 44.7c + 57.2

CBG (nM) 76.7 + 6.8 43.0 + 5.7c 45.2 f 6.oC 77.3 + 13.0

LOS chickenswere injectedsubcutaneouslywith the indicateddoses in sesame oil per kg body weight;

0.05,

TEM Vol. 3, No. 4. 1992

0.1,

1 mglkg

treatment from the day of hatching, every other day until sacrifice at the age of 30 days. b Thyroids were fixed and processed to hematoxylin-eosin-stained paraffin sections. Eight sections cut at different planes were evaluated for the percentage of mononuclear infiltration per cross section. c Significantly different (p < 0.05, Student’s t test) from respective value of untreated or sesame-oil-onlytreated controls (data pooled). All values are expressed as mean + SEM. From Faessler et al. (1988a) with permission.

01992, Elsevier Science Publishing Co., 1043-2760/92/$5.00

143

are elaborated

Table 2. Corticosterone (CN) concentrations, binding capacity, and equilibrium dissociation constants in OS and NWL plasma sfrcl/fP

CN @g/L plasma)

C6G (nM In pkwma)

K,., (nM In Incub. tluM)

OS

2.0 f 0.7 (n = 26) 1.9 f 0.6 (n = 28)

77+46(n =46)b 44f14(n=40)

1.95 f 0.58 (n = 30) 2.02 f 0.46 (n = 28)

QSince no age or sex difference emerged in chickens of each strain, the results were pooled from males and females of different ages; mean + SD. bSignificantly different from the NWL control @ < 0.01, Student’s t test). CN was determined radioimmunologically, binding capacities and equilibrium dissociation constants in a direct-binding assay, dextrancoated charcoal separation, and Scatchard plot analysis. From Faessler et al. (1988b) with permission.

concentration of testosterone actually reflects its real bioavailability. Finally, the basal blood levels of the respective steroids were similar in both strains throughout their lives (Faessler et al. 1988a). The preventive and therapeutic effects of testosterone in the OS seem to be exerted by a twofold mechanism: in vivo application of androgens inhibits formation of the epithelial bursal anlage, and androgens lead to decreased production of corticosterone-binding globulin (CBG) in the liver (Table 2). Disturbed Immunoendocrine Communication in AID

Feedback

The glucocorticoid tonus is the combined result of corticosterone (CN) production, metabolism, and excretion, and the binding of CN to CBG and glucocorticoid receptors. As mentioned, OS and NWL chickens do not differ with respect to basal (that is, unstimulated) CN serum levels, or glucocorticoid-receptor concentration and characteristics (Faessler et al. 1988b). In a further study, it has been shown that OS and NWL splenocytes were equally sensitive to the suppressive effects of glucocorticoids in vitro, thus excluding a postreceptor alteration in the former. However, OS chickens exhibit significantly elevated CBG serum levels (Faessler et al. 1986b), albeit without any abnormalities in physicochemical characteristics (that is, equilibrium affinity or specificity spectrum: see Table 2). This leads to decreased levels of free, functionally active CN. Such relative CN deficiency may contribute to the general (auto)immune hyperreactivity of OS chickens. Among the many effects of cytokines on the endocrine system, those interacting with the hypothalamo-pituitaryadrenal axis (HPA) have been studied in depth (Bateman et al. 1989). Antigenic challenge entails not only a specific

144

cellular and/or humor-al immune response, but also a concomitant surge of serum glucocorticoids peaking 3-6 days after primary stimulation. When a second, unrelated, antigen is administered several days after the first, the immune response to the latter is absent or impaired, a phenomenon previously called antigenic competition. This immunosup pressive effect seems to be due to the fact that the high glucocorticoid serum levels primarily affect the induction phase of lymphocyte activation rather than the growth-factor-dependent proliferation of fully activated cells (Besedovsky et al. 1983). The functional role of this glucocorticoid increase after antigenic stimulation may then be the assurance of immunologic specificity by suppression of other clones that may be coelicited in the course of the primary reaction, including “forbidden” autoreactive clones. The stimuli for increased production of glucocorticoids by the adrenal glands

by cells of the immune

system and act via the HPA. Besedovsky et al. (1983) were the first to show that injections of conditioned medium (CM) of T-cell mitogen-stimulated mouse or rat spleen cells induce a significant increase of serum CN levels. These authors identified IL-1 as the main glucocorticoid-increasing factor (GIF) (Eksedovsky et al. 1986). Binding of IL-1 to specific receptors in the hypothalamus leads to secretion of CRH (Sapolsky et al. 1987), which entails release of ACTH horn the pituitary and, finally, CN production by the adrenals (Figure 4). Other authors have presented evidence that GIF can act directly on the pituitary, for example, by induction of the POMC gene by IL-1 (Blalock and Smith 1985). In addition, ACTH-like substances derived from the immune system and II-2 may stimulate the adrenal (Smith et al. 1986).

cortex

directly

We have, not surprisingly, shown that a similar immunoendocrine feedback loop exists in chickens (Kroemer et al. 1988), and that IL-l is also the main GIF in an avian species (Brezinschek et al. 1990). We did, however, exclude direct action of factors in concanavalin A (ConA)stimulated spleen cell CM on the adrenals. Affinity chromatography depletion of CM from IL-1 led to a significant decrease, but not complete abolition, of GIF activity, which may indicate that other unknown factors may have the

Figure 4. hnmunoendocrine feedback loop via the hypothalam+pituitary-adrenal axis: MO, macrophage; B, B-lymphocyte; T, T-lymphocyte; AC, antigen; GIF, glucocorticoid-inducing factor, ILI, interleukin-1; ACTH, adnxwcorticotropic hormone; POMC, proopiomelanocortin; CRH, corticotropin-releasing hormone; and NA, noradrenaline.

I

I

BRAIN

I

GIFand/w

GLUCOCeRTlCOlDS

1

I

I

t LYMPHOCYTE PRECURSORS

631992, Elsevier Science Publishing

Co., 1043-2760/9265.00

TEM Vol. 3. No. 4, 1992

capacity to stimulate directly or indirectly a glucocorticoid surge. Chicken IL-2 has been found to be inactive in this respect, and other mediators are now being systematically examined for GIF in our laboratory. Interestingly, OS chickens show a significant deficiency of this immunoendocrine feedback loop (Schauenstein et al. 1987): in contrast to age- and sex-matched NWL controls, OS birds show a drastically decreased or even absent CN response after immunization with antigen or injection of CM or IL-1 (Figure 5). Mitogen (ConA or phytohemagglutinin, PHA) stimulation tests parallel with the determination of serum CN levels showed a clear-cut inverse correlation of these two variables. Thus, the impaired glucocorticoid feedback regulation may be at least partially responsible for the known T-cell hyperreactivity in the OS. This alteration of immunoendocrine communication can be observed prior to a SAT development and is, therefore, not a sequel of the disease. Furthermore, it was shown that CM derived from Corn&stimulated OS spleen cells was equally effective as that of NWL, thus ruling out a deficiency of GIF in the former. A blockade of pituitary function by the glucocorticoid superagonist dexamethasone and subsequent assessment of the adrenal response to the synthetic ACTH analogue Synacthen revealed no abnormality of adrenal function in the OS (Brezinschek et al. 1990). The defect of the immunoendocrine feedback loop could thus be localized to the hypothalamic or pituitary level of the HPA. Treatment of freshly hatched OS chickens with cortisol led to a dosedependent prevention of an SAT development; therapy commenced after disease onset, for instance, at 3 weeks of age, resulted in a significant improvement of thyroid infiltration and inhibition of Tg-AAb formation (Faessler et al. 1986b). Finally, we report on a series of experiments that revealed a possible correlation between the presence of an endogenous virus (ev) locus and the altered glucocorticoid tonus in OS chickens. In a separate study on the ev pattern of the OS, we performed Southern-blot analyses of OS DNA with a radiolabeled probe derived from the Schmidt-Ruppin strain of Rous sarcoma virus (PSRA-2) that contains the whole avian ev information. Until that time, 21 different ev

TEM Vol. 3, No. 4, I992

loci were known in the chicken. Using DNA digested with different restriction enzymes, we were able to define an additional ev, denoted ev22, detected only in the OS, but not in any of the control strains (Ziemiecki et al. 1988). A genetic study on the mode of inheritance of ev22 using OS, NWI, (OSxNWL) Fl, F2, and backcrosses showed that ev22 is transmitted vertically as an autosomal dominant trait not linked to the MHC. The only other trait of the OS with which the presence of ev22 correlated was the disturbed GIF response (Kroemer et al. 1990). This correlation is specific for GIF activity of lymphokines, because no difference was found between ev22+ and ev22- animals in their response to ACTH. We have not yet determined whether this correlation is due to a functionally irrelevant genetic linkage or to a cis- or transactivation of genes involved in the regulation of the immunoendocrine feedback loop. We believe this was the first demonstration of a disturbed immunoendocrine feedback regulation involving autoimmunity. In the meantime, the possible role of a dysregulated HPA axis in modulating the development of AID has also been demonstrated in other, albeit artificially induced, experimental models, such as streptococcal cell-wallinduced arthritis and experimental allergic encephalomyelitis (EAE) in rats. Wilder and Sternberg ( 1990) have identified a major abnormality in immunoendocrine communication in Lewis rats, which are known to be highly susceptible to the induction of a variety of experimental AID, including streptococcal cell-wall arthritis that closely resembles human rheumatoid arthritis. Lewis rats have a profoundly blunted CN response to streptococcal cell walls and to IL- 1, as well as other types of ‘stress.” In contrast, the arthritis-resistant Fisher 344 rat strain shows a rapid increase in serum CRH, ACTH, and CN after such treatment. Corticosteroid replacement therapy prevents the development of arthritis in Lewis rats, and treatment of Fisher 344 rats with the glucocorticoid-receptor antagonist RU 486 renders these animals susceptible to arthritis. McPhee et al. (1989) observed substantially increased CN blood levels in Lewis rats with EAE, which play an important role in the spontaneous recovery from this condition. The potential

RPMI

Cal

RPMI

au

Figure 5. Plasma corticosterone (CN) changes in 3-week-old normal (CR) and autoimmune (OS) chickens 1 h after intravenous injection of conditioned medium (CM) from ConAstimulated normal spleen cells. The dose for CM (50x concentrated) was 1.0 pL/g body weight. Each bar representsthe mean + SEM of plasma CN from seven animals. *S&n& cantly different 03 < 0.01) from CB control. All animals were conditioned for jugular vein bleeding for 7 days prior to the experiment. RPMI, tissue culture medium RPM1 1640 only. clinical importance of all these findings is underlined by a recent description of the development of autoimmune thyroiditis in Cushing’s disease patients with adrenal tumors who underwent partial therapeutic adrenalectomy (Takasu et al. 1990).

0 Acknowledgments The original investigations of reported in this review were by grants from the Austrian Council (project 7391) and laumsfonds of the Austrian

our group supported Research the JubiNational

Bank (project 3724). Dr. S. Schwarz kindly provided Figure 2, and Dr. A.H.W.M. Schuurs provided Table 1. We would like to acknowledge the constructive criticism of this work by Dr. R. Kofler and Dr. N. Neu, the technical assistance of M. Ginzel, the help in the maintenance of our animal colonies by Dr. H. Dietrich, and the preparation of the manuscript by A. Rathgeber. References Alnemri ES, Litwack G: 1989. Glucocorticoidinduced lymphocytolysis is not mediated by an induced endonuclease. J Biol Chem 264:4101-4111. Bateman A, Singh A, Kral T, Solomon S: 1989. The immune hypothalamo-pituitaryadrenal axis. Endocr Rev 10:92-l 12. Besedovsky HO, de1 Rey A, So&in E: 1983. What do the immune system and the brain

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know about each other? Immunol Today 4:342-345. Besedovsky HO, de1 Rey A, So&in E, Dinareho CA: 1986. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233~652-654. BlaIock JE, Smith EM: 1985. The immune system: our mobile brain? Immunol Today 6:115-117. Brezinschek HP, Faessler R, KIocker H, et al.: 1990. Analysis of the immune-endocrine feedback loop in the avian system and its alteration in chickens with spontaneous autoimmune thyroiditis. Eur J Immunol 20:2155-2159. Cole RK, Kite JH, Witebsky E: 1968. Hereditary autoimmune thyroiditis in the fowl. Science 160:1357-1358. Compton MM, CidIowski JA: 1987. Identification of a glucocorticoid-induced nuclease in thymocytes. J Biol Chem 262:8288-8292. Cupps TR, Fauci AS: 1982. Corticosteroidmediated immunoregulation in man. Immunol Rev 65:133-155. Faessler R, Schwarz S, Dietrich H, Wick G: 1986a. Sex steroid and glucocorticoid receptors in the bursa of Fabricius of obese strain chickens spontaneously developing autoimmune thyroiditis. J Steroid Biochem 24:405-411. Faessler R, Schauenstein K, Kroemer G, Schwarz S, Wick G: 1986b. Elevation of corticosteroid-binding globulin in obese strain (OS) chickens: possible implications for the disturbed immunoregulation and the development of spontaneous autoimmune thyroiditis. J Immunol 136:36573661.

feedback loop. Immunol Today 9: 163-165 Kroemer G, Gastinel LN, Neu N, Auffray C, Wick G: 1990. How many genes code for organ-specific autoimmunity? Autoimmunity 6:215-233. McPhee IAM, Antoni FA, Mason DW: 1989. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med 169:431445. Roubinian JR, Talal N, Greenspan JS, Goodman JR, Siiteri PK: 1977. Effect of castration and sex hormone treatment on survivaI, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F, mice. J Exp Med 147:1568-1583. Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W: 1987. Interleukin-1 stimulates the secretion of hypothalamic corticotropinreleasing factor. Science 238:522-524. Schauenstein K, Faessler R, Dietrich H, Schwarz S, Kroemer G, Wick G: 1987. Disturbed immunoendocrine communication in autoimmune disease: lack of corticosterone response to immune signals in obese strain (OS) chickens with spontaneous autoimmune thyroiditis. J Immunol 139:1830-1833. Shoenfeld Y, Schwartz RS: 1984. Immunologic and genetic factors in autoimmune disease. N Engl J Med 311:1019-1029. Smith EM, Morill AG, Meyer III WJ, Blalock JE: 1986. Corticotropin-releasing factor in-

duction of leukocyte derived immunoreactive ACTH and endorphins. Nature 32 1:88 l882. Takasu N, Komiya I, Nagasawa Y, Asawa T, Yamada T: 1990. Exacerbation of autoimmune thyroid dysfunction after unilateral adrenalectomy in patients with Cushing’s syndrome due to an adrenocortical adenoma. N Engl J Med 322:1708-1712. Trails KN, Huber LA, Wick G, Juergens G: 1990. Lipoprotein interactions with T cells: an update. Immunol Today 11:41 l-417. Verheul HAM, Stimson WI-I, Den Hollander FC, Schuurs AHW: 1981. The effects of nandrolone, testosteroneand their decanoate esters on murine lupus. Clin Exp Immunol 44:11-17. Wick G, Kroemer G, Neu N, et al.: 1987. The multifactorial pathogenesis of autoimmune disease. Immunol Lett 16:249-258. Wick G, H&a K, Brezinschek HP, Dietrich H, Wolf H, Kroemer G: 1989. The obese strain (OS) of chicken: an animal model for spontaneous autoimmune thyroiditis. Adv Immunol47:433-500. Wilder RL, Stemberg EM: 1990. Neuroendocrine hormonal factors in rheumatoid arthritis and related conditions. Curr Opin Rheumatol2:436-440. Ziemiecki A, Kroemer G, Mueller R, H&Ia K, Wick G: 1988. ev22, a new endogenous virus locus found in chickens with spontaneous autoimmune thyroiditis. Arch Virol TEM 100:267-271.

Why wait for it to circulate?Read your own copy of

Faessler R, Dietrich H, Kroemer G, Boeck G, Brezinschek HP, Wick G: 1988a. The role of testosterone in spontaneous autoimmune thyroiditis of obese strain (OS) chickens. J Autoimmun 1:97-l 08. Faessler R, Dietrich H, Kroemer G, Schwarr.S, Brezinschek HP, Wick G: 1988b. Diminished glucocorticoid tonus in obese strain (OS) chickens with spontaneous autoimmune thyroiditis: increased plasma level of physicochemically unaltered corticosteroid-binding globulin but normal total corticosterone plasma concentration and normal glucocorticoid receptor contents in lymphoid tissues. J Steroid Biochem 30:375-379. Helmberg A, FaessIer R, Geley S, Joehrer K, Kroemer G, Boeck G, Kofler R: 1991. Glucocorticoid-regulated gene expression in the immune system: analysis of glucocorticoid-regulated transcripts from the mouse macrophage-like cell line P388D. J Immuno1 145:4332-4337. Kroemer G, Brezinschek HP, Faessler R, Schauenstein K, Wick G: 1988. Physiology and pathology of an immunoendocrine

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