Autoantibodies against ?-MSH, ACTH, and LHRH in
anorexia and bulimia nervosa patients
Sergueï O. Fetissov*†, Jarmila Hallman‡, Lars Oreland‡, Britt af Klinteberg§, Eva Grenba ¨ck¶, Anna-Lena Hulting¶,
and Tomas Ho ¨kfelt*
Departments of *Neuroscience and¶Endocrinology, Karolinska Institute, SE-171 77 Stockholm, Sweden;‡Department of Neuroscience, Biomedical Center,
SE-751 24 Uppsala, Sweden; and§Department of Psychology, Stockholm University, SE-106 91 Stockholm, Sweden
Contributed by Tomas Ho ¨kfelt, October 30, 2002
The hypothalamic arcuate nucleus is involved in the control of
energy intake and expenditure and may participate in the patho-
genesis of eating disorders such as anorexia nervosa (AN) and
bulimia nervosa (BN). Two systems are of particular interest in this
respect, synthesizing ?-melanocyte-stimulating hormone (?-MSH)
42 of 57 (74%) AN and?or BN patients studied had in their plasma
Abs that bind to melanotropes and?or corticotropes in the rat
pituitary. Among these sera, 8 were found to bind selectively to
?-MSH-positive neurons and their hypothalamic and extrahypo-
thalamic projections as revealed with immunostaining on rat brain
sections. Adsorption of these sera with ?-MSH peptide abolished
this immunostaining. In the pituitary, the immunostaining was
blocked by adsorption with ?-MSH or adrenocorticotropic hor-
mone. Additionally, 3 AN?BN sera bound to luteinizing hormone-
releasing hormone (LHRH)-positive terminals in the rat median
eminence, but only 2 of them were adsorbed with LHRH. In the
control subjects, 2 of 13 sera (16%) displayed similar to AN?BN
staining. These data provide evidence that a significant subpopu-
lation of AN?BN patients have autoantibodies that bind to ?-MSH
ment of the stress axis. It remains to be established whether these
Abs interfere with normal signal transduction in the brain mela-
nocortin circuitry?LHRH system and?or in other central and periph-
eral sites relevant to food intake regulation, to what extent such
effects are related to and?or could be involved in the pathophys-
iology or clinical presentation of AN?BN, and to what extent
increased stress is an important factor for production of these
debut at young age and are characterized by hyperactivity and
exaggerated concern about body shape and weight, and they
often occur in the same patients (2). AN is manifested by an
aversion to food, often resulting in life-threatening weight loss
and amenorrhea, whereas BN includes large uncontrolled eating
episodes followed by compensatory vomiting without significant
change in body weight. Even if the cause(s) of AN and BN is still
unclear, a body of data exists suggesting a primary neurobio-
logical origin (3), and neuropeptides also have been implicated
in these disorders (4). These assumptions are paralleled by
growing evidence for a role of hypothalamic peptidergic neurons
in conditions associated with energy deprivation or energy
excess, providing a concept for central mechanisms controlling
food intake and body weight (5–7). In a search of possible
mechanisms implicating hypothalamic peptidergic neurons in
the etiology and pathogenesis of AN?BN, we hypothesized that
hypothalamic systems responsible for the regulation of food
intake could be targeted by autoantibodies in AN?BN patients
as shown for several other neurological diseases (8). To test our
hypothesis, we used immunohistochemistry to explore the pos-
sibility that sera from AN?BN patients contain Abs that bind to
epitopes present in the rat hypothalamus and pituitary.
norexia nervosa (AN) and bulimia nervosa (BN) are two
officially recognized eating disorders that affect ?3% of
Materials and Methods
Human Sera. Sera from 57 female patients (ages 17–42) with
eating disorders, diagnosed according to the Diagnostic and
were used in this study. Among them 28 AN patients (average
body weight ? SD, 39.4 ? 6.2 kg), 22 BN patients (66.1 ? 25 kg),
and seven patients with combination of both AN and BN (47.1 ?
1.4 kg) were diagnosed. Sera from 13 healthy female volunteers
(age 20–41, 64.7 ? 5.6 kg) served as control.
Immunohistochemistry. Sprague–Dawley male rats (body weight
200–250 g; B & K Universal, Sollentuna, Sweden) were housed
under controlled environmental conditions with a constant
light-dark cycle (light on between 6 a.m. and 6 p.m.), a temper-
ature of 21–22°C, and a relative humidity of 40–50%; food and
water were given ad libitum. To detect peptides?proteins more
readily in neuronal cell bodies, we blocked centrifugal axonal
transport in some rats by injection of colchicine (120 ?g in 20 ?l
of 0.9% NaCl) into the brain lateral ventricle under anesthesia
with a mixture of 1 ml of Midasolam (5 mg?ml) and 1 ml of
Hypnorm (2.7 ml?kg), both given i.p. After colchicine injection
(24 h), rats were anaesthetized with sodium pentobarbital (0.15
mg?100 g body weight, i.p.) and perfused via the ascending aorta
with Tyrode’s Ca2?-free solution at 37°C, followed by a mixture
of 4% paraformaldehyde and 0.4% picric acid in 0.16 M phos-
phate buffer (pH 6.9, 37°C)?and then by the same, but ice-cold,
mixture. The brains and pituitaries were rapidly dissected out,
immersed in the same fixative for 90 min, and rinsed with 10%
sucrose in 0.1 M phosphate buffer (pH 7.4) overnight. Tissue was
snap-frozen by using solid CO2. Coronal brain and pituitary
sections (14 ?m thick) were cut on a cryostat (Microm, Heidel-
berg, Germany) and thaw-mounted on chrome alum-gelatin-
coated glass slides.
The tyramide signal amplification immunohistochemical
technique (9) was used for single labeling. Incubation with
AN?BN or control sera (1:200–1:5,000) overnight at 4°C was
followed by horseradish peroxidase-conjugated, donkey anti-
human IgG (1:500, Dako) using the Tyramide signal amplifi-
cation-plus fluorescein system (DuPont?NEN). For double-
labeling, the tyramide signal amplification technique was
followed by conventional immunohistochemistry (10) with
primary rabbit antisera against ?-melanocyte-stimulating hor-
mone (?MSH, 1:400; Chemicon) and cocaine- and amphet-
amine-regulated transcript (CART) peptide (1:400; Phoenix
Pharmaceuticals, St. Joseph, MO) or with mouse Abs against
adrenocorticotropic hormone (ACTH) (1:500, Peninsula Lab-
oratories) and luteinizing hormone-releasing hormone
(LHRH) (1:50, Biogenesis, Kingston, NH). Secondary Abs
Abbreviations: ?-MSH, ?-melanocyte-stimulating hormone; AN, anorexia nervosa; BN,
bulimia nervosa; LHRH, luteinizing hormone-releasing hormone; ACTH, adrenocortico-
tropic hormone; CART, cocaine- and amphetamine-regulated transcript; POMC,
†To whom correspondence should be addressed. E-mail: Serguei.Fetissov@neuro.ki.se.
?Zamboni, L. & De Martino, C. (1967) J. Cell Biol. 35, 148A (abstr.).
www.pnas.org?cgi?doi?10.1073?pnas.222658699 PNAS ?
December 24, 2002 ?
vol. 99 ?
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conjugated with rhodamine red were used at 1:50 dilution
(Jackson ImmunoResearch). The specificity of the binding was
tested by preadsorption of human sera (1:1,000–1:5,000) with
?-MSH, ACTH, ?-endorphin, or LHRH (10?6and 10?5M)
purchased from Bachem. Sections were mounted in a mixture
of glycerol and 0.1 M PBS (3:1), pH 7.4, containing 0.1%
para-phenylenediamine (Sigma) as antifading agent (11). Af-
ter processing, the sections were examined in a Bio-Rad
Radiance Plus confocal laser scanning system, installed on a
Nikon Eclipse E600 fluorescence microscope. Digital images
resulting from the confocal scanning microscopy were opti-
mized for image resolution by using Adobe PHOTOSHOP 6.0
(Adobe Systems, Mountain View, CA).
We found that 42 of 57 (74%) AN and?or BN patients studied
had in their plasma Abs that bind to melanotropes and?or
corticotropes in the rat pituitary. Among these sera, 8 of 42
(20%) were found to bind selectively to ?-MSH-positive neurons
and their projections in the rat brain.
After incubation of sections of colchicine-treated rat brain
with patient sera, a selective staining was found with the
following eight sera: AN, five sera; AN?BN, two sera; and BN,
one serum. Thus, a strong immunoreactivity was detected in
neuronal somata (Fig. 1a) in the lateral part of the arcuate
nucleus and in neuronal processes (Fig. 1b) distributed over
hypothalamic and extrahypothalamic sites. This pattern was
similar to the previously described distribution of the arcuate
pro-opiomelanocortin (POMC) neurons and their projections
(see ref. 12). Using serum from the BN patient with the most
distinct staining, immunopositive varicose fibers were found in
the hypothalamic periventricular region and dorsomedial nu-
cleus (Fig. 1c) as well as in the amygdala (Fig. 1d) and the
paraventricular thalamic nucleus (Fig. 1e). Additionally, this
serum resulted in weak immunostaining of cell bodies in the
lateral hypothalamic area (Fig. 1c). We could not see any distinct
differences between AN and BN sera immunoreactivity. In 17
sera a distinct staining of tanycytes in the median eminence was
observed. Among the sera from control subjects, two sera
displayed peptide-like immunostaining similar to the one de-
To determine the neurochemical phenotype of neurons that
were labeled with AN?BN sera, we used double-immunohisto-
chemistry for ?-MSH or CART, which are normally colocalized
in arcuate nucleus neurons (13). The results showed a total
?-MSH-positive neurons (Fig. 2 a–c). CART immunostaining
showed that most of the arcuate CART-positive neurons were
also positive for AN?BN sera. However, several CART-positive
neurons and a dense network of CART-positive terminals in the
external layer of the median eminence were AN?BN sera-
negative (Fig. 2 d–f), thereby excluding CART as a possible
antigen targeted by the human sera.
Incubation of rat pituitary sections with sera from AN?BN
patients yielded a strong immunostaining of melanotropes in the
intermediate lobe and corticotropes in the anterior lobe (Fig. 2
g–i). This was seen in 74% of the sera. However, only eight of
these sera resulted in the neuronal immunostaining in the brain
described above. Three AN sera bound to terminals in the lateral
median eminence, which by double staining with mAbs were
identified as LHRH terminals (Fig. 2 j–k).
To determine which antigen is targeted by AN?BN sera in
ACTH-positive neurons as well as in melanotropes and cor-
ticotropes, we used adsorption test with different peptides
present in the POMC precursor, including ?-MSH, ACTH, or
?-endorphin. ?-MSH at both 10?6and 10?5M completely
abolished AN?BN sera-positive staining in the cell bodies and
nerve terminals in the brain (compare Fig. 3 b and f to a and
e). Adsorption test with ?-endorphin did not result in a
detectable change in intensity of the staining (Fig. 3 d and h),
whereas staining after ACTH adsorption at most appeared
somewhat weaker (Fig. 3c). In the pituitary intermediate lobe,
immunostaining was reduced by adsorption with 10?5M
?-MSH (compare Fig. 3 j to i, k, and l). However, with some
sera, immunostaining in both melanotropes and corticotropes
was reduced only by adsorption with 10?5M ACTH (compare
Fig. 3 o to m, n, and p). Adsorption of sera that stained LHRH
terminals with LHRH resulted in reduction of immunostaining
for two sera (compare Fig. 3 s to r), whereas one serum
displayed no reduction but rather an increase of immunostain-
ing after adsorption with the peptide (compare Fig. 3 u to t).
In the present work we found that ?74% (42 of 57) of sera
from AN?BN patients bind to pituitary melanotropes and
corticotropes, including ?20% (8 of 42), which stained hypo-
thalamic ?-MSH-expressing neurons and their projections. We
also found that staining in the brain was completely blocked by
?-MSH peptide, and in pituitary melanotropes and cortico-
neuronal cell bodies in the arcuate nucleus (a) and to varicose fibers in the
dorsomedial nucleus (DMN) (b and c). Immunopositive cell bodies are also
lar thalamic nucleus (PVNT) (e). f, fornix. [Scale bars ? 20 ?m (a and b) and
100 ?m (c–e).]
Rat brain sections show binding of serum from a BN patient to
www.pnas.org?cgi?doi?10.1073?pnas.222658699Fetissov et al.
(Arc). However, some CART-positive?BN-negative cells (arrowheads) are seen in this nucleus and in terminals in the median eminence (ME) (d–f). In the pituitary, AN
serum stains melanotropes in the intermediate lobe (IL) and corticotropes in the anterior lobe (AL) as revealed with ACTH double-staining (g–i). Colocalization of AN
serum immunostaining with LHRH in fibers in the ME (j–l). PL, posterior pituitary lobe; 3v, third ventricle. [Scale bars ? 50 ?m (a–c and g–l) and 100 ?m (d–f).]
Double-staining with a BN serum shows complete colocalization with ?-MSH (a–c) and partial colocalization with CART peptide (d–f) in the arcuate nucleus
Fetissov et al.
December 24, 2002 ?
vol. 99 ?
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tropes it was reduced by either ?-MSH or ACTH peptide,
suggesting that a significant subset of AN?BN sera contain
?-MSH and?or ACTH autoantibodies. Because ?-MSH rep-
resents the first 13 aa of ACTH, it is not surprising that
autoantibodies may recognize both or preferentially one of
these two molecules. The fact that some AN?BN sera also
weakly stained neurons in the lateral hypothalamus, which
normally do not express ?-MSH or ACTH, could be explained
immunostaining in both cell bodies (compare b and a) and terminals (compare f and e) only when ?-MSH was used. Adsorption test of AN?BN serum with
POMC-derived peptides in the pituitary shows a reduction of immunostaining by use of ?-MSH (i–l) and by use of ACTH in a BN serum (m–p). Adsorption with
LHRH completely abolishes staining of LHRH-like fibers in the median eminence (ME) in one AN serum (r and s), but not in another one (t and u). Arc, arcuate
nucleus; f, fornix; AL, IL, or PL, anterior, intermediate, or posterior pituitary lobe, respectively. 3v, third ventricle. [Scale bar ? 50 ?m (a–u).]
Adsorption tests of a BN serum with POMC-derived peptides (?-MSH, b and f; ACTH, c and g; ?-endorphin, d and h) show a complete blockade of
www.pnas.org?cgi?doi?10.1073?pnas.222658699Fetissov et al.
by the fact that these cells express melanin-concentrating
hormone, the precursor of which is known to have epitopes
that cross react with ?-MSH Abs (14).
Because the melanocortin system seems to play an important
role in the regulation of food intake and body weight (refs.
15–18; see refs. 19–23), our data raise the possibility that the
disturbance in food intake observed in AN?BN could involve an
autoimmune process against ?-MSH?ACTH in a subpopulation
of patients. The function of the melanin-concentrating hormone
precursor (14) is currently unknown; however, it can perhaps not
be excluded that the melanin-concentrating hormone system
could also be affected by an autoimmune process in patients who
have ?-MSH-Abs and may therefore contribute to feeding
If and how autoantibodies to ?-MSH?ACTH could interfere
with signaling in the melanocortinergic pathway in vivo is
obscure. However, one can envisage several scenarios. First,
because the medial part of the arcuate nucleus is outside the
blood–brain barrier, ?-MSH?ACTH autoantibodies may access
arcuate food intake regulatory neurons such as neuropeptide Y
neurons and the dendrites of POMC neurons and disrupt
interarcuate melanocortin signaling at the MC3 receptor, which
is expressed on both neuropeptide Y and POMC neurons (24).
Second, ?-MSH?ACTH autoantibodies could interfere with
signaling on the MC4 receptor, another melanocortin receptor
that is involved in the regulation of body weight (17), by
penetration through the blood–brain barrier. This barrier does
not always seem to prevent Abs from reaching their targets in the
brain, as reflected in a number of neurological autoimmune
diseases (see ref. 8). A third possibility is that ?-MSH?ACTH
autoantibodies may block ?-MSH function to suppress produc-
tion of cytokines such as IL-1 and tumor necrosis factor-? (see
ref. 25), which are potent inhibitors of food intake (see ref. 26).
Considering that POMC and its products are also expressed in
leukocytes (27), both central and peripheral-impaired melano-
cortin signaling by ?-MSH?ACTH autoantibodies may trigger
anorectic (28) and hypothalamo-pituitary-adrenal axis stimula-
tory (29) actions of cytokines. A final possibility could be related
to a previously reported common feature of ?-MSH, ACTH, as
well as LHRH to bind serotonin (30). Occupation of such
serotonin-binding sites by autoantibodies could potentially lead
to interference with serotonin action and consequently to in-
creased serotonin concentration, which in fact has been found in
plasma of AN patients (31). Furthermore, dysregulation of the
central serotonergic system is a common feature in AN?BN
patients (see ref. 32).
The origin of ?-MSH?ACTH autoantibodies in AN?BN pa-
tients has not been identified. A host of mechanisms by which
tolerance might be broken has been proposed to explain auto-
immunity in neurological diseases (see ref. 8). For instance, this
could be related to the concept of molecular mimicry, whereby
the specific immune response triggered by an invading pathogen
results in propagation of T cell clones or Abs that crossreact by
happenstance with self tissue (33). This concept also has been
postulated to be relevant to pediatric autoimmune neuropsychi-
atric disorders associated with streptococcal infection, in which
antistreptococcal Abs react with basal ganglia proteins (34), and
which can be also accompanied by anorexia (35). Conversely, in
27% of AN patients with symptoms of obsessive-compulsive
disorder, Abs against human putamen have been identified (36).
However, because ?-MSH neurons do not project to the corpus
striatum, these findings could be relevant to a specific subgroup
of AN distinct from the one discussed here. Another possibility
for the induction of autoimmunity in AN can be related to
genetic polymorphism, and several mutations of the POMC gene
in AN have been identified (37). Interestingly, serotonin-binding
sites on ?-MSH?ACTH and LHRH were also found to bind
muramyl dipeptide, a component of Freund’s adjuvant (38).
It is also possible that ?-MSH?ACTH autoantibodies appear
as a result of concomitant activation of the hypothalamo-
pituitary-adrenal axis and the immune system. In fact, the
activation of the hypothalamo-pituitary-adrenal axis is one char-
acteristic feature of AN (see ref. 40). Of interest, the two control
subjects carrying ?-MSH Abs both had supranormal plasma
cortisol levels. These data also suggest that the presence of
?-MSH?ACTH autoantibodies does not necessarily imply the
presence of AN or BN. In fact, severe stress may represent a
common denominator for production of such antibodies. It will
therefore be necessary to analyze sera of a number of other,
especially stress-related, disorders with regard to autoantibodies,
In conclusion, we have demonstrated that subpopulations of
AN?BN patient sera have ?-MSH?ACTH or LHRH Abs. To
what extent these Abs can target the central melanocortinergic
pathway?the neuroendocrine LHRH loop and contribute to the
development AN?BN remains to be established, as does the
mechanism underlying this immune response.
Special thanks are forwarded to the Uppsala Centre for Eating Disorders
(Adults), Uppsala University Hospital (Uppsala, Sweden). This study was
supported by the Swedish Medical Research Council (04X-2887; 03X-
10350), Marianne and Marcus Wallenberg’s Foundation, Knut and Alice
Unrestricted Bristol-Myers Squibb Neuroscience Grant, and the European
Foundations and Tore Nilsons Stiftelse fo ¨r Medicinsk Forskning.
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