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Stress Response And The Immune And Endocrine Systems. Neuroendocrine
Immune Basis of the Rheumatic Diseases
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HOWEDY People,


THIS is HOWE you're KILLIN your dogs your children
and yourselves: Stress Response And The Immune
And Endocrine Systems. Neuroendocrine Immune
Basis of the Rheumatic Diseases


The Second International Conference on the Neuroendocrine
Immune Basis of the Rheumatic Diseases


Maurizio Cutolo MD
Division of Rheumatology, Department
of Internal Medicine,
University of Genoa, Genoa, Italy
IMAJ 2002;4:309=B1311


At the Second International Conference on the
Neuroendocrine Immune Basis of the Rheumatic
Diseases, held in Genoa (Santa Margherita, Italy)
on 21=B123 September 2001, researchers from 20
different countries presented their latest works in
this fascinating field of study.


General overview


Elenkov and Wilder (Bethesda, USA) introduced the
state of art of neuroimmuno-endocrinology. Substantial
progress has been made in delineating molecular,
cellular and systemic physiologic mechanisms that
underlie the communication between components
of the stress response and the immune and endocrine
systems.


Progress has also been made in defining how abnormalities
involving hormones (i.e., estrogens, androgens, cortisol,
catechola- mines, etc.) may contribute to the initia- tion,
progression and severity of auto- immune rheumatic diseases
such as rheu- matoid arthritis and systemic lupus erythe-
matosus.


For RA, the available data support the view that inflammatory
and immune system inhibitory mechanisms involving the
hypothalamic-pituitary-adrenal axis and sympathetic nervous
system are deficient.


For SLE, accumulating recent data indicate that estrogens
and andro- gens exert contrasting effects on B lym- phocytes
(i.e., estrogens enhance, testosterone suppresses). Elenkov
and Sternberg (Bethesda, USA) reported on neural pathways
that play a role in inflammatory disease regulation, including
the sympathetic and peripheral nervous systems that modulate
inflammation at regional or local levels.


New therapeutic interventions currently being developed
based on this research include the use of anti-inflammatory
drugs in Alzheimer's disease, anti-stress hormone drugs in
arthritis, neurotransmitter-related drugs for aging-associated
immunosuppression, and cytokine antagonists and immune
T cells for treatment of spinal cord injury, nerve trauma and
stroke.


A=2ET. Masi (Chica- go, USA) discussed the adrenal steroid
deficiencies in RA patients and the different expression of
the hypoadrenal gland function in many subsets of patients.


These conditions, among other risk factors, may permit
modeling immunologic development or reactivity. The
neuroendocrine aspects of the central nervous system
involvement in the antiphospholipid syndrome were
discussed by Y. Shoenfeld (Tel Hashomer, Israel).


Stress and rheumatic diseases


Stress is a well-known stimulator of the hypothalamic-
autonomic nervous system axis and the HPA axis,
and may =B1 based on the above and other interactions =B1
influence the immune response. RA and SLE patients
differ in their immunologic response to acute psychological
stress: natural killer activity increased in healthy controls
only,
while there was an increase in interleukin-4-producing cells
in SLE patients only.


Phytohemagglutinin-stimulated peripheral blood morphonuclear
cell cultures demonstrated increased interferon-gamma and IL-10
levels in healthy subjects but not in SLE or RA patients after
stress exposure. Further- more, the number of beta2-drenoceptors
on PBMC significantly increased only in healthy subjects after
stress but not in SLE patients.


RA patients showed an increased sensitivity to beta2-adrenoceptor
stimula- tion, accompanied by a decrease
in G- protein-coupled receptor kinase activity.


This may be a potential pathway whereby inflammatory
mediators may influence stress-associated mechanisms
that can modulate outcome in inflammatory dis- eases
(Schedlowski, Essen, Germany). In a follow-up study of
symptomatic Gulf War veterans, in vitro immune response
tests showed no significant impairment (Everson, Birmingham,
USA), indicating that the relation between stress and the
immune system in these otherwise healthy people is not
always straightforward.


In an animal model of stress induced by chronic food
restriction, adjuvant arthritis developed less frequently
and was less severe in the stressed group of animals
(Seres, Prague).


Role of the autonomic nervous system


The adrenal hormone epinephrine and the sympathetic
neurotransmitters norepinephrine and adenosine (after
conversion from ATP) play an immunomodulatory role
due to their binding to different receptor subtypes on
cells of the immune system.


Epinephrine preferentially binds beta-adrenoceptors, and
norepinephrine binds alpha-adrenoceptors (at high concentra- tions
also beta-adrenoceptors). Studies in early rheumatoid
arthritis indicate that the expression of beta2-adrenoceptors
on lym- phocytes is reduced, followed by a reduced cAMP
production and an impaired auto- RA =3D rheumatoid arthritis
SLE =3D systemic lupus erythematosus HPA =3D hypothalamic-
pituitary-adrenal IL =3D interleukin PBMC =3D peripheral blood
morphonuclear cells 309 IMAJ . Vol 4 . April 2002


Neuroendocrine Basis of Rheumatic Diseases autonomic
nervous function. These beta2-adre- noceptors play an
inhibitory role for production of pro-inflammatory cytokines
such as tumor necrosis factor, IL-2, IL-12 and IFN-gamma,
lymphocyte proliferation, energy metabolism, expression of
adhesion molecules, and other aspects of the im- mune reaction.


Therefore, reduced beta2- adrenergic action may contribute to
the pathogenesis of RA. A negative correlation has been found
between disease activity of RA and beta2-adrenoceptors (Wahle
and Baerwald, Leipzig, Germany). It was also shown that
catecholamines inhibit energy metabolism of immune cells
within sec- onds; propranolol (beta-adrenoreceptor antagonist)
but not phentolamine (alpha- adrenoreceptor antagonist)
reversed the norepinephrine-induced inhibition in quiescent
cells. Conversely, phentolamine but not propranolol was
capable of block- ing norepinephrine-mediated effects in
activated cells (Buttgereit, Berlin).


This indicates that depending on the activation state of
immune cells differential alpha- and beta-adrenoceptors
play a regulatory role. In elegant experiments, Straub
(Regens- burg, Germany) demonstrated a decrease of
sympathetic nerve fibers in synovial tissues of RA patients,
accompanied by a marked norepinephrine release from
tyrosine-hydroxylase positive cells in this tissue.


This norepinephrine secretion is probably anti-inflammatory
(reduces IL-6, IL-8 and TNF) to counteract local inflammation,
but its exact role remains to be determined. Dendritic cells are
potent antigen-presenting cells involved in inflam- mation and
autoimmunity. Maestroni (Lo- carno, Switzerland) demonstrated
that norepinephrine enhances these cells to migrate, while the
alpha-adrenergic antagonist prazosin inhibits this migration.


Pain modulation Inflammation causes peripheral and central
sensitization, which is the basis of pain. Sensitization also
facilitates the efferent arm of sensory neuronal pathways by
releasing a local substance P, whereby the nervous system
influences the inflammatory process. Peripheral sensitization
is induced by inflammatory mediators such as bradykinin,
prostaglandins, neuropep- tides and cytokines.


Hyperexcitability of spinal cord neurons is predominantly
regulated by glutamate that activates N- methyl-D-aspartate
(NMDA) and non- NMDA-receptors.


Blockade of these receptors can prevent and reduce
central sensitization. Substance P and CGRP, but also
prostaglandin E2, facilitate this transmis- sion; indomethacin
is able to significantly attenuate the development of
hyperexcitability (Schaible, Jena, Germany). During this
sensitization the increase in intraneur- onal cAMP
concentration plays a pivotal role. Morphine inhibits this
cAMP forma- tion by inhibiting adenylate cyclase.


Morphine may prevent not only the development of pain,
but also the resulting inflammation, as shown in experimental
and degenerative models of arthritis (Kont- tinen, Helsinki).
This finding is in line with the detection of novel opioid
peptides
endomorphine-1 and 2 in inflamed syno- vial tissue (Jessop,
Bristol, UK). Corticotropin-releasing hormone Corticotropin-
releasing hormone is a key regulator of the HPA axis and
coordinator of the stress response.


Its crucial role was further confirmed by the identification
of local up-regulation of CRH and the CRH receptor type
1alpha (CRH-R1) in inflamed synovial tissue. CRH receptor-
mediated signaling, in part through the nuclear transcription
factor NURR1, plays a role in both the vascular and pathologic
changes associated with joint inflammation.


NURR1 is up-regulated in inflamed synovial tissue; treatment
with prostaglandin E2, IL-1 and TNF enhances NURR1 mRNA
and protein levels. This up-regulation requires a proximal
promoter region that contains a consensus nuclear factor kB
(NFkB) DNA- binding motif and a direct cAMP response element
binding protein-1 (CREB-1)- dependent regulation by PGE2
(McEvoy, Dublin). CRH stimulation has been studied in different
rheumatic diseases.


Conflicting data have been observed in fibromyalgia patients.
Neeck (Bad Nauheim, Germany) divided the cortisol response
to CRH in fibromyalgia patients based on their scoring on a
depressive mood scale; those who scored higher had a low
cortisol response while those with low scores had a higher
cortisol response.


Pro-inflammatory cytokines, especially IL-6 and
IL-1, stimulate CRH, ACTH and cortisol. In the acute phase
this stimulation is adequate while in the more chronic
situation the increase in ACTH and cortisol is blunted.


There is also an indirect path- way via the release of
catecholamines, independent of the HPA axis (Bornstein,
Du=C8 sseldorf). Furthermore, there is a hormone-independent
way of stimulating adrenal steroid hormone secretion due to
intra-adrenal cell-cell contacts, which may be an important
regulatory element in inflammatory diseases (Bornstein, Du=C8
ssel- dorf).


Glucocorticoids


We have known for over 50 years that glucocorticoids
play a pivotal role in the endocrine regulation of the
immune re- sponse. Not only are glucocorticoids the
most effective antiphlogistic and immune suppressive
substances with instant effect, but low dose long-term
treatment in patients with RA had clear antiproliferative
effects on cartilage and bone (Neeck, Bad Nauheim).


The immune suppressive effects of glucocorticoids
are related to inhibition of processes such as cytotoxicity,
phagocytosis and synthesis of inflammatory cytokines
such as TNF, IL-1, IL-2 and IL-8. Other anti- inflammatory
actions have been ascribed to the synthesis of a protein
termed lipocortin 1 or annexin 1, which inhibits phospholipase
A2 activity with subsequent reduction in arachidonic acid
release and eicosanoid production.


Another relevant mechanism is the capacity of glucocorticoids
to interfere with intercellular adhesion processes, which are
instrumental in mediating leukocytes to endothelial cells and
cell migration into peripheral tissues (Pitzalis, London). This
regulation may be effected by the classical genomic pathways,
but also by non-genomic pathways in cases of higher dosages
of glucocorticoids.


These actions occur rapidly (within seconds) and are related
to physicochemical effects on membranes and putative
membrane receptors. Clinically relevant glucocorticoid con-
centrations inhibit plasma membrane Ca2+ and Na+ uptake,
RNA/DNA synthesis and substrate oxidation reactions, and
stimu- late the leak of protons across the mito- chondrial inner
membrane (Buttgereit, Berlin).


Glucocorticoid receptor concentrations have been studied in
different groups of Congress Points IFN =3D inteferon TNF =3D
tumor necrosis factor CRH =3D corticotropin-releasing hormone
310 M. Cutolo IMAJ . Vol 4 . April 2002 patients with RA.
Huisman (Utrecht, the Netherlands) found decreased levels in
early diagnosed, disease-modifying anti- rheumatic drug-naive
and prednisone- naive female patients, in combination with low
cortisol levels. In patients with more long-standing and more
active RA other researchers found increased levels, in
combination with higher cortisol levels.


Glucocorticoid resistance is becoming a better understood
clinical entity. Steroid- resistant RA patients have enhanced
expression of glucocorticoid receptor beta isoform in their
PBMC. The molecular mechanisms possibly involved are
alterations in intracellular signaling, cytokine profile,
dysregulation of GCR function, enhanced AP-1 expression
and others (Chikanza, London).


The effects of glucocorticoids on bone are well established,
but the underlying mechanisms are not yet fully elucidated.


Glucocorticoids increase bone resorption due to a
decrease in osteoprotegerin, and an increase in RANK ligand
expression with an increase in osteoclastogenesis. Gluco-
corticoids have a direct inhibitory effect on osteoblast
formation and function, possibly also by inducing their
apoptosis.


Glucocorticoids also enhance collagen degradation
by inducing collagenase 3 expression in osteoblasts.
Glucocorticoids also reduce the synthesis of insulin-like
growth factor, which stimulates bone formation (Canalis,
Hartford, USA).


The clinical value of glucocorticoids in the treatment of
patients with RA was further confirmed by a new study
investigating the effect of prednisone versus placebo
in DMARD-na=F5=C8ve early RA patients. Symptomatic relief
was seen in the first months; after 2 years a significant
reduction in (progression of) erosions occurred, combined
with a decrease in the use of non-steroidal ant-inflammatory
drugs and other interventions such as physical therapy and
intraarticular injections (Bijlsma, Utrecht).


Four different very recent studies reported a reduction in
(progression of) erosions during treatment with low dose
glucocorticoids, but the effect of the combination of DMARD
plus glucocorticoids was better than that of glucocorticoids
alone.


This suggests that the anti-inflammatory properties of
glucocorticoids are different from their disease-modifying
effects. Gonadal hormones Generally, estrogens are
implicated as enhancers of the immune response, and
androgens as natural suppressors.


In syno- vial tissue of patients with RA, receptors for estrogens
as well as androgens were found on macrophages and B and T
lymphocytes. Estrogens may stimulate macrophages to produce
TNF-alpha, IL-1 and IL-6, B lymphocytes to produce
immunoglobulins and inhibit T lymphocytes to produce IL-4,
IL-2 and IFN-gamma.


Androgens may (to a lesser degree) have the opposite
effects. Concentrations of estrogens at the level of the
inflammatory area are increased due to increased
aromatase activity (Cutolo, Gen- oa, Italy).


Levels of expression of cytokines and cytokine inhibitors
are ruled by hormones: estrogens increase the expression
of IL-1 mRNA on monocytes, while androgens inhibit the
production of IL-1 and TNF by monocytes/macrophages.


Estrogens tend to inhibit TH1 cytokines, while androgens
tend to inhibit TH2 cytokines (Dayer, Geneva). The important
role of the vascular endothelium in inflammation has become
increasingly more apparent.


Estrogens enhance a number of endothelial cell biologic
activities, such as proliferation, adhesion to matrix proteins,
migration, and cell differentiation, which promote inflammation
and angiogenesis (Cid, Barcelona).


An interesting aspect of gonadal hormones is its interaction
with glucocorticoids. Estrogens influence the secretion of
CRH by the hypothalamus and the expression of glucocorticoid
receptors, thus affecting the negative feedback to the
hypothalamus.


When the response of ACTH and cortisol to IL-6 was
measured in healthy adult males and females, maximum
cortisol levels correlated with IL-6 dosage in males but not
in females. The opposite was found for a correlation between
ACTH and cortisol.


This suggests that the adrenals of males and females
may have different sensitivity to ACTH and IL-6 (da Silva,
Coimbra, Portugal). Data were submitted by Sullivan
(Bos- ton) on the influence of gonadal hormones on the dry
eye in Sjogren's syndrome. Androgen deficiency and estrogens
(and progesterone) promote the development of the dry eye
syndrome as demonstrated in animal models and epidemiologic
studies.


Melatonin


The pineal hormone melatonin has a variety of effects
on the immune system. Melatonin enhances IL-1, IL-6,
IL-12, TNF and IFN-gamma production. It has been
suggested that melatonin counteracts immunosuppression
and thymus atrophy induced by stress or glucocorticoids (Maes-
troni, Locarno).


Also an indirect effect via modulation of androgens has
been suggested. Melatonin receptors are present on
synovial macrophages of RA patients. Melatonin serum
levels are higher in RA patients, but have the same
nocturnal rhythm, with the peak level early in the morning. It
has been suggested that symptoms such as morning gelling,
stiff- ness and swelling might be related to the
neuroimmunomodulatory effect of melato- nin (Cutolo, Genoa).


Aging and rheumatic diseases


Aging has a clear influence on our endocrine, nervous and immune
status. During aging many changes occur in cytokines,
hormones and neurotransmitters, depend- ing on oxidative damage,
non-enzymatic glycosylation, mitochondrial mutations,
defects in cell cycle control, genome instability, telomere
shortening, and other pathologies.


To mention a few: during aging IL-6 levels increase, DHEA levels
decrease, the ratio cortisol/ACTH decreases (more evident in
women then in men), and a shift in TH1/TH2 in favor of TH2 is
observed. These changes may be relevant for the occurrence of
neuroendocrine immune-mediated diseases in different age
groups (Straub, Regensburg).


The Third International Conference on Neu- roendocrine Immune
Basis of the Rheumatic Diseases is scheduled to be held in
Genoa in 2004. In 2004 Genoa will celebrate its official position
as ``2004 Cultural MainTown'' in Europe and important events are
planned. Correspondence: Dr. M. Cutolo, Division of reumatology,
Dept.of Internal Medicine, University of Genova, Viale Benedetto
xv, 6 16132, Genova, Italy. Phone: (39-10) 353-7994 Fax:
(39-10) 353-8885 email: mcut...@unige.it Congress Points DMARD=3D
disease-modifying anti-rheumatic drug 311 IMAJ .
Vol 4 .April 2002 Neuroendocrine Basis of Rheumatic Diseases