Brain, Behavior, and Immunity 25 (2011) 1–5

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Brain, Behavior, and Immunity

journal homepage: www.elsevier.com/locate/ybrbi

Presidential Address

Concepts of evolutionary medicine and energy regulation contribute

to the etiology of systemic chronic inflammatory diseases
Rainer H. Straub ⇑
Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Division of Rheumatology, Department of Internal Medicine I, University Hospital,
93042 Regensburg, Germany

a r t i c l e i n f o a b s t r a c t

Article history: The etiology of chronic inflammatory diseases (CIDs) is usually based on four criteria: (1) genetic suscep-
Received 9 July 2010 tibility, (2) complex environmental priming, (3) exaggerated and continuous immune response against
Received in revised form 3 August 2010 harmless self or foreign antigen, and (4) tissue destruction with a continuous wound response without
Accepted 4 August 2010
proper healing but with a fibrotic scarring response. These elements do not include the systemic compo-
Available online 10 August 2010
nents of CIDs. Due to improved health care with excellent therapies in CIDs, it becomes more and more
clear that many systemic responses need to be future targets of therapies. It is suggested that ‘‘the sys-
Keywords:
temic response” should be added to the four etiologic criteria that constitute the full picture of CIDs.
Bioenergetics
Chronic inflammatory diseases
As shown in the present review, the systemic response becomes comprehensible in the context of evo-
Disease sequelae lutionary medicine and energy regulation. Next to the brain and muscles, the immune system is the third
Energy regulation major energy consumer in the body. In the context of long-term activation of the immune system during
CIDs, the subsequent stimulation of systemic neuroendocrine pathways is necessary to re-allocate
energy-rich fuels to the activated immune system. However, re-allocation of energy-rich fuels is the basis
of systemic disease sequelae of CIDs, one of which is the metabolic syndrome.
It is suggested that Selye’s alarm reaction of the 1930s, which is necessary to re-allocate energy-rich
fuels to the body, should be called ‘‘energy appeal reaction”. In CIDs, a continuous energy appeal reaction
triggers systemic detrimental consequences for the rest of the body.
Ó 2010 Elsevier Inc. All rights reserved.

1. Introduction It is always much more satisfying and sensational when one

Etiology remains the most difficult issue in pathogenesis
research, aiming to elucidate the causation of a given disease. It
was long thought that chronic inflammatory systemic diseases
(CIDs) have one, and only one, important triggering factor that
underlies etiology. This thought style originated at a time when
sensational discoveries have been made, which delineated that
only one factor is responsible for one disease. For example, the loss
of insulin was found to be responsible for type 1 diabetes mellitus
(Banting et al., 1922), and gliadins were responsible for coeliac dis-
ease (Dicke et al., 1953; Van de Kamer and Weijers, 1955). Still
today, those marvelous discoveries are made when we recall the
Canale-Smith syndrome, where the CD95 (Fas/APO-1) receptor is
mutated and a lymphoproliferative disease develops (Drappa
et al., 1996), or the autoimmune polyglandular syndrome type I,
where the gene of the important thymic transcription factor AIRE
is mutated (Finnish-German APECED Consortium, 1997; Nagamine
et al., 1997).
⇑ Fax: +49 941 944 7121.
E-mail address: rainer.straub@klinik.uni-regensburg.de
responsible factor can be found, and the reputation of the discov-
ering researcher(s) rises up to the sky. However, finding the one
and only factor was most often not possible in almost all CIDs. Gen-
ome-wide and epidemiologic association studies were disappoint-
ing because they did not show the single magic bullet that we all
have expected.
In light of current research, pathogenesis of most diseases is
heterogeneous. Therefore, it is not surprising that no single pre-
dominant mechanism for CIDs has emerged. As it is always the
case when multiple pathogenic pathways are proposed, no real
leading paradigm evolves. This is a dilemma for the strict thinker
because he wants to solve the pending problem. However, some-
times problems cannot be solved due to financial, logistical, logical,
complex, and other circumstances. In such a situation, we have no
choice but to sum up the important etiologic concepts to make
sure that we have not forgotten one (Table 1).
The main focus of research during the last century was directed
towards points 1–4 of Table 1. Point 5 of the table is a very recent
addition that I wish to highlight in this Presidential Address. His-
torically, point 5 is the last add-on in the list, originating from
the fact that we are able to treat patients with CIDs to a point
where these systemic problems start to play a disease-relevant

0889-1591/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.bbi.2010.08.002
2 R.H. Straub / Brain, Behavior, and Immunity 25 (2011) 1–5
Table 1
Etiologic factors in chronic inflammatory systemic diseases.
1. Genetic susceptibility (gene polymorphisms; polygenic)
2. Complex environmental priming (microbes, toxins, drugs, injuries,
radiation, cultural background, and geography)
3. Immune response (exaggerated and continuous immune response against
harmless self or foreign antigen)
4. Tissue destruction (continuous wound response without proper healing
but fibrotic scarring)
5. Systemic response (support of the immune and wound responses with
detrimental consequences for the rest of the body)
role. Even with excellent therapies, point 5 of Table 1 becomes
more and more important because our patients grow older and
inflammation cannot be completely stopped. Since a mild proin-
flammatory condition is present in CIDs, even after excellent ther-
apy, long-term detrimental consequences for the rest of the body
can materialize. But what is the reason for the systemic response
with its terrible sequelae?
2. A systemic response
We have often discussed the role of the systemic response in
CIDs and we even call many CIDs ‘‘systemic in nature”. We know
that there exists an acute phase response which is the unspecific
activation of the liver and other organs in order to produce im-
mune system supporting factors such as C-reactive protein, serum
amyloid A, and others. This includes the fact that CIDs – albeit
starting at a local site (the lymph node or the inflamed target tis-
sue) – involve many other organ systems, including the central
nervous system. In rheumatoid arthritis, patients usually suffer
from local joint disease. However, they can also have depression-
like sickness behavior and fatigue, anorexia, hypovitaminosis D,
cachexia, cachectic obesity, insulin resistance, hyperinsulinemia,
dyslipidemia, fat deposits near inflamed tissue, hypoandrogenism,
mild hypercortisolemia, activation of the sympathetic nervous sys-
tem (hypertension), CID-related anemia, and osteopenia (including
the metabolic syndrome) (Straub et al., 2010). But why does this
happen?
In recent years, we recognized that circulating cytokines, circu-
lating activated immune cells, and the activation of sensory nerve
fibers by immunological factors play an important role in the
systemic response. These mediators announce local inflammation
to the rest of the body. Nevertheless, the question remains: why
is general announcement necessary? Is it simply an accident dur-
ing the process of inflammation or does it have any deeper
meaning?
3. Evolutionary aspects
To answer the above question, one needs to think of CID-related
responses in the context of the evolutionary development of Homo
sapiens. The evolutionary principle of replication with variation
and selection is undeniably fundamental and it has history. It
was a successful history of positive selection, which can only hap-
pen under circumstances of unrestricted gene transfer to the prog-
eny. However, genes that might play a specific role in CIDs were
evolutionarily not conserved because unrestricted gene transfer
in the context of CIDs was not possible due to the following
reasons:
1. High negative selection pressure (CIDs lead to loss of reproduc-
ibility because affected individuals are excluded from competi-
tion fights for nutrients, positions in the group, and sexual
partners. In addition, the long-term high inflammatory activity
stops the hypothalamic–pituitary–gonadal axis).
2. No selection pressure at all (many CIDs of today manifest in
higher ages, and due to low life expectancy of our ancestors,
they did not suffer from CIDs that we know today).
3. There was no time for natural selection (various chronic inflam-
matory systemic diseases did not exist some 100–200 years
ago).
All the mentioned factors 1–3 strongly speak against the trans-
fer of genes which might have influenced CIDs in the overt symp-
tomatic phase. Although some diseases such as rheumatoid
arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis,
ankylosing spondylitis and some others also appear in a juvenile
form, the above-mentioned items #1 and #3 still apply to the juve-
nile forms. With respect to item #1, the loss of reproducibility is a
severe problem in a young individual with CID (see Refs. in (Straub
et al., 2007; Straub and Besedovsky, 2003)).
Thus, the regulatory mechanisms of the neuroendocrine and
immune systems evolved to cope with non-life-threatening
inflammatory episodes but not with serious life-threatening CIDs
(Straub et al., 2007; Straub and Besedovsky, 2003). In the world
of today, mechanisms used in the symptomatic phase of CIDs are
borrowed from normal or non-life-threatening inflammatory epi-
sodes listed in Table 2 (Straub et al., 2007; Straub and Besedovsky,
2003). Thus, there are no specific favorable or unfavorable genes
specifically conserved for CIDs.
In a recent extensive review, we elaborated on these facets used
in CIDs in a detailed way (Straub et al., 2007; Straub and Besedov-
sky, 2003). The interested reader is referred to this literature.
In conclusion, every systemic response during the course of
CIDs is not specific for a chronic inflammatory situation because
it has not been evolutionarily conserved for it. A systemic response
has been evolutionarily conserved to cope with short-lived normal
or non-life-threatening inflammatory episodes (Table 2). However,
in order to give the known systemic response a fundamental
meaning, we need to add a further level of complexity, which is en-
ergy regulation of the body and its bioenergetic pathways.
4. Energy regulation
It was delineated above that mechanisms used in the symptom-
atic phase of CIDs are borrowed from normal or non-life-threaten-
ing inflammatory episodes (Table 2). Similarly, pathways of energy
regulation have evolved to cope optimally with normal life and
brief inflammatory episodes, rather than with CIDs. Non-life-
threatening inflammatory episodes are transient (Table 2) because
prolonged episodes imply a huge negative selection pressure. After
a prolonged period of time, most non-life-threatening inflamma-
tory problems are solved because the situation becomes energeti-
cally too costly and this will be incompatible with life (Straub et al.,
2010). Table 3 summarizes energy expenditure of different organs
and systems under different conditions.
Table 2
Normal or non-life-threatening inflammatory episodes developed and conserved
during the process of evolution.
Immune response due to infection
Control of inner and outer body surfaces
Reactions with foreign bodies
Wound healing
Immunosurveillance in tissue
Implantation of stems cells into injured tissue
Implantation of a blastocyst into the uterine epithelium
Immune phenomena facilitating semiallogenic pregnancy
Replacement of cells and tissue (physiological regeneration and
degeneration)
Apoptosis
 R.H. Straub / Brain, Behavior, and Immunity 25 (2011) 1–5
Table 3
Energy expenditure of systems and organs (Blaxter, 1989; Iemitsu et al., 2000; Rassow
et al., 2008; Rolfe and Brown, 1997; Straub et al., 2010).
System/organ Energy expenditure per day
(kJ/day)
Basal metabolic rate 7000
Total body with usual activity 10,000
Total body of a Tour de France bicyclist 30,000a
Total body during minor surgery 11,000
Total body with multiple bone fractures 11,500–13,000
Total body with sepsis 15,000
Total body with extensive burns 20,000
Immune system under normal conditions 1600b
Immune system moderately activated 1750–2080b
Central nervous system 2000
Muscles at rest 2500
Muscles activated 2500 to more than 6000
Thoracic organs (together) 1600–2400
Abdominal organs (together) 3000–3700
a
Such a high energy expenditure can be maintained only for a very short period
of time.
b
See derivation in Ref. (Straub et al., 2010). Leukocytes use all types of fuels, but
the main source is glucose and glutamine making roughly 70% of the fuels needed
(Calder, 1995; Frauwirth and Thompson, 2004; Maciver et al., 2008).
From the numbers in Table 3, it becomes clear that the main
consumers of energy appear to be muscles, the brain, and the im-
mune system, each with approximately 2000–2500 kJ/d. It is clear
that energy allocation to these main consumers needs to be regu-
lated in a very careful way. During the day, energy is allocated to
the brain and muscles but not to the immune system or to
growth-dependent pathways (Straub et al., 2010). This is different
during the night when the brain and muscles mainly operate at
basal levels while energy is allocated to the immune system or
growth-dependent pathways (Straub et al., 2010).
The main supporters of energy-rich fuel storage in liver, muscle,
and adipose tissue are insulin, insulin-like growth factor 1, andro-
gens/estrogens, and the parasympathetic nervous system (PSNS).
In contrast, provision of energy-rich fuels to the entire body in
the form of glucose and fatty acids is mainly supported by media-
tor substances of the sympathetic nervous system (SNS) (via
b2-adrenoceptors), of the hypothalamic–pituitary–hormonal axes
(cortisol and growth hormone), and of the pancreas (glucagon).
Provision of energy-rich fuels to the entire body is mainly stimu-
lated in the morning hours, when the brain and muscles are acti-
vated (SNS and HPA axis). Importantly, hormones of the SNS and
the HPA axis have immune inhibiting activities when present at
high concentrations, which plays a role during the morning so that
allocation of energy is directed to muscles and the brain but less to
the suppressed immune system. This is opposite in the evening and
during the first hours of the night because, now, the activity of the
SNS and the HPA axis are reduced so that immune responses and
growth are less disturbed.
Now, we recognize that systemic responses of the SNS, HPA
axis, PSNS, and other systems are of outstanding importance in en-
ergy regulation under normal and non-life-threatening conditions.
The neuroendocrine pathways, particularly the SNS and the HPA
axis, are switched-on by an activated immune system. However,
such activation of neuroendocrine pathways only happens under
certain circumstances.
5. Compartmentalized and systemic inflammation
Usually, immune and inflammatory responses are confined to a
local space which is best indicated by local immune responses in
secondary lymphoid organs. If compartmentalized inflammation
is restricted to a small space (e.g., a small skin wound), local fuel
3
stores and circulating glucose are preferentially used. Local stores
are made available by extracellular matrix breakdown (see Ref.
(Straub et al., 2010)). Moreover, local lipolysis leads to release of
free fatty acids used by immune cells. An important element in
local inflammation is adequate supply of calcium and phosphorus,
which can be provided by increased local bone breakdown when
inflammation is in the proximity of bones (Straub et al., 2010).
When inflammation is strong, a spillover of cytokines, circulat-
ing immune cells, and activation of sensory nerves report inflam-
mation to the entire body. The deeper significance of these
messages is not inhibition of the immune system as usually stated
(the classical view of the negative feedback loop), but it is much
more an appeal for energy-rich fuels: it is an ‘‘energy appeal reac-
tion” (Straub et al., 2010). Spillover inflammation activates the HPA
axis (cortisol) and the SNS (adrenaline, noradrenaline). All this is
part of a program to allocate energy-rich fuels to the immune sys-
tem by mobilizing energy-rich fuels from distant stores (reviewed
in (Straub et al., 2010)).
Importantly, coordination of interwoven pathways is not func-
tioning in CIDs as expected for short-lasting non-life-threatening
diseases because energy regulation and the neuroendocrine im-
mune interplay have not evolved to cope with long-lasting CIDs
(Straub et al., 2007; Straub and Besedovsky, 2003). As a conse-
quence, one observes multiple systemic disease-related sequelae,
the pathogenesis of which is explained by alterations of systemic
energy regulation.
6. Alterations of energy regulation and disease sequelae
Many known disease sequelae of CIDs are systemic in nature be-
cause they involve other parts of the body far away from local
inflammation. The increased awareness of these disease sequelae
is a consequence of better long-term therapy. Disease sequelae find
the pathophysiological origin in allocation of energy-rich fuels from
energy stores to the activated immune system (Table 4). Re-alloca-
tion of energy-rich fuels to the activated immune system is a conse-
quence of the energy appeal reaction discussed above. All these
alterations evolved to cope optimally with short-lasting inflamma-
tory episodes, and their long-term use in CIDs is deleterious.
In addition, in uncontrolled CIDs circadian rhythms are disturbed
due to the continuous activation of the immune system leading to a
flattening of the usual undulation (Neeck et al., 1990; Straub and
Cutolo, 2007). Disruption of circadian rhythms support uncoupling
phenomena observed in inflammatory diseases (Härle et al., 2005;
Straub et al., 2002b), and the loss of cooperative systems such as
the HPA axis and the SNS increases the inflammatory state (Straub
et al., 2002a).
Some of the above-mentioned disease sequelae are part of the
metabolic syndrome, including inflammation-induced cachectic
obesity, hypertension and sympathetic hyperactivity, insulin resis-
tance and hyperinsulinemia, and dyslipidemia. Since this type of
the metabolic syndrome depends on a proinflammatory state with
spillover inflammation one might label it ‘‘inflammatory metabolic
syndrome”. In recent years, the inflammatory metabolic syndrome
has been linked to increased cardiovascular risk and to higher mor-
tality in patients with CIDs (Chung et al., 2007; Cohen et al., 2008;
Dessein et al., 2002; Karvounaris et al., 2007; McCarey and Stur-
rock, 2009).
7. Conclusions
In 1937 Hans Selye called an activation of stress systems ‘‘alarm
reaction”, which is the reaction of an organism ‘‘when first con-
fronted with a stimulus to which it is quantitatively or qualita-
tively not adapted” (Selye and Fortier, 1949). Energy regulation
4 R.H. Straub / Brain, Behavior, and Immunity 25 (2011) 1–5

Table 4
Sequelae of chronic inflammatory diseases in the light of altered energy regulation. References that demonstrate the respective disease sequelae and the pathophysiological
explanation can be found in detail in Ref. Straub et al. (2010).

Disease sequelae Pathophysiological elements in chronic inflammation leading to energy allocation to an activated immune system
Depressive symptoms/fatigue Cytokine (e.g., IL-1b)-driven sickness behavior and fatigue which increase time at rest (muscles and brain in an
inactive state)
Anorexia Consequence of sickness behavior and fatigue
Malnutritiona Consequence of anorexia and sickness behavior
Muscle wasting-cachexia Protein breakdown in muscles as a consequence of anorexia, sickness behavior and androgen deficit
Cachectic obesity Protein breakdown in muscles as a consequence of anorexia and sickness behavior (protein breakdown > fat
breakdown)
Insulin (IGF-1) resistance (with Cytokine (e.g., TNF)-induced insulin signaling defects in liver, muscle, and fat tissue but not in immune cells. Immune
hyperinsulinemia) cells need insulin so that high insulin levels support the activity of the immune system (similar for IGF-1)
Dyslipidemiab Cytokine-driven acute phase reaction of lipid metabolism leading to higher delivery of cholesterol and other lipids to
macrophages
Increase of adipose tissue in the proximity of Presence of adipose tissue surrounding lymph nodes and in the proximity of inflammatory lesions reflects a local store
inflammatory lesions of energy-rich fuels (increased local estrogens might be important to drive local accumulation of adipose tissue).
Adipokines play a proinflammatory role
Alterations of steroid hormone axes Cytokine/leptin-driven hypoandrogenemia supports muscle breakdown and protein delivery for gluconeogenesis and
support of an activated immune system (alanine and glutamine). Cortisol-to-androgen preponderance in chronic
inflammation is catabolic
Elevated sympathetic tone and local Cytokine-driven increase of SNS activity increases gluconeogenesis and lipolysis. The parallel loss of sympathetic
sympathetic nerve fiber loss nerve fibers in inflamed tissue supports local inflammation. It also stimulates lipolysis in the surrounding adipose
tissue because sympathetic nerve fibers are increased there (unpublished results of R.H. Straub)
Decreased parasympathetic tone Cytokine-driven decrease of the PSNS activity supports allocation of energy-rich fuels to an activated immune system
Inflammation-related anemia Cytokine-driven anemia is linked to reduced energy expenditure for erythropoiesis, increased time at rest, and insulin
resistance (see above), all of which support energy allocation to the immune system
Osteopenia Driven by cytokines and PTH-related peptide during inflammation. In addition, an activated SNS and HPA axis
stimulate bone resorption. High calcium and phosphorus are mandatory for energy-consuming reactions
a
Hypovitaminosis D and others, deficiency in zink, iron, copper, magnesium, and similar.
b
Dyslipidemia in chronic inflammation reflects low levels of HDL cholesterol and/or apolipoprotein A–I and appearance of an ‘‘inflammatory HDL subfraction” with
increased serum amyloid A and ceruloplasmin. Abbreviations: HPA axis, hypothalamic–pituitary–adrenal axis; IGF, insulin-like growth factor; IL, interleukin; PTH, parathyroid
hormone; SNS, sympathetic nervous system; TNF, tumor necrosis factor.

was not included in this fist concept. With the demonstrated inclu-
sion of energy regulation into the neuroendocrine immune inter-
play, we can call this reaction an ‘‘energy appeal reaction”, which
includes the ‘‘alarm reaction” on a higher integrative level. It turns
out that many independent systemic CID-related disease phenom-
ena can be explained under consideration of this long-standing en-
ergy appeal reaction.
From this concept, we might think of interfering with energy
pathways in order to treat our CID patients. At present, we focus
much on anti-inflammatory therapies but this might change in
the future because we might use therapies that focus on energy
expenditure in the immune system.
Acknowledgments
The author was supported by multiple grants of the DFG (STR
511/5-1, STR 511/9-1, STR 511/10-1, STR 511/11-1, STR 511/14-1,
STR 511/15-1, STR 511/16-1, STR 511/17-1, PO 801/1-1, and WI
1502/2-1), DFG Research Unit (FOR696, STR 511/9-1, STR 511/20-
1, STR 511/21-1, STR 511/23-1, STR 511/25-1, STR 511/26-1, and
CA 933/1-1), DFG SFB (SFB585 project B8), DFG Mercator (Re
287/35-1), the DAAD (A/96/13772, 323-01-sr, and 423/kcw) and
BMBF (Immuno-Pain).
References
Banting, F.G., Best, C.H., Collip, J.B., Campbell, W.R., Fletcher, A.A., 1922. Pancreatic
extracts in the treatment of diabetes mellitus. Can. Med. Assoc. J. 12, 141–146.
Blaxter, K., 1989. Energy Metabolism in Animals and Man. Cambridge University
Press, Cambridge, New York, New Rochelle, Melbourne, Sydney.
Calder, P.C., 1995. Fuel utilization by cells of the immune system. Proc. Nutr. Soc. 54,
65–82.
Chung, C.P., Avalos, I., Oeser, A., Gebretsadik, T., Shintani, A., Raggi, P., Michael, S.C.,
2007. High prevalence of the metabolic syndrome in patients with systemic
lupus erythematosus: association with disease characteristics and
cardiovascular risk factors. Ann. Rheum. Dis. 66, 208–214.
Cohen, A.D., Sherf, M., Vidavsky, L., Vardy, D.A., Shapiro, J., Meyerovitch, J., 2008.
Association between psoriasis and the metabolic syndrome. A cross-sectional
study. Dermatology 216, 152–155.
Dessein, P.H., Stanwix, A.E., Joffe, B.I., 2002. Cardiovascular risk in rheumatoid
arthritis versus osteoarthritis: acute phase response related decreased insulin
sensitivity and high-density lipoprotein cholesterol as well as clustering of
metabolic syndrome features in rheumatoid arthritis. Arthritis Res. 4, R5.
Dicke, W.K., Weijers, H.A., Van der Kamer, J.H., 1953. Coeliac disease. II. The
presence in wheat of a factor having a deleterious effect in cases of coeliac
disease. Acta Paediatr. Scand. 42, 34–42.
Drappa, J., Vaishnaw, A.K., Sullivan, K.E., Chu, J.L., Elkon, K.B., 1996. Fas gene
mutations in the Canale-Smith syndrome, an inherited lymphoproliferative
disorder associated with autoimmunity. N. Engl. J. Med. 335, 1643–1649.
Finnish-German APECED Consortium, 1997. An autoimmune disease, APECED,
caused by mutations in a novel gene featuring two PHD-type zinc-finger
domains. Nat. Genet. 17, 399–403.
Frauwirth, K.A., Thompson, C.B., 2004. Regulation of T lymphocyte metabolism. J.
Immunol. 172, 4661–4665.
Härle, P., Straub, R.H., Wiest, R., Maier, A., Schölmerich, J., Atzeni, F., Carrabba, M.,
Cutolo, M., Sarzi-Puttini, P., 2005. Increase of sympathetic outflow measured by
NPY and decrease of the hypothalamic–pituitary–adrenal axis tone in patients
with SLE and RA – another example of uncoupling of response systems. Ann.
Rheum. Dis. 65, 51–56.
Iemitsu, M., Itoh, M., Fujimoto, T., Tashiro, M., Nagatomi, R., Ohmori, H., Ishii, K.,
2000. Whole-body energy mapping under physical exercise using positron
emission tomography. Med. Sci. Sports Exerc. 32, 2067–2070.
Karvounaris, S.A., Sidiropoulos, P.I., Papadakis, J.A., Spanakis, E.K., Bertsias, G.K.,
Kritikos, H.D., Ganotakis, E.S., Boumpas, D.T., 2007. Metabolic syndrome is
common among middle-to-older aged Mediterranean patients with rheumatoid
arthritis and correlates with disease activity: a retrospective, cross-sectional,
controlled, study. Ann. Rheum. Dis. 66, 28–33.
Maciver, N.J., Jacobs, S.R., Wieman, H.L., Wofford, J.A., Coloff, J.L., Rathmell, J.C., 2008.
Glucose metabolism in lymphocytes is a regulated process with significant
effects on immune cell function and survival. J. Leukoc. Biol. 84, 949–957.
McCarey, D., Sturrock, R.D., 2009. Comparison of cardiovascular risk in ankylosing
spondylitis and rheumatoid arthritis. Clin. Exp. Rheumatol. 27, S124–S126.
Nagamine, K., Peterson, P., Scott, H.S., Kudoh, J., Minoshima, S., Heino, M., Krohn, K.J.,
Lalioti, M.D., Mullis, P.E., Antonarakis, S.E., Kawasaki, K., Asakawa, S., Ito, F.,
Shimizu, N., 1997. Positional cloning of the APECED gene. Nat. Genet. 17, 393–
398.
Neeck, G., Federlin, K., Graef, V., Rusch, D., Schmidt, K.L., 1990. Adrenal secretion of
cortisol in patients with rheumatoid arthritis. J. Rheumatol. 17, 24–29.
Rassow, J., Hauser, K., Netzker, R., Deutzmann, R., 2008. Biochemistry. Georg
Thieme, Stuttgart.
Rolfe, D.F., Brown, G.C., 1997. Cellular energy utilization and molecular origin of
standard metabolic rate in mammals. Physiol. Rev. 77, 731–758.
 R.H. Straub / Brain, Behavior, and Immunity 25 (2011) 1–5
Selye, H., Fortier, C., 1949. Adaptive reactions to stress. Res. Publ. Assoc. Res. Nerv.
Ment. Dis 29, 3–18.
Straub, R.H., Besedovsky, H.O., 2003. Integrated evolutionary, immunological, and
neuroendocrine framework for the pathogenesis of chronic disabling
inflammatory diseases. FASEB J. 17, 2176–2183.
Straub, R.H., Cutolo, M., 2007. Circadian rhythms in rheumatoid arthritis:
implications for pathophysiology and therapeutic management. Arthritis
Rheum. 56, 399–408.
Straub, R.H., Cutolo, M., Buttgereit, F., Pongratz, G., 2010. Energy regulation and
neuroendocrine-immune control in chronic inflammatory diseases. J. Intern.
Med. 267, 543–560.
Straub, R.H., Del Rey, A., Besedovsky, H.O., 2007. Emerging concepts for the
pathogenesis of chronic disabling inflammatory diseases: neuroendocrine-
5
immune interactions and evolutionary biology. In: Ader, R. (Ed.),
Psychoneuroimmunology. Elsevier – Academic Press, San Diego, CA, pp. 217–
232.
Straub, R.H., Günzler, C., Miller, L.E., Cutolo, M., Schölmerich, J., Schill, S., 2002a.
Anti-inflammatory cooperativity of corticosteroids and norepinephrine in
rheumatoid arthritis synovial tissue in vivo and in vitro. FASEB J. 16, 993–
1000.
Straub, R.H., Herfarth, H., Falk, W., Andus, T., Schölmerich, J., 2002b. Uncoupling of
the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis
in inflammatory bowel disease? J. Neuroimmunol. 126, 116–125.
Van de Kamer, J.H., Weijers, H.A., 1955. Coeliac disease. V. Some experiments on the
cause of the harmful effect of wheat gliadin. Acta Paediatr. 44, 465–469.