FASEB J.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by STRAUB, R. H.
Right arrow Articles by BESEDOVSKY, H. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by STRAUB, R. H.
Right arrow Articles by BESEDOVSKY, H. O.
(The FASEB Journal. 2003;17:2176-2183.)
© 2003 FASEB

Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases

RAINER H. STRAUB1 and HUGO O. BESEDOVSKY*

Department of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany; and
* Institute of Normal and Pathological Physiology, University of Marburg, 35033 Marburg, Germany

1 Correspondence: Department of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany. E-mail: rainer.straub{at}klinik.uni-regensburg.de

ABSTRACT

The pathogenesis of chronic disabling inflammatory diseases (CDIDs) is poorly understood. Current concepts that focus on abnormalities of the immune system are, in our view, incomplete. Here we propose that chronic disruption of homeostasis through abnormal neuronal and endocrine host responses to transient inflammatory reactions contributes to the appearance of CDIDs. Coordinated reactions of the supersystems (immune, nervous, endocrine, and reproductive) that maintain homeostasis have been evolutionarily conserved to respond to and eliminate foreign agents over a period of days to a few weeks. If the responses of these supersystems fail to return to normal after elimination of the pathogen, a continuous aggressive immune response is created; this situation can trigger development of CDIDs. Maladaptation of the supersystems during CDIDs has not been evolutionarily conserved but is nevertheless still prevalent because a large proportion of these diseases tend to appear after the reproductive phase. We propose that this integrated systems hypothesis may permit better identification of a patient at risk or in the early stages of developing a CDID such as rheumatoid arthritis and enable more coordinated intervention than is presently attempted.—Straub, R. H., Besedovsky, H. O. Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases.


Key Words: chronic inflammatory disease • immune system • endocrine system • nervous system • reproductive system

IMMUNE TOLERANCE AND IMMUNE AGGRESSION: WHAT IS THE ROLE OF THE FOUR SUPERSYSTEMS?

IN CHRONIC DISABLING inflammatory diseases (CDIDs), various immunological models such as "self-nonself" (1) , "infectious-nonself" (2) ,"danger model" (3) , "missing self," and "altered self" (4) explain facets of these diseases (including the relevance of autoantigen or commensurate foreign antigen). In recent years, it has been shown that tolerance against an antigen occurs when dendritic cells ingest and present this antigen in the context of low expression of MHC class II and costimulatory molecules and in a microenvironment in which the cytokine cocktail is of anti-inflammatory nature (5) . If this cocktail is proinflammatory, an aggressive response will follow (Fig. 1 ) (5) .



View larger version (60K):
[in this window]
[in a new window]
  		Figure 1. Induction of tolerance and aggression. Left panel: Upon entrance of an antigen into the skin or mucosa, local macrophages and dendritic cells take up the antigen (ingestion area). If local cells react in a peaceful manner, the antigen does not induce a strong immune reaction (blue and green). Nerve fibers and hormone concentrations remain in a normal homeostatic balance. In the ingestion area, dendritic cells are programmed for tolerance, supported by neurotransmitters and hormones. The dendritic cell then migrates to the secondary lymphoid organ to present the processed antigen to T and B cells (presentation area). T and B cells clonally expand within 1–2 wk. Under anti-inflammatory conditions, most of the T and B cells become regulatory. Right panel: The local antigen induces a strong inflammatory wound response with hyperinnervation of sensory nerves, reduction of sympathetic nerves, and scar formation (red and violet). Due to disruption of local homeostasis, secondary responses provide a continuous proinflammatory milieu that leads to an aggressive immune response. Dendritic cells migrate to the secondary lymphoid organ in order to present the processed antigen. Due to programming of dendritic cells, presentation happens in a proinflammatory microenvironment. Under these conditions, most of T and B cells become aggressive.

In the last decade it became evident that the presence of self-reactive lymphocytes is rather normal (6) . However, in healthy people, autoimmune diseases do not establish because the antigens are presented under anti-inflammatory conditions and regulatory T cells are generated. In animal models of autoimmune diseases, coinjection of a strong immune stimulus such as Freund’s adjuvant is needed to guarantee a proinflammatory condition during ingestion and presentation of the antigen. During situations that are not polarized regarding aggression vs. tolerance, the impact of other factors such as hormones and neurotransmitters becomes decisive (Table 1 ). If an acute inflammatory disease is not rapidly resolved, aggression predominates (see below) and the disease becomes chronic, using different types of immune reactions such as Th1, Th2, and intermediate responses. Whether the immune system uses one or the other response depends mainly on the antigen (concentration, epitope, antigen receptor density), the dendritic cells involved, pattern recognition, and the microenvironment (7) .


View this table:
[in this window]
[in a new window]
  		Table 1. Effect of various mediators of the nervous and endocrine system on function of dendritic cells

ADVANTAGEOUS ADAPTATION TO CHRONIC DISABLING INFLAMMATORY DISEASES WAS NOT EVOLUTIONARILY CONSERVED

At the time of the homo erectus (1 million years ago), the reproductive period lasted ~12–25 years (16) . Prolongation of life expectancy as a consequence of hygienic and nutritive practices and modern medicine was not predicted by biological evolution and, paradoxically, allowed the expression of many CDIDs that appear after the age of 25 years. Any tendency to chronicity is a handicap for the individual (e.g., in competition for nutrients and vulnerability to predators), implying a negative selection pressure. Furthermore, systemic inflammatory episodes lead to the production of cytokines that mediate strong inhibition of the hypothalamus–pituitary–gonadal axis at different levels, resulting in inhibition of reproduction (17) . Such linkage between blunted reproductive functions and proinflammatory cytokines has most likely not allowed the evolutionary acquisition of well-adjusted immune neuroendocrine responses to impede the chronic development of a disease.

A typical example is the adult form of rheumatoid arthritis, a CDID with severe polyarticular inflammatory symptoms. We hypothesize that, under natural conditions, this disabling disease would hardly be expressed for a long time (as a chronic disease) because of the need to cope with the environmental threats and to compete for nutrients. However, the genetic background that predisposes to the disease can still be transmitted to the progeny by an individual that would suffer from rheumatoid arthritis later in life. Conversely, advantageous mechanisms to prevent late-manifesting rheumatoid arthritis and other CDIDs might have not been evolutionarily conserved possibly because advantageous genes were not retained in the offspring. Genes that may be beneficial in the early period of life may be deleterious in the elderly with a CDID: e.g., sickle cell disease is the genetic condition selected for in regions of endemic malaria (18) . This is called the pleiotropy theory of aging (19) , but it can also be applied to CDIDs.

There is still a need to explain why genetic (e.g., HLA-linked) predisposition for CDIDs that appears before or during the reproductive period has been retained. Indeed, a juvenile form of a CDID might have been a tremendous obstacle for reproduction. Even today, CDIDs such as juvenile chronic arthritis significantly diminish the probability of successful conception (20) . The question arises: Why do CDIDs still exist in young people. In our view, a solution to this apparent paradox resides in the fact that CDIDs have a multifactorial, genetically polymorph background. For example, HLA-B27 is important for ankylosing spondylitis (relative risk=90). HLA-B27 could have been retained in the offspring because in most cases the disease does not develop due to the lack of additional factors (genetically inherited or environmental). Thus, the genetic prerequisites for a CDID can be retained over generations through individuals that never express the full manifestation of the disease because relevant cofactors either may not occur or are expressed following very irregular patterns and only after the reproductive phase (Table 2 ). This scenario would allow the appearance of CDIDs in the young (we may call it the "accumulation theory").


View this table:
[in this window]
[in a new window]
  		Table 2. HLA association of disease and age at disease onseta

HOMEOSTATIC MECHANISMS ARE EVOLUTIONARILY CONSERVED FOR TRANSIENT INFLAMMATORY REACTIONS AND ARE MISTAKEN IN CHRONIC DISABLING INFLAMMATORY DISEASES

The innate immune system, the nervous system, the endocrine system, and the reproductive system (which includes the tissue repair system with stem cells) are homeostatic supersystems that integrate many reactions for transient inflammatory events (Table 3 ). During a period of ~109 years, an extremely efficient pattern of receptors for recognition of foreign agents has been evolutionarily conserved in our genome (30) . Responses triggered by stimulation of these receptors are immediate, nonclonal, independent of gene rearrangement, and the pattern repertoire is small. In contrast to innate immunity, the young adaptive immune system (arising with the vertebrates 450 million years ago) demonstrates a striking dissociation from these older evolutionary elements: gene rearrangement in T and B cells is no longer fixed in the genome, which leads to a high number of 109 to 1011 antigenic determinants. In antigen-activated peripheral B cells, every infection leads to a high rate of somatic point mutations (hypermutation), which improves affinity for the antigen. Both factors bear a highly significant risk for errors of discrimination of self and foreign. The big advantage of the adaptive immune system is its memory for the antigen, specificity, and diversity (which allows the recognition of future emerging antigens) (30 , 31) . This has been evolutionarily advantageous, as ~94% of the human population profits from the adaptive immune system and only 6% suffer from CDIDs. What homeostatic mechanisms have been evolutionarily conserved for transient inflammatory reactions that are mistaken in CDIDs?


View this table:
[in this window]
[in a new window]
  		Table 3. Evolutionarily conserved transient inflammatory reactions

The immune system
The evolutionarily conserved reaction against an unwanted antigen is continuous aggressive attack until it is completely eliminated. In the case of a harmless self or foreign antigen, the continuous attack is no longer meaningful. In rheumatoid arthritis, a large list of self antigens has been reported (32) , and some epitopes are identical for the human disease and in experimental models (33) . However, whether rheumatoid arthritis is an autoimmune disease with broken tolerance against self rather than a disease with an inflammatory reaction against a foreign antigen is still a matter of debate. Nevertheless, rheumatoid arthritis is a severe CDID with continuously strong proinflammatory and destructive behavior (continuous aggression).

The endocrine system
In the early phase of an inflammatory episode an immediate rise of serum cortisol, plasma epinephrine, and norepinephrine is observed (34 35 36) . These endocrine reactions were most likely conserved to control inflammatory reactions and cytokine production (37) . It has been demonstrated that cortisol and norepinephrine are necessary to establish an adequate immune reaction (38 39 40) as well as early mobilization of immune cells and their redistribution (41 , 42) . However, a prolonged increase in the activity of the HPA axis and the sympathetic nervous system during immune processes predisposes to severe infections. Endotoxin-induced increase of cortisol levels is achieved at the expense of adrenal androgens (43) , which are anti-inflammatory (reviewed in ref 44 ). Thus, during infection, the fast cortisol rise and fall and the loss of adrenal androgens have been evolutionarily conserved to support a strong immune reaction. In the case of a prolonged immune aggression such as in rheumatoid arthritis, these evolutionarily conserved mechanisms are used in the wrong way: a rapid loss of the anti-inflammatory mediators cortisol and androgens and their continuous inadequate production are unfavorable in CDIDs (45 46 47 48) .

The behavior of another important endocrine mediator should be considered. During an infectious disease, prolactin sharply increases (49) . Furthermore, prolactin is a strong stimulator of the immune system (50 , 51) . The evolutionarily conserved reaction during an infectious episode is the increase of prolactin, particularly to shelter mother and baby during breast-feeding. In rheumatoid arthritis and other CDIDs, the increase in serum prolactin provides a continuous unfavorable proinflammatory situation (52) . Again, the evolutionarily conserved response to transient infectious disease or other harmless inflammatory episodes has adverse consequences in CDIDs.

The nervous system
After invasion by a pathogen (e.g., foreign body with or without infectious agents), 1) the sensory nervous system signals this event to the central nervous system. 2) In parallel, substance P is locally released from sensory nerve terminals and attracts monocytes and neutrophils (53 , 54) . Substance P activates these cells to produce proinflammatory cytokines such as IL-1ß and TNF (55) . 3) In a later phase of the wound healing process, substance P stimulates fibroblasts to generate matrix in order to close the wound (56) . The reaction of the sensory nervous system is accompanied by peripheral and central sensitization, which imprints pain pathways (57) , an evolutionarily conserved learning phenomenon to get rid of the foreign body. 4) On the other hand, sympathetic nerves hinder the wound healing process (58 , 59) . Thus, for 3 up to 21 days of a wound reaction, the preponderance of sensory over sympathetic nerve fibers was evolutionarily conserved for wound healing (60 , 61) . In the case of an improper immune reaction such as in rheumatoid arthritis, the same wound healing phenomena (62 , 63) combined with an inadequate cortisol secretion exists (64) . Now they support the continuation of a local aggressive immune response. This evolutionarily conserved wound reaction is no longer advantageous in a CDID.

Another phenomenon of acute infectious disease is sickness behavior in the form of malaise, fatigue, numbness, coldness, muscle and joint aches, reduced appetite, anxiety, and depressive mood triggered by proinflammatory cytokines in the CNS (65 , 66) . The behavioral components of sickness represent, together with the fever response and the associated neuroendocrine changes, a highly organized strategy to fight infection. In a CDID such as rheumatoid arthritis, the same proinflammatory cytokines induce comparable symptoms such as depression, anxiety, hypersensitivity, and numbness (reviewed in ref 67 ). This evolutionarily conserved behavior is now incorrect because it is used for the wrong situation.

The reproductive system
Before the embryonic blastocyst can enter the mucosa, the mucosa must be prepared by estrogens and progesterone (68) . 17ß-Estradiol and progesterone are strong stimulators of vascular endothelial growth factor (VEGF) (68) . Furthermore, adhesion molecules such as ß 1 integrins and {alpha}5 ß3 integrin are needed for attachment of the blastocyst (69) . 17 ß-Estradiol is a stimulator of these adhesion molecules (70) . The same adhesion molecules play an essential role in angiogenesis during a wound healing process and in leukocyte traffic and homing (71) . During the transient inflammatory wound healing process, the repair system is stimulated so that multipotent stem cells can enter the tissue, which is prepared by estrogens and supported by vessel formation. During rheumatoid arthritis, the inflammatory process leads to a local preponderance of estrogens vs. androgens (72) . These estrogens up-regulate adhesion molecules and induce neovascularization via VEGF (73) . The same mechanisms are used continuously during an immune aggression against a harmless antigen, which adds to the continuation of inflammation. One would expect that women, in particular, with a perfect estrogen/progesterone-driven reproductive system use more of these erroneous mechanisms during a CDID in later life (pleiotropy theory).

The accumulation of these mistaken reactions of all homeostatic supersystems, which were evolutionarily conserved for transient inflammatory reactions, would start the chronic process in CDIDs. One may use the following formula for a simple illustration:

In this formula, "n" is the maximum number and "i" is the ordinal of the reactions included in the equation. The potential of chronic development increases with the number of erroneous adaptational reactions included. The weighing factor gives an impression of how important the respective element may be.

THE TIME POINT WHEN CDIDS BECOME CHRONIC

Two explanations are provided that demonstrate a possible time point when CDIDs become chronic:

1) It should be considered that the above-mentioned adaptation processes to transient inflammatory reactions are terminated within 3 to 5 wk (Table 3) . In the case of an erroneous immune reaction against a harmless antigen (self or foreign), the antigen is not eliminated after 3 to 5 wk, but possible tolerance-inducing anti-inflammatory responses of the other supersystems (apart from the adaptive immune system) may not be available after 3 to 5 wk due to the cited evolutionarily conserved reactions for only transient inflammatory responses (Fig. 2 ).



View larger version (124K):
[in this window]
[in a new window]
  		Figure 2. Evolutionarily conserved changes of the supersystems related to acute immune challenges, the maintenance of which induces an overall proinflammatory nontolerogenic situation. This includes inadequate low levels of systemic cortisol (A, two different time courses of cortisol increase are demonstrated), decreased local androgens and progesterone (C), decrease in local neurotransmitters of the sympathetic nerve terminal due to nerve fiber repulsion (E) and elevated systemic levels of prolactin (B), locally increased 17ß-estradiol (D), and high levels of local substance P due to sensory hyperinnervation (nerve fiber sprouting) (F). The systemic or local level of all mentioned factors changes in relation to the initial level into an aggressive direction (red zone) but never into a tolerogenic direction (blue zone). ß-END, ß-endorphin (from sympathetic nerve terminals); NE, norepinephrine, NPY, neuropeptide Y; VIP, vasoactive intestinal peptide.

2) The erroneous responses of the supersystems change with time. In the early phase of a CDID (first weeks), clonal expansion of highly affine aggressive immune cells and generation of memory are most important; the adaptive immune system is the main player (before appearance of overt clinical symptoms). After the appearance of overt clinical symptoms, the local inflammatory process in a joint involves many other cell types such as neutrophils, macrophages, natural killer cells, fibroblasts, endothelial cells, nerve fibers, and others (evolutionarily, the old players). Since the supersystems influence these two portions of the disease in a very different way, their influence on the course of a CDID must change when the local inflammatory process acquires a dominant role. This happens within the first weeks after the appearance of clinical symptoms (e.g., arthritis).

CONCLUSIONS

At the beginning of CDIDs, immune tolerance against self or harmless foreign antigens is broken and all supersystems differentially contribute to the deleterious process: the accumulation of erroneous adaptive processes of all supersystems is responsible for the preponderance of aggression vs. tolerance. CDIDs become chronic due to aberrant expression of programs that have been preserved to cope with acute events during transient inflammatory reactions only.

Therapeutical approaches must correct the individual elements of the mistaken adaptational processes of all supersystems. In our view, the continuous suppression of the immune system used as therapeutical approach during the last 50 years has been only partly successful in treating CDIDs because other aspects have been neglected. According to this view, therapeutic interventions during the early phase of the disease must be a combination of therapy intended to correct the erroneous adaptational processes of all supersystems.

The patient at risk of a CDID with first symptoms should immediately enter specialized care, where the potential of developing a CDID would be evaluated. This evaluation must be based on novel diagnostic predictive tools that have to be developed in the near future. The predictive tools of necessity must include diagnostic tests to evaluate defined parameters of all supersystems. Early, improved diagnosis on this basis should lead to fast and adequate therapy in order to prevent extensive irreparable tissue destruction.

ACKNOWLEDGMENTS

We thank our colleagues, particularly D. Jessop, Bristol, UK, and A. del Rey, Marburg, Germany, as well as D. J. J. Carr, Oklahoma City, USA; M. Cutolo, Genova, Italy; J. A. P. da Silva, Coimbra, Portugal; T. Glück, Regensburg, Germany; S. Huber, Freiburg, Germany; D. N. Männel, Regensburg, Germany; U. Müller-Ladner, Regensburg, Germany; M. Schmidt, Jena, Germany; J. Schölmerich, Regensburg, Germany; V. M. Sanders, Columbus, USA; J. Westermann, Lübeck, Germany, for helpful suggestions in preparing this manuscript. This work was supported by several national grants of the Deutsche Forschungsgemeinschaft (DFG), the Volkswagen Foundation (VWS), and the Nationales Genom-Forschungsnetz (NGFN) (Straub: Str 511/5-1,2,3; Str 511/9-1,2,3; Str 511/10-1,2; Str 511/11-1,2; Wi 1502/2-1; SFB 585/B8, VWS I/68950; Besedovsky: SFB 297/C1; VWS I/67419; (NGFN) NV-S14T02).

FOOTNOTES

doi: 10.1096/fj.03-0433hyp

Received for publication May 30, 2003. Accepted for publication July 2, 2003.

REFERENCES

  1. Burnett, F. M. (1959) The Conal Selection Theory of Acquired Immunity Vanderbilt University Press Nashville, Tennessee.
  2. Janeway, C. A., Jr (1989) Approaching the asymptote?Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54,1-13
  3. Matzinger, P. (2002) The danger model: a renewed sense of self. Science 296,301-305[Abstract/Free Full Text]
  4. Medzhitov, R., Janeway, C. A., Jr (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296,298-300[Abstract/Free Full Text]
  5. Lutz, M., Schuler, G. (2002) Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?. Trends Immunol 23,445-449[CrossRef][Medline]
  6. Agrawal, B., Manickasundari, M., Fraga, E., Singh, B. (1991) T cells that recognize peptide sequences of self MHC class II molecules exist in syngeneic mice. J. Immunol. 147,383-390[Abstract]
  7. Murray, J. S. (1998) How the MHC selects Th1/Th2 immunity. Immunol. Today 19,157-163[CrossRef][Medline]
  8. Seiffert, K., Hosoi, J., Torii, H., Ozawa, H., Ding, W., Campton, K., Wagner, J. A., Granstein, R. D. (2002) Catecholamines inhibit the antigen-presenting capability of epidermal Langerhans cells. J. Immunol. 168,6128-6135[Abstract/Free Full Text]
  9. Lambrecht, B. N., Germonpre, P. R., Everaert, E. G., Carro-Muino, I., De Veerman, M., de Felipe, C., Hunt, S. P., Thielemans, K., Joos, G. F., Pauwels, R. A. (1999) Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur. J. Immunol. 29,3815-3825[CrossRef][Medline]
  10. Torii, H., Tamaki, K., Granstein, R. D. (1998) The effect of neuropeptides/hormones on Langerhans cells. J. Dermatol. Sci. 20,21-28[CrossRef][Medline]
  11. Delneste, Y., Herbault, N., Galea, B., Magistrelli, G., Bazin, I., Bonnefoy, J. Y., Jeannin, P. (1999) Vasoactive intestinal peptide synergizes with TNF-alpha in inducing human dendritic cell maturation. J. Immunol. 163,3071-3075[Abstract/Free Full Text]
  12. de Jong, E. C., Vieira, P. L., Kalinski, P., Kapsenberg, M. L. (1999) Corticosteroids inhibit the production of inflammatory mediators in immature monocyte-derived DC and induce the development of tolerogenic DC3. J. Leukoc. Biol. 66,201-204[Abstract]
  13. Komi, J., Lassila, O. (2000) Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells. Blood 95,2875-2882[Abstract/Free Full Text]
  14. Komi, J., Mottonen, M., Luukkainen, R., Lassila, O. (2001) Non-steroidal anti-oestrogens inhibit the differentiation of synovial macrophages into dendritic cells. Rheumatology (Oxford) 40,185-191
  15. Galasso, F., Altamura, V., Sbano, E. (1996) Effects of topical testosterone propionate on the positive nickel patch test. J. Dermatol. Sci. 13,76-82[CrossRef][Medline]
  16. Baur, M., Ziegler, G. (2001) Die Odyssee des Menschen—Es begann in Afrika Econ Ullstein List Verlag München, Germany.
  17. Adashi, E. Y., Resnick, C. E., Croft, C. S., Payne, D. W. (1989) Tumor necrosis factor alpha inhibits gonadotropin hormonal action in nontransformed ovarian granulosa cells.A modulatory noncytotoxic property. J. Biol. Chem. 264,11591-11597[Abstract/Free Full Text]
  18. Monekosso, G. L., Ibiama, A. A. (1966) Splenomegaly and sickle-cell trait in a malaria-endemic village. Lancet 1,1347-1348[CrossRef][Medline]
  19. Kirkwood, T. B., Austad, S. N. (2000) Why do we age?. Nature (London) 408,233-238[CrossRef][Medline]
  20. Ostensen, M., Almberg, K., Koksvik, H. S. (2000) Sex, reproduction, and gynecological disease in young adults with a history of juvenile chronic arthritis. J. Rheumatol. 27,1783-1787[Medline]
  21. Thomas, L. (1998) Clinical Laboratory Diagnostics: Use and Assessment of Clinical Laboratory Results TH-Books Frankfurt, Germany.
  22. Braun, J., van der Heijde, D., Pincus, T. (2002) Novel anti-rheumatic therapies challenge old views on ankylosing spondylitis and other spondylarthropathies. Clin. Exp. Rheumatol. 20,S-1-S-2
  23. Fan, P. T., Yu, D. T. Y. (1993) Reiter's syndrome. Kelley, W. N. Harris, E. D. Ruddy, S. Sledge, C. B. eds. Textbook of Rheumatology ,961-973 Saunders Philadelphia.
  24. Simmons, D. (1990) Prevalence and age of onset of type 1 diabetes in adult Asians in the Coventry Diabetes Study. Diabet. Med. 7,238-241[Medline]
  25. Smith, J. B., Tulloch, J. E., Meyer, L. J., Zone, J. J. (1992) The incidence and prevalence of dermatitis herpetiformis in Utah. Arch. Dermatol. 128,1608-1610[Abstract]
  26. Bell, D. A., Rigby, R., Stiller, C. R., Clark, W. F., Harth, M., Ebers, G. (1984) HLA antigens in systemic lupus erythematosus: relationship to disease severity, age at onset, and sex. J. Rheumatol. 11,475-479[Medline]
  27. Croker, B. P., Dawson, D. V., Sanfilippo, F. (1983) IgA nephropathy. Correlation of clinical and histologic features. Lab. Invest. 48,19-24
  28. Kurtzke, J. F., Page, W. F., Murphy, F. M., Norman, J. E., Jr (1992) Epidemiology of multiple sclerosis in US veterans. 4. Age at onset. Neuroepidemiology 11,226-235[Medline]
  29. Sklar, C. A., Qazi, R., David, R. (1986) Juvenile autoimmune thyroiditis.Hormonal status at presentation and after long-term follow-up. Am. J. Dis. Child. 140,877-880[Abstract]
  30. Marchalonis, J. J., Kaveri, S., Lacroix-Desmazes, S., Kazatchkine, M. D. (2002) Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system. FASEB J 16,842-848[Abstract/Free Full Text]
  31. Abbas, A. K., Lichtman, A. H., Pober, J. S. (1997) Cellular and Molecular Immunology Saunders Philadelphia, Pennsylvania.
  32. Bläß, S., Engel, J. M., Burmester, G. R. (1999) The immunologic homunculus in rheumatoid arthritis. Arthritis Rheum 42,2499-2506[CrossRef][Medline]
  33. Burkhardt, H., Koller, T., Engstrom, A., Nandakumar, K. S., Turnay, J., Kraetsch, H. G., Kalden, J. R., Holmdahl, R. (2002) Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse. Arthritis Rheum 46,2339-2348[CrossRef][Medline]
  34. Jones, S. B., Romano, F. D. (1984) Plasma catecholamines in the conscious rat during endotoxicosis. Circ. Shock 14,189-201[Medline]
  35. Suzuki, S., Oh, C., Nakano, K. (1986) Pituitary-dependent and -independent secretion of CS caused by bacterial endotoxin in rats. Am. J. Physiol. 250,E470-E474[Medline]
  36. Christeff, N., Auclair, M. C., Benassayag, C., Carli, A., Nunez, E. A. (1987) Endotoxin-induced changes in sex steroid hormone levels in male rats. J. Steroid Biochem. 26,67-71[CrossRef][Medline]
  37. Besedovsky, H. O., Del Rey, A., Sorkin, E., Dinarello, C. (1986) Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233,652-654[Abstract/Free Full Text]
  38. Madden, K. S., Felten, S. Y., Felten, D. L., Sundaresan, P. R., Livnat, S. (1989) Sympathetic neural modulation of the immune system.I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy. Brain Behav. Immun. 3,72-89[CrossRef][Medline]
  39. Del Rey, A., Kabiersch, A., Petzoldt, S., Besedovsky, H. O. (2002) Involvement of noradrenergic nerves in the activation and clonal deletion of T cells stimulated by superantigen in vivo. J. Neuroimmunol. 127,44-53[CrossRef][Medline]
  40. Kohm, A. P., Sanders, V. M. (2000) Norepinephrine: a messenger from the brain to the immune system. Immunol. Today 21,539-542[CrossRef][Medline]
  41. Toft, P., Helbo-Hansen, H. S., Tonnesen, E., Lillevang, S. T., Rasmussen, J. W., Christensen, N. J. (1994) Redistribution of granulocytes during adrenaline infusion and following administration of cortisol in healthy volunteers. Acta Anaesthesiol. Scand. 38,254-258[Medline]
  42. Dhabhar, F. S., Miller, A. H., McEwen, B. S., Spencer, R. L. (1995) Effects of stress on immune cell distribution.Dynamics and hormonal mechanisms. J. Immunol. 154,5511-5527[Abstract]
  43. Straub, R. H., Schuld, A., Mullington, J., Haack, M., Schölmerich, J., Pollmächer, T. (2002) The endotoxin-induced increase of cytokines is followed by an increase of cortisol relative to dehydroepiandrosterone (DHEA) in healthy male subjects. J. Endocrinol. 175,467-474[Abstract]
  44. Cutolo, M., Wilder, R. (2000) Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheum. Dis. Clin. N. Am. 26,825-839[CrossRef][Medline]
  45. Masi, A. T., Josipovic, D. B., Jefferson, W. E. (1984) Low adrenal androgenic-anabolic steroids in women with rheumatoid arthritis (RA): gas-liquid chromatographic studies of RA patients and matched normal control women indicating decreased 11-deoxy-17-ketosteroid excretion. Semin. Arthritis Rheum. 14,1-23[CrossRef][Medline]
  46. Cutolo, M., Balleari, E., Giusti, M., Monachesi, M., Accardo, S. (1988) Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation. Arthritis Rheum 31,1314-1317[Medline]
  47. Crofford, L. J., Kalogeras, K. T., Mastorakos, G., Magiakou, M. A., Wells, J., Kanik, K. S., Gold, P. W., Chrousos, G. P., Wilder, R. L. (1997) Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J. Clin. Endocrinol. Metab. 82,1279-1283[Abstract/Free Full Text]
  48. Straub, R. H., Paimela, L., Peltomaa, R., Schölmerich, J., Leirisalo-Repo, M. (2002) Inadequately low serum levels of steroid hormones in relation to IL-6 and TNF in untreated patients with early rheumatoid arthritis and reactive arthritis. Arthritis Rheum 46,654-662[CrossRef][Medline]
  49. Feldman, C., Joffe, B., Panz, V. R., Levy, H., Walker, L., Kallenbach, J. M., Seftel, H. C. (1989) Initial hormonal and metabolic profile in critically ill patients with community-acquired lobar pneumonia. S. Afr. Med. J. 76,593-596[Medline]
  50. Spangelo, B. L., Hall, N. R., Ross, P. C., Goldstein, A. L. (1987) Stimulation of in vivo antibody production and concanavalin-A-induced mouse spleen cell mitogenesis by prolactin. Immunopharmacology 14,11-20[CrossRef][Medline]
  51. Matera, L., Cesano, A., Bellone, G., Oberholtzer, E. (1992) Modulatory effect of prolactin on the resting and mitogen-induced activity of T, B, and NK lymphocytes. Brain Behav. Immun. 6,409-417[CrossRef][Medline]
  52. Jorgensen, C., Bressot, N., Bologna, C., Sany, J. (1995) Dysregulation of the hypothalamo-pituitary axis in rheumatoid arthritis. J. Rheumatol. 22,1829-1833[Medline]
  53. Ruff, M. R., Wahl, S. M., Pert, C. B. (1985) Substance P receptor-mediated chemotaxis of human monocytes. Peptides 6,107-111
  54. Roch-Arveiller, M., Regoli, D., Chanaud, B., Lenoir, M., Muntaner, O., Stralzko, S., Giroud, J. P. (1986) Tachykinins: effects on motility and metabolism of rat polymorphonuclear leucocytes. Pharmacology 33,266-273[Medline]
  55. Lotz, M., Vaughan, J. H., Carson, D. A. (1988) Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 241,1218-1221[Abstract/Free Full Text]
  56. Nilsson, J., von Euler, A. M., Dalsgaard, C. J. (1985) Stimulation of connective tissue cell growth by substance P and substance K. Nature (London) 315,61-63[CrossRef][Medline]
  57. Schaible, H. G., Grubb, B. D. (1993) Afferent and spinal mechanisms of joint pain. Pain 55,5-54[CrossRef][Medline]
  58. Perez, E., Lopez-Briones, L. G., Gallar, J., Belmonte, C. (1987) Effects of chronic sympathetic stimulation on corneal wound healing. Invest. Ophthalmol. Vis. Sci. 28,221-224[Abstract/Free Full Text]
  59. Wucherpfennig, A. L., Chiego, D. J., Jr, Avery, J. K. (1990) Tritiated thymidine autoradiographic study on the influence of sensory and sympathetic innervation on periodontal wound healing in the rat. Arch. Oral Biol. 35,443-448[CrossRef][Medline]
  60. Westerman, R. A., Carr, R. W., Delaney, C. A., Morris, M. J., Roberts, R. G. (1993) The role of skin nociceptive afferent nerves in blister healing. Clin. Exp. Neurol. 30,39-60[Medline]
  61. Reynolds, M. L., Fitzgerald, M. (1995) Long-term sensory hyperinnervation following neonatal skin wounds. J. Comp. Neurol. 358,487-498[CrossRef][Medline]
  62. Pereira, d. S. J., Carmo-Fonseca, M. (1990) Peptide containing nerves in human synovium: immunohistochemical evidence for decreased innervation in rheumatoid arthritis. J. Rheumatol. 17,1592-1599[Medline]
  63. Miller, L. E., Jüsten, H. P., Schölmerich, J., Straub, R. H. (2000) The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages. FASEB J 14,2097-2107[Abstract/Free Full Text]
  64. Straub, R. H., Günzler, C., Miller, L. E., Cutolo, M., Schölmerich, J., Schill, S. (2002) Anti-inflammatory cooperativity of corticosteroids and norepinephrine in rheumatoid arthritis synovial tissue in vivo and in vitro. FASEB J 16,993-1000[Abstract/Free Full Text]
  65. Bluthe, R. M., Pawlowski, M., Suarez, S., Parnet, P., Pittman, Q., Kelley, K. W., Dantzer, R. (1994) Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice. Psychoneuroendocrinology 19,197-207[CrossRef][Medline]
  66. Reichenberg, A., Yirmiya, R., Schuld, A., Kraus, T., Haack, M., Morag, A., Pollmächer, T. (2001) Cytokine-associated emotional and cognitive disturbances in humans. Arch. Gen. Psychiatry 58,445-452[Abstract/Free Full Text]
  67. Herrmann, M., Schölmerich, J., Straub, R. H. (2000) Stress and rheumatic diseases. Rheum. Dis. Clin. N. Am. 26,8-1-8-27
  68. Shifren, J. L., Tseng, J. F., Zaloudek, C. J., Ryan, I. P., Meng, Y. G., Ferrara, N., Jaffe, R. B., Taylor, R. N. (1996) Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during themenstrual cycle and in the pathogenesis of endometriosis. J. Clin. Endocrinol. Metab. 81,3112-3118[Abstract]
  69. Yoshimura, Y., Miyakoshi, K., Hamatani, T., Iwahashi, K., Takahashi, J., Kobayashi, N., Sueoka, K., Miyazaki, T., Kuji, N., Tanaka, M. (1998) Role of beta 1 integrins in human endometrium and decidua during implantation. Horm. Res. 50,46-55
  70. Shiokawa, S., Yoshimura, Y., Nagamatsu, S., Sawa, H., Hanashi, H., Oda, T., Katsumata, Y., Koyama, N., Nakamura, Y. (1996) Expression of beta 1 integrins in human endometrial stromal and decidual cells. J. Clin. Endocrinol. Metab. 81,1533-1540[Abstract]
  71. Tonnesen, M. G., Feng, X., Clark, R. A. (2000) Angiogenesis in wound healing. J. Investig. Dermatol. Symp. Proc. 5,40-46[CrossRef][Medline]
  72. Castagnetta, L. A., Carruba, G., Granata, O. M., Stefano, R., Miele, M., Schmidt, M., Cutolo, M., and Straub, R. H. (2003) Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. J. Rheumatol., In press
  73. Cid, M. C., Kleinman, H. K., Grant, D. S., Schnaper, H. W., Fauci, A. S., Hoffman, G. S. (1994) Estradiol enhances leukocyte binding to tumor necrosis factor (TNF) -stimulated endothelial cells via an increase in TNF-induced adhesion molecules E-selectin, intercellular adhesion molecule type 1, and vascular cell adhesion molecule type 1. J. Clin. Invest. 93,17-25[Medline]



This article has been cited by other articles:


Home page
 EndocrinologyHome page
D. S. Jessop
The Fragile Mind: Early Life Stress and Inflammatory Disease
Endocrinology, June 1, 2008; 149(6): 2724 - 2726.
[Full Text] [PDF]

Home page
 GutHome page
R H Straub, R Wiest, U G Strauch, P Harle, and J Scholmerich
The role of the sympathetic nervous system in intestinal inflammation.
Gut, November 1, 2006; 55(11): 1640 - 1649.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. del Rey, E. Roggero, A. Randolf, C. Mahuad, S. McCann, V. Rettori, and H. O. Besedovsky
IL-1 resets glucose homeostasis at central levels
PNAS, October 24, 2006; 103(43): 16039 - 16044.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
J. W.J. BIJLSMA, A. MASI, R. H. STRAUB, R. LAHITA, and M. CUTOLO
Neuroendocrine Immune System Involvement in Rheumatology
Ann. N.Y. Acad. Sci., June 1, 2006; 1069(1): xviii - xviii.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by STRAUB, R. H.
Right arrow Articles by BESEDOVSKY, H. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by STRAUB, R. H.
Right arrow Articles by BESEDOVSKY, H. O.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS