Category: Immune System

The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system

Abstract:

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system “talk to each other” and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis.

Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors.

Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest.

In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta.

Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production.

Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages.

The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth.

Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

 

Source: Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000 Dec;52(4):595-638. http://pharmrev.aspetjournals.org/content/52/4/595.long (Full article)

 

Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis

Abstract:

Chronic Fatigue and/or Fibromyalgia have long been diseases without definition. An explanatory model of coagulation activation has been demonstrated through use of the ISAC panel of five tests, including, Fibrinogen, Prothrombin Fragment 1+2, Thrombin/ AntiThrombin Complexes, Soluble Fibrin Monomer, and Platelet Activation by flow cytometry. These tests show low level coagulation activation from immunoglobulins (Igs) as demonstrated by Anti-B2GPI antibodies, which allows classification of these diseases as a type of antiphospholipid antibody syndrome. The ISAC panel allows testing for diagnosis as well as monitoring for anticoagulation protocols in these patients.

 

Source: Berg D, Berg LH, Couvaras J, Harrison H. Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis. Blood Coagul Fibrinolysis. 1999 Oct;10(7):435-8. http://www.ncbi.nlm.nih.gov/pubmed/10695770

 

Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome

Abstract:

The present study was designed to investigate the interaction between neuroendocrine mediators and the immune system in chronic fatigue syndrome (CFS). We examined the sensitivity of the immune system to the glucocorticoid agonist dexamethasone and the beta2-adrenergic agonist terbutaline in 15 adolescent girls with CFS and 14 age- and sex-matched controls.

Dexamethasone inhibits T-cell proliferation in healthy controls and in CFS patients. However, the maximal effect of dexamethasone on T-cell proliferation is significantly reduced in CFS patients as compared with controls. The beta2-adrenergic receptor agonist terbutaline inhibits tumor necrosis factor-alpha production and enhances interleukin-10 production by monocytes. Our data demonstrate that the capacity of a beta2-adrenergic agonist to regulate the production of these two cytokines is also reduced in CFS patients.

We did not observe differences in baseline or CRH-induced cortisol and ACTH between CFS patients and controls. Baseline noradrenaline was similar in CFS and controls, whereas baseline adrenaline levels were significantly higher in CFS patients. We conclude that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication.

 

Source: Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ. Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. J Clin Endocrinol Metab. 2000 Feb;85(2):692-6. http://www.ncbi.nlm.nih.gov/pubmed/10690878

 

Acute phase responses and cytokine secretion in chronic fatigue syndrome

Abstract:

This study addresses the hypothesis that clinical manifestations of chronic fatigue syndrome (CFS) are due in part to abnormal production of or sensitivity to cytokines such as interleukin-1beta (IL-1beta) and IL-6 under basal conditions or in response to a particular physical stress: 15 min of exercise consisting of stepping up and down on a platform adjusted to the height of the patella. The study involved 10 CFS patients and 11 age-, sex-, and activity-matched controls: of these, 6 patients and 4 controls were tested in both the follicular and the luteal phases of the menstrual cycle, and the remainder were tested in only one phase, for a total of 31 experimental sessions.

Prior to exercise, plasma concentrations of the acute phase reactant alpha2-macroglobulin were 29% higher in CFS patients (P < 0.008) compared to controls. Secretion of IL-6 was generally higher for CFS patients (approximately 38%), however, this difference was statistically significant only if all values over a 3-day period were analyzed by repeated-measures ANOVA (P = 0.035). IL-6 secretion correlated with plasma alpha2-macroglobulin in control subjects at rest (R = 0.767, P = 0.001).

Immediately after exercise, the CFS patients reported greater ratings of perceived exertion (P=0.027) compared to the healthy control subjects. Ratings of perceived exertion correlated with IL-1beta secretion by cells from healthy control subjects (R = 0.603, P = 0.022), but not from CFS patients, and IL-1beta secretion was not different between groups. Exercise induced a slight (< 12%) but significant (P = 0.006) increase in IL-6 secretion, but the responses of the CFS patients were not different than controls. Furthermore, no significant exercise-induced changes in body temperature or plasma alpha2-macroglobulin were observed.

These data indicate that under basal conditions, CFS is associated with increased IL-6 secretion which is manifested by chronically elevated plasma alpha2-macroglobulin concentrations. These modest differences suggest that cytokine dysregulation is not a singular or dominant factor in the pathogenesis of CFS.

 

Source: Cannon JG, Angel JB, Ball RW, Abad LW, Fagioli L, Komaroff AL. Acute phase responses and cytokine secretion in chronic fatigue syndrome. J Clin Immunol. 1999 Nov;19(6):414-21. http://www.ncbi.nlm.nih.gov/pubmed/10634215

 

TNF-alpha and chronic fatigue syndrome

Abstract:

Based upon the clinical presentation of chronic fatigue syndrome (CFS), we hypothesized that proinflammatory cytokines may play a role in the pathogenesis of the disease. We therefore undertook a retrospective cross-sectional study to examine the role of TNF-alpha in patients with CFS. Our results suggest a significant increase serum TNF-alpha in patients with CFS (P<0.0001) compared to non-CFS controls. This study supports the further examination of the role of proinflammatory mediators in CFS. Furthermore, the clinical testing of TNF-alpha blockers and other antiinflammatory agents for the treatment of this disease is warranted.

 

Source: Moss RB, Mercandetti A, Vojdani A. TNF-alpha and chronic fatigue syndrome. J Clin Immunol. 1999 Sep;19(5):314-6. http://www.ncbi.nlm.nih.gov/pubmed/10535608

 

Clinical features and IgG subclass distribution of anti-p80 coilin antibodies

Abstract:

We examined the clinical features of patients presenting antinuclear autoantibodies against p80-coilin and the IgG subclass distribution of anti- p80-coilin antibodies. Sera from 365 Japanese patients were analysed. Immunoblotting and indirect immunofluorescence microscopy techniques were used with a polyclonal rabbit antiserum against p80-coilin. Eleven patients with anti-p80-coilin antibodies were found. All the patients were female and nine were in their twenties. None could be diagnosed with differentiated rheumatic disease except for one case of systemic scleroderma and another of Sjögren’s syndrome. Most patients had general fatigue, arthralgia, headaches, dysmenorrhea, lymph node swelling and/or low grade fever such as chronic fatigue syndrome (CFS), and showed low complement. One patient fulfilled the criteria for CFS. All were younger females than those often diagnosed with rheumatic disease in previous reports. Patients’ sera had a predominant distribution of subclass IgG(1)anti-p80-coilin antibodies and five sera had concomitant subclass IgG(2). Two rheumatic disease patients had a relatively high titer of IgG(2)anti-p80-coilin antibodies. The IgG(2)subclass of anti-p80-coilin antibodies may be a specific marker for systemic autoimmune disease.

 

Source: Onouchi H, Muro Y, Tomita Y. Clinical features and IgG subclass distribution of anti-p80 coilin antibodies. J Autoimmun. 1999 Sep;13(2):225-32. http://www.ncbi.nlm.nih.gov/pubmed/10479391

 

Autoimmune fatigue syndrome and fibromyalgia syndrome

Abstract:

We have encounted two patients with fibromyalgia (FM) initially diagnosed as having autoimmune fatigue syndrome (AIFS). To investigate the relationship between AIFS and FM, the distribution of the tender points in patients with AIFS was assessed according to the ACR criteria for FM.

It was revealed that AIFS patients had 5.6 tender points on averages. Patients with headaches, digestive problems, or difficulty going to school had more tender points than patients without. Patients with ANA titers < 1: 160 had more tender points than patients with ANA > or = 1: 160. Anti-Sa negative patients had more tender points than positive patients.

These results suggest a relationship between AIFS and FM in terms of the pathophysiologic mechanisms of the numerous tender points. In other words, ANA-positive FM patients could be one form of AIFS, as well as ANA-positive chronic fatigue syndrome patients. Thus, autoimmunity could explain the controversial disease entities of FM and/or CFS.

 

Source: Itoh Y, Igarashi T, Tatsuma N, Imai T, Yoshida J, Tsuchiya M, Murakami M, Fukunaga Y. Autoimmune fatigue syndrome and fibromyalgia syndrome. Nihon Ika Daigaku Zasshi. 1999 Aug;66(4):239-44. [Article in Japanese] http://www.ncbi.nlm.nih.gov/pubmed/10466339

 

Is depression associated with immune activation?

Abstract:

BACKGROUND: Some research immunologists have suggested that major depression amd chronic fatigue syndrome (CFS) are characterized by immune activation. To test this hypothesis, we compared immunological function in patients with major depression and in patients with CFS who developed major depression after the onset of CFS to that of sedentary healthy controls.

METHODS: Subjects completed the Centers for Epidemiological Study-Depression (CES-D) questionnaire and allowed venisection. We performed flow cytometric analysis on 13 groups of white blood cells and used a reverse transcriptase PCR method to assay m-RNA of eight cytokines.

RESULTS: CES-D scores were high in both patient groups and did not differ significantly. We found no evidence for immune activation in either patient group. Instead the data suggested immunological downregulation in depression.

LIMITATIONS: Not all the subjects in the two patient groups were off antidepressants.

CONCLUSIONS: The data indicate that immune activation is not necessary in depression–either alone or with CFS.

 

Source: Natelson BH, Denny T, Zhou XD, LaManca JJ, Ottenweller JE, Tiersky L, DeLuca J, Gause WC. Is depression associated with immune activation? J Affect Disord. 1999 May;53(2):179-84. http://www.ncbi.nlm.nih.gov/pubmed/10360413

 

Single aetiological agent may not be feasible in CFS patients

Comment on: Cortisol deficiency may account for elevated apoptotic cell population in patients with chronic fatigue syndrome. [J Intern Med. 1999]

 

Dear Sir, I would like to thank Dr Baschetti for his very interesting letter. I hope clinicians and CFS patients will be able to benefit from its contents. We agree that chronic fatigue syndrome (CFS) is an illness with uncertain aetiology. Although it is true that no single infectious agent has been identified as a primary cause of CFS, a variety of pathogens, including HTLV-II, EBV, cytomegalovirus, herpes simplex viruses 1 and 2, and human herpes viruses 6, 7 and 8, have been identified in CFS patients [1–7]. In addition to the pathogens previously mentioned, a recent study by our laboratory has identified Mycoplasma fermentans in a statistically significant number of CFS patients over non-CFS control subjects [8]. Further investigation is necessary to determine whether these pathogens are occurring secondarily to some immunological disturbances, as some investigators believe, or whether they are involved as a primary cause of symptoms characteristic of CFS. As mentioned by Dr Baschetti, various measures of immune function have been reported to be altered in CFS subjects, thereby suggesting an association rather than demonstrating a causative link. Abnormalities that have been reported include increased circulating immune complexes, reduced CD4 and CD8 T-lymphocyte subsets, diminished natural killer cell activity, reduction in IgG subclasses, reduced mitogenic response of lymphocytes, altered cytokine production, elevated titres of antibodies to a number of viruses and abnormal production of IFN [9–15]. However, similar immune functional abnormalities have been reported in patients exposed to toxic chemicals without evidence of viral infection or reactivation [16, 17]. Moreover, the symptomatologies described in these patients overlap with CFS patients, thus making the differentiation between the two groups extremely difficult [18–21]. In these articles, the substantial overlap between chemical sensitivity, fibromyalgia and CFA was discussed. It was concluded that the latter two conditions may involve chemical sensitivity and may even be the same disorder. In fact, in a separate study strictly with CFS patients without evidence of viral reactivation but exposed to methyl tertiary-butyl ether (MTBE) and benzene, we showed that programmed cell death and cell cycle were abnormal in both groups [22]. Similarly, in our original article published in this journal, we reported elevated apoptosis and abnormal cell cycle in CFS patients without a history of exposure to toxic chemicals. The interferon-induced protein kinase RNA (PKR) was found to be elevated in these patients as well and was therefore proposed as a possible mechanism of induction of apoptosis and cell cycle abnormalities [23].

 

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Source: Vojdani A. Single aetiological agent may not be feasible in CFS patients. J Intern Med. 1999 Apr;245(4):410-2. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.1999.00479.x/full

 

Cortisol deficiency may account for elevated apoptotic cell population in patients with chronic fatigue syndrome

Comment in: Single aetiological agent may not be feasible in CFS patients. [J Intern Med. 1999]

Comment on: Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. [J Intern Med. 1997]

 

Dear Sir, Vojdani et al. [1] report that patients with chronic fatigue syndrome (CFS) display an increased apoptotic cell population. This abnormality, according to the authors, is due to the activation of protein kinase RNA pathway, which, in turn, ‘could result from disregulated immune system or chronic viral infection’[1].The latter explanation, however, seems unlikely, because no specific virus has been identified in CFS patients, despite extensive research [2]. Special attention, therefore, should mainly be paid to the immune system of CFS patients, because its repeatedly reported abnormalities may help reveal both the aetiology of CFS and an effective treatment against it.

As Vojdani et al. [1] point out, decreased natural killer (NK) cell activity and altered cytokine production characterize CFS patients. These immunological abnormalities, however, may simply reflect the hypocortisolism of CFS patients [3], because a mere lack of steroid restraint on the immune system may well account for its derangement [3]. In fact, since NK cell activity is directly associated with the circadian rhythm of cortisol [4], the decreased NK cell activity observed in CFS patients may simply be due to their cortisol deficiency [3]. The latter, additionally, may also explain why the release of the cytokines interleukin-lβ, interleukin-6, and tumour necrosis factor-α has been found to be increased in peripheral blood mononuclear cell cultures from patients with CFS [5]. All those cytokines, in fact, have been reported to rise during hypocortisolism [6]. This suggests, therefore, that the cortisol deficiency of CFS patients may play a central role in causing both their immunological abnormalities and, presumably, their elevated apoptotic cells.

In view of the role of hypocortisolism in CFS, Vojdani and coworkers might be interested in determining whether the enhanced apoptosis found in their subjects with CFS could be reduced by giving them small daily doses of hydrocortisone and fludrocortisone. The latter, notably, already has been reported to be of great benefit to CFS patients [7]. The rationale for treating CFS patients with the two steroids that are routinely administered to Addisonian patients [8] lies primarily in the fact that no medical condition, except Addison’s disease, shares 20 features with CFS [3]. Five additional symptoms (dizziness upon standing, orthostatic tachycardia, nausea, diarrhoea, and constipation) can be found in both CFS [9] and Addison’s disease [8, 10, 11]. Rather surprisingly, however, despite the staggering similarities between CFS and Addison’s disease, as yet no published attempt has been made to treat CFS patients with both hydrocortisone and fludrocortisone.

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Source: Baschetti R. Cortisol deficiency may account for elevated apoptotic cell population in patients with chronic fatigue syndrome. J Intern Med. 1999 Apr;245(4):409-10. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.1999.00478.x/full