Altered immune response to exercise in patients with CFS/ME: a systematic literature review

[WillowJ]

OK, this is a bit weird as all forms of complement response (there are three different types) target "foreign" molecules, eg bacterial cell wall sugars or antibodies bound to pathogens.

Did it say whether the levels were upregulated or downregulated? If I understand correctly, altered complement response can go with autoimmunity (among other things) if it's downregulated (this is a test they use in SLE).

 

[WillowJ]

None of the studied applied a true experimental design, or studied the effects of exercise therapy on the
immune system in CFS patients.

Pretty sure this is a complaint about the topic more than the design, although I am not certain the authors understand this.

Some of these papers did not set out to study exercise therapy: Therefore they would not be studying the effects of exercise therapy on the immune system.

What some of those papers wanted to know was: in what ways in the immune system different in the subjects than in the controls. Knowing there is a problem with exercise, they used exercise to flush it out.

 

[Simon]

Did it say whether the levels were upregulated or downregulated? If I understand correctly, altered complement response can go with autoimmunity (among other things) if it's downregulated (this is a test they use in SLE).

They don't say, but since the level of c4a - the activated form - is normally negligible, I'm guessing it must be increased.

That SLE is for overall levels of C4, the inactive precursor, which is a different thing: it's looking at overall levels of complement, not activation status.

Separately, I see that the Sorenson study found:

Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a

which is odd: it's an enzyme cascade, and C4a is supposed to cleave inactive C3 into C3a & b , which cleaves inactive C5 into C5a and C5b. So it's odd that C3a and C5a are not elevated as this suggests that complement system isn't really activated. Also, the p values were marginal in this study and they look to have made a lot of comparisons without correcting for multiple comparisons (more comparisons increase the chance of false positives) ie there may be a degree of data mining going on here and the association between complement C4a and symptoms may to be real.

edited to clarify some details

 

[WillowJ]

thanks @Simon

 

[WillowJ]

Lloyd et al. did not find alterations in the blood level of interferon-γ, interferon-α,
interleukin-1β, or tumour necrosis factor-α at baseline, during, and up to 24
hours following 30 minutes of submaximal isometric (hand-grip) exercise (24).
They compared twelve male CFS patients with 13 male matched healthy controls
(24).

Similar findings were reported in the Peterson et al. study, who failed to
detect alterations in serum cytokine levels of interleukin-1β, interleukin-6, or
tumour necrosis factor-α in any of the participants (CFS-patients or healthy) com-
paring levels at rest with values immediately and 40 minutes following walking
on a horizontal treadmill at a speed of 1 mph for a maximum of 30 minutes or
until exhaustion (39).

This is surprising given the well-established cytokine
response to strenuous exercise in healthy people (56, 60), questioning the validity
of the study.

.....

the lack of alterations in blood interleukin-1β in response to
exercise in CFS patients was later confirmed in a larger study (n=22 per group)
performing quantitative in vitro detection of human interleukin-1β using two different
assays (37).

Others were similarly unable to find alterations of interleukin1β
in response to exercise in CFS patients (7, 39, 47).

The Peterson et al. study,
however, did detect serum transforming growth factor-β differences at rest
between CFS patients and healthy controls, with higher values in the CFS group,
but this cytokine did not respond to exercise either (39).

Would that show a downregulation in part of the immune system? I was unable to classify all the cytokines as to being in a particular group. Or are the studies too small?

 

[MeSci]

I've been thinking for some time that we desperately need literature reviews for specific research topics, especially this one. We can't expect most doctors to locate and read a ton of literature and attempt to synthesise it - we need these systematic reviews so that we've got evidence that we can easily point to and that people can easily read.

Even then, many/most doctors will be unable or unwilling to look at scientific papers as, in the UK at least, it doesn't seem to be part of their job description and/or they don't have time/claim not to have time.

 

[MeSci]

It could perhaps potentially be explained in a number of ways? e.g. If exercise activates a latent virus, or if exercise precipitates an auto-immune response involving the complement response system.


These are the two references in the paper in relation to the "complement C4a split" (I haven't looked at them yet):

37. NijsJ, Van Oosterwijck J, Meeus M,LambrechtL, Metzger K, Fremont M, and Paul L.
Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta.
Journal of internal medicine 267: 418-435, 2010
http://www.ncbi.nlm.nih.gov/pubmed/20433584

47. Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, and Jones JF.
Complement activation in a model of chronic fatigue syndrome.
The Journal of allergy and clinical immunology 112: 397-403, 2003.
http://www.ncbi.nlm.nih.gov/pubmed/12897748

This paper says

Complement is part of the innate immune system. Its major function is recognition and elimination of pathogens via direct killing and/or stimulation of phagocytosis. Activation of the complement system is, however, also involved in the pathogenesis of the systemic autoimmune diseases. Activation via the classical pathway has long been recognized in immune complex-mediated diseases such as cryoglobulinemic vasculitis and systemic lupus erythematosus (SLE). In SLE, the role of complement is somewhat paradoxical. It is involved in autoantibody-initiated tissue damage on the one hand, but, on the other hand, it appears to have protective features as hereditary deficiencies of classical pathway components are associated with an increased risk for SLE. There is increasing evidence that the alternative pathway of complement, even more than the classical pathway, is involved in many systemic autoimmune diseases. This is true for IgA-dominant Henoch Schönlein Purpura, in which additional activation of the lectin pathway contributes to more severe disease. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis the complement system was considered not to be involved since immunoglobulin deposition is generally absent in the lesions. However, recent studies, both in human and animal models, demonstrated complement activation via the alternative pathway as a major pathogenic mechanism. Insight into the role of the various pathways of complement in the systemic autoimmune diseases including the vasculitides opens up new ways of treatment by blocking effector pathways of complement.

Personally I don't bother wasting time reading any animal studies if I am trying to learn about humans, as they are generally just as likely to be irrelevant as they are to be relevant (these two possibilities cancelling each other out, so why bother?). But this does appear to be generally relevant to us.

 

[anciendaze]

...
Activation of complement leads to:

• direct destruction of cells through lysis (via the Membrane Attack Complex, which basically stabs holes in target cells)
• 'opsonisation', which is making target cells 'tastier' to Neutrophils and other phagocytosing cells
• Attracting immune cells players to the target cells/infected area
• Clumping together of pathogens, which takes them out of play and makes them easier prey for the immune system.

Anyway, a surprising but interesting finding.

Opsonisation is one of the few parts of immune response with a long research history going back to 1907. It even made it into world literature via the works of G.B. Shaw and Sinclair Lewis. At that time the most important diseases were syphilis, typhoid and TB, which were very hard to treat without antibiotics.

Chemotherapy meant something different at that time than it does today, but one aspect of the ideas has not changed: there are bad cells in there, and it is up to us to destroy them. The principle goal was to find what Ehrlich called "magic bullets" (Zauberkugeln). From the German word it is clear he was thinking about a scatter-shot approach. This was total war, with the patient's body as the unfortunate battlefield.

The other aspect was that besides homing in on the offending cells, it was necessary for these bullets to have a toxic payload. In the case of Salvarsan, that was arsenic.

When Protosil was discovered, many years later, the idea was that a dye molecule would bind to bacteria, which would then be poisoned by the rest of the chemical. Scientists at the Pasteur Institute then found that metabolism separated the dye from the sulfanilamide molecule before it reached bacteria. This unpatentable molecule had stronger antibacterial action than Prontosil.

The final question about toxicity was answered even later. Sulfanilamide has remarkably low toxicity, which allowed it to be sprinkled directly on fresh wounds during WWII. It is an antimetabolite which bacteria will consume without gaining energy. In effect it is diet food for germs. It didn't directly kill them, but it slowed their metabolism enough to limit reproduction so that ordinary immune cells could cope.

So, in short, the two fundamental features of that theory of chemotherapy were wrong. It was only through a great deal of trial and error that researchers stumbled across an antibacterial that did more harm to bacteria than to patients.

Even this account leaves a major question unanswered: what did these toxic payloads do to the phagocytes which cleaned up the mess after bacteria died? Damaging patient immune systems or organs like the liver could lead to even worse problems.

We are just now emerging from that era, with techniques like adoptive immunotherapy, to concentrate on properly directing the patient's own immune cells. These turn out to be quite capable of disposing of pounds of cancer cells without killing patients. Doctors dealing with infectious disease and autoimmune diseases are just beginning to recognize that something is wrong with the predominant paradigms in these fields. Having cleared away a great many microbes which could be killed with crude measures we are now forced to deal with those which have developed sophisticated strategies for misdirecting immune response. Our own ability to direct immune response is severely hampered by not even knowing what we are aiming at in most clinical cases.

What we can say about current practice is that doctors find it convenient, and most patients survive, most of the time. Such is the state of the art.

 

[Sasha]

Even then, many/most doctors will be unable or unwilling to look at scientific papers as, in the UK at least, it doesn't seem to be part of their job description and/or they don't have time/claim not to have time.

Mine will look - I hope he's not the only one. He's very sympathetic and keen to do what he can but not very willing to step outside of what there's evidence for. The NHS is very big on evidence-based medicine, as we all know - so when there's some actual evidence, we need a good summary of it.

 

[MeSci]

Mine will look - I hope he's not the only one. He's very sympathetic and keen to do what he can but not very willing to step outside of what there's evidence for. The NHS is very big on evidence-based medicine, as we all know - so when there's some actual evidence, we need a good summary of it.

In general, mine will not look properly at printed info I give them, even if I have spent a lot of time summarising things. Even if they look at it, they are not prepared to act on it unless they really understand it and are familiar with the contents (which I suspect they are not).

You sound lucky with yours. Even a willingness to listen and be supportive is very welcome. I suspect that few people with ME have such a doctor. I really envy those who have.

 

[osisposis]

J Neuroimmunol. 2010 Jun;223(1-2):124-7. doi: 10.1016/j.jneuroim.2010.03.014. Epub 2010 Apr 20.
Elevated plasma C4a levels in multiple sclerosis correlate with disease activity.
Ingram G1, Hakobyan S, Robertson NP, Morgan BP.
Author information
Abstract

Complement plays a pivotal role in the pathogenesis of multiple sclerosis. C4a, an activated fragment of complement component C4, has been linked to disease activity. We correlated plasma C4 and plasma and CSF C4a with clinical disease in a well-characterised cohort of patients and controls. Plasma C4 was non-significantly and CSF C4a was significantly elevated overall in patients compared to controls. Plasma C4a was raised only in acute relapse, decreasing over 2 months. Results demonstrate intrathecal and systemic activation of complement, reflected in changes in CSF and plasma C4a. The data support a role for complement activation in pathogenesis and suggest a systemic component to the disease.

http://www.ncbi.nlm.nih.gov/pubmed/20409594

 

[osisposis]

According to the complement activation-associated genes, complement factor B (Bf), complement component 2 and 4a (C4a), and C1 inhibitor genes were up-regulated in CAPs-exposed rat lung.

Inhal Toxicol. 2011 Dec;23(14):897-905. doi: 10.3109/08958378.2011.625058.

Hasegawa G1, Hirano M, Ishihara Y.
Differential gene expression associated with inflammation and blood pressure regulation induced by concentrated ambient particle exposure.
Author information
Abstract

Epidemiological studies have indicated that exposure to particle matter (PM) increased the risk of respiratory and cardiovascular morbidity and mortality. It is suggested that PM smaller than 2.5 μm in aerodynamic diameter (PM(2.5)) may contribute to these responses. However, the molecular mechanism is still unknown. To elucidate the changes in molecular level, we investigated the gene expression profile of concentrated ambient particles (CAPs)-exposed rats. Aged F344 rats were exposed with CAPs (594 μg/m(3)) or clean air 4 h per day for 3 days, and lung and heart tissues were then excised for DNA microarray analysis. Expression profiles related to inflammation and blood pressure regulation revealed differential expression of 7 genes in the lung and that of 3 genes in the heart ventricle. According to the complement activation-associated genes, complement factor B (Bf), complement component 2 and 4a (C4a), and C1 inhibitor genes were up-regulated in CAPs-exposed rat lung. Bf and C4a genes were also up-regulated in the heart. These suggest the treated animal ready for production of these proteins when activation of complement cascade is required. Pro-inflammatory cytokine, interleukin-1β, was also up-regulated in CAPs-exposed rat lung. Gene related with blood pressure regulation (angiotensin I converting enzyme) was also up-regulated in CAPs-exposed rat lung. Negative regulator of blood pressure (neuropeptide Y) was down-regulated in CAPs-exposed rat heart. These results indicate that CAPs may affect respiratory and cardiovascular organs by activation of inflammatory responses and disintegration of blood pressure regulation in early stage of CAPs exposure.

PMID:
22122303
[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/22122303



http://informahealthcare.com/doi/abs/10.3109/08958378.2011.625058

 

[osisposis]

Inhal Toxicol. 2011 Dec;23(14):897-905. doi: 10.3109/08958378.2011.625058.

Hasegawa G1, Hirano M, Ishihara Y.
Differential gene expression associated with inflammation and blood pressure regulation induced by concentrated ambient particle exposure.
Author information
Abstract



PMID:
22122303
[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/22122303



http://informahealthcare.com/doi/abs/10.3109/08958378.2011.625058

factor B (BF) and complement component 2 (C2) genes
These two genes, along with genes encoding complement components 4A (C4A) and 4B (C4B), reside
in the major histocompatibility complex (MHC) class III region.

C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation

http://journal.frontiersin.org/journal/10.3389/fncel.2014.00269/full

 

[osisposis]

C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation

http://journal.frontiersin.org/journal/10.3389/fncel.2014.00269/full

I think this well all tie in with WDB exposure , heres another interesting one that may point to mast cell involvement with deficient or dysfunction of C1 inhibitor

Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.

Immunity. 2011 Feb 25;34(2):258-68. doi: 10.1016/j.immuni.2011.02.008.
Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.
Oschatz C1, Maas C, Lecher B, Jansen T, Björkqvist J, Tradler T, Sedlmeier R, Burfeind P, Cichon S, Hammerschmidt S, Müller-Esterl W, Wuillemin WA, Nilsson G, Renné T.
Author information
Abstract

Activated mast cells trigger edema in allergic and inflammatory disease. We report a paracrine mechanism by which mast cell-released heparin increases vascular permeability in vivo. Heparin activated the protease factor XII, which initiates bradykinin formation in plasma. Targeting factor XII or kinin B2 receptors abolished heparin-triggered leukocyte-endothelium adhesion and interfered with a mast cell-driven drop in blood pressure in rodents. Intravital laser scanning microscopy and tracer measurements showed heparin-driven fluid extravasation in mouse skin microvessels. Ablation of factor XII or kinin B2 receptors abolished heparin-induced skin edema and protected mice from allergen-activated mast cell-driven leakage. In contrast, heparin and activated mast cells induced excessive edema in mice deficient in the major inhibitor of factor XII, C1 esterase inhibitor.
Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.

http://www.ncbi.nlm.nih.gov/pubmed/21349432

http://www.cell.com/immunity/abstract/S1074-7613(11)00046-X

http://ac.els-cdn.com/S107476131100...t=1412734881_6dd4113da27aca6d0735a0f76e94ca12

 

[osisposis]

osisposis, post: 510502, member: 14586"]Immunity. 2011 Feb 25;34(2):258-68. doi: 10.1016/j.immuni.2011.02.008.
Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.
Oschatz C1, Maas C, Lecher B, Jansen T, Björkqvist J, Tradler T, Sedlmeier R, Burfeind P, Cichon S, Hammerschmidt S, Müller-Esterl W, Wuillemin WA, Nilsson G, Renné T.
Author information
Abstract

Activated mast cells trigger edema in allergic and inflammatory disease. We report a paracrine mechanism by which mast cell-released heparin increases vascular permeability in vivo. Heparin activated the protease factor XII, which initiates bradykinin formation in plasma. Targeting factor XII or kinin B2 receptors abolished heparin-triggered leukocyte-endothelium adhesion and interfered with a mast cell-driven drop in blood pressure in rodents. Intravital laser scanning microscopy and tracer measurements showed heparin-driven fluid extravasation in mouse skin microvessels. Ablation of factor XII or kinin B2 receptors abolished heparin-induced skin edema and protected mice from allergen-activated mast cell-driven leakage. In contrast, heparin and activated mast cells induced excessive edema in mice deficient in the major inhibitor of factor XII, C1 esterase inhibitor.
Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.

http://www.ncbi.nlm.nih.gov/pubmed/21349432

http://www.cell.com/immunity/abstract/S1074-7613(11)00046-X

http://ac.els-cdn.com/S107476131100...t=1412734881_6dd4113da27aca6d0735a0f76e94ca12

some others of interest that tie in

Microglia, Alzheimer's Disease, and Complement
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432348/


Formation of bradykinin: a major contributor to the innate inflammatory response.
http://www.ncbi.nlm.nih.gov/pubmed/15705422

Kinins, Airway Obstruction, and Anaphylaxis
http://www.karger.com/Article/FullText/315938

Adv Immunol. 2014;121:41-89. doi: 10.1016/B978-0-12-800100-4.00002-7.
Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway.
http://www.ncbi.nlm.nih.gov/pubmed/24388213

http://www.sciencedirect.com/science/article/pii/B9780128001004000027

The plasma bradykinin-forming pathways and its interrelationships with complement
http://www.sciencedirect.com/science/article/pii/S0161589010001690


Chem Immunol Allergy. 2014;100:205-13. doi: 10.1159/000358739. Epub 2014 May 22.
The bradykinin-forming cascade: a historical perspective.
http://www.ncbi.nlm.nih.gov/pubmed/24925400

Chem Immunol Allergy. 2014;100:140-7. doi: 10.1159/000358619. Epub 2014 May 22.
Bradykinin-mediated diseases.
http://www.ncbi.nlm.nih.gov/pubmed/24925394
World Allergy Organ J. 2008 Jun;1(6):103-13. doi: 10.1097/WOX.0b013e31817aecbe.
Angioedema.
http://www.ncbi.nlm.nih.gov/pubmed/23282406

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651192/

 

[osisposis]

some other articles that you may be interested in

Age-related macular degeneration and the complement system

complement may be activated by oxidative stress

http://www.sciencedirect.com/science/article/pii/S0171298511001598


The new face of anaphylatoxins in immune regulation

http://www.sciencedirect.com/science/article/pii/S0171298511001471



J Immunol. 1996 Aug 15;157(4):1693-8.
C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway.
http://www.ncbi.nlm.nih.gov/pubmed/8759757


Int Immunopharmacol. 2012 Jan;12(1):158-68. doi: 10.1016/j.intimp.2011.11.006. Epub 2011 Dec 7.
Inhibitory effects of C4a on chemoattractant and secretagogue functions of the other anaphylatoxins via Gi protein-adenylyl cyclase inhibition pathway in mast cells.

http://www.ncbi.nlm.nih.gov/pubmed/22155625

http://www.sciencedirect.com/science/article/pii/S1567576911004462

-------------

Elevated plasma C4a levels in multiple sclerosis correlate with disease activity.
J Neuroimmunol. 2010; 223(1-2):124-7 (ISSN: 1872-8421)

http://www.medscape.com/medline/abstract/20409594


Mult Scler. Oct 2012; 18(10): 1401–1411.
doi: 10.1177/1352458512438238
PMCID: PMC3697901
Systemic complement profiling in multiple sclerosis as a biomarker of disease state

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697901/


Acta Neuropathol Commun. 2014; 2(1): 53.
Published online May 9, 2014. doi: 10.1186/2051-5960-2-53
PMCID: PMC4048455
Complement activation in multiple sclerosis plaques: an immunohistochemical analysis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048455/

-------------------------------------------------


Immunobiology. 2012 Nov;217(11):1067-79. doi: 10.1016/j.imbio.2012.07.015.
The immunoglobulin, IgG Fc receptor and complement triangle in autoimmune diseases.


http://www.ncbi.nlm.nih.gov/pubmed/22964232

--------------------------------
J Allergy Clin Immunol. 2013 Feb;131(2):541-8.e1-9. doi: 10.1016/j.jaci.2012.05.009. Epub 2012 Jun 22.
Mast cell anaphylatoxin receptor expression can enhance IgE-dependent skin inflammation in mice.

http://www.ncbi.nlm.nih.gov/pubmed/22728083


Arthritis Res Ther. 2014 Mar 17;16(2):R72. doi: 10.1186/ar4512.
Roles of mast cells in the pathogenesis of inflammatory myopathy.
http://www.ncbi.nlm.nih.gov/pubmed/24636001


Exp Mol Med. 2014 Mar 14;46:e83. doi: 10.1038/emm.2014.7.
New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development.

http://www.ncbi.nlm.nih.gov/pubmed/24626169


Immunol Res. 2007;37(3):161-75.
Anaphylatoxins: their role in bacterial infection and inflammation.

http://www.ncbi.nlm.nih.gov/pubmed/17873401


Mast cells and inflammation
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318920/

 

[osisposis]

Mediators of Inflammation
Volume 2013 (2013), Article ID 342931, 19 pages
http://dx.doi.org/10.1155/2013/342931

Review Article
Innate Immunity and Neuroinflammation


http://www.hindawi.com/journals/mi/2013/342931/


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697414/

http://www.ncbi.nlm.nih.gov/pubmed/23843682

 

[osisposis]

Brain Res Brain Res Rev. 2005 Apr;48(2):388-99. Epub 2005 Jan 28.
Closed head injury--an inflammatory disease?
Schmidt OI1, Heyde CE, Ertel W, Stahel PF.
Author information
Abstract

Closed head injury (CHI) remains the leading cause of death and persisting neurological impairment in young individuals in industrialized nations. Research efforts in the past years have brought evidence that the intracranial inflammatory response in the injured brain contributes to the neuropathological sequelae which are, in large part, responsible for the adverse outcome after head injury. The presence of hypoxia and hypotension in the early resuscitative period of brain-injured patients further aggravates the inflammatory response in the brain due to ischemia/reperfusion-mediated injuries. The profound endogenous neuroinflammatory response after CHI, which is phylogenetically aimed at defending the intrathecal compartment from invading pathogens and repairing lesioned brain tissue, contributes to the development of cerebral edema, breakdown of the blood-brain barrier, and ultimately to delayed neuronal cell death. However, aside from these deleterious effects, neuroinflammation has been recently shown to mediate neuroreparative mechanisms after brain injury as well. This "dual effect" of neuroinflammation was the focus of extensive experimental and clinical research in the past years and has lead to an expanded basic knowledge on the cellular and molecular mechanisms which regulate the intracranial inflammatory response after CHI. Thus, head injury has recently evolved as an inflammatory and immunological disease much more than a pure traumatological, neurological, or neurosurgical entity. The present review will summarize the so far known mechanisms of posttraumatic neuroinflammation after CHI, based on data from clinical and experimental studies, with a special focus on the role of pro-inflammatory cytokines, chemokines, and the complement system.

http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15850678

 

[osisposis]

Shock. 2012 Aug;38(2):220-5. doi: 10.1097/SHK.0b013e31825bf40e.
C1 inhibitor suppresses the endotoxic activity of a wide range of lipopolysaccharides and interacts with live gram-negative bacteria.
Mejia P1, Davis AE 3rd.
Author information
Abstract

Human C1 inhibitor (C1INH) prevents endotoxin shock via a direct interaction with Gram-negative bacterial lipopolysaccharide (LPS) and improves survival in animal models of sepsis. In this report, we further characterize the interaction of C1INH with LPS and whole live bacteria. We investigate C1INH interactions with LPS from five different strains of Gram-negative enteric bacteria known to participate in the pathogenesis of human sepsis. Treatment with C1INH improved survival in mice with endotoxin shock induced by LPS from Salmonella enterica serovar typhimurium as previously shown, as well as LPS from Escherichia coli O55:B5 and Pseudomonas aeruginosa, and a trend to improved survival was observed when Klebsiella pneumoniae and Serratia marcescens LPS were used. Enzyme-linked immunosorbent assay and native polyacrylamide gel electrophoresis shift experiments demonstrated a direct interaction of C1INH with LPS from all the strains studied. The binding of both native and reactive center-cleaved, inactive C1INH results in inhibition of LPS-induced proinflammatory cytokine production. Furthermore, we demonstrate the ability of C1INH to bind at the surface of only a restricted number of whole live Gram-negative bacteria as well as mutant bacteria expressing a truncated LPS lacking the O-antigen. These data reveal the interaction of C1INH with a wide range of enteric bacterial LPS and strongly suggest that the interaction between C1INH and the surface of Gram-negative microorganisms is determined by the length of the polysaccharide chain of the endotoxin molecule.

http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=22576004

 

[Sea]

@osisposis the theme of this thread is altered immunity in CFS after exercise. You will get more discussion on your postings if you start another thread instead of adding off topic research here