ME og fysisk aktivitet

Det ses sommetider anbefalet, at ME patienter skal udføre gradvis øget motion (graded exercise therapy, GET).

Nyere gennemgang af forsøg med gradvis øget motion viser imidlertid tre problemstillinger:

• Forsøgene har medtaget patienter, som ikke har ME diagnosen, idet man har anvendt Oxford eller Fukuda diagnose kriterierne til udvælgelse af patienter. I dag ved man, at disse diagnose kriterier ikke er præcise nok. Der indgår derfor også patietner med andre diagnoser. Disse patienter kan opnå forbedringer med motion. Dette drager forsøgenes konklusioner i tvivl.
• Forsøgene omfatter som regel kun de mildt til moderat syge ME patienter. De hjemme- eller helt sengebundne patienter kan af gode grunde ikke møde op og deltage i forsøgene, som oftest kræver fremmøde.
• Forsøgene har ofte en stor frafaldsprocent, hvoraf en del udgøres af de ME patienter, som har fået forværring af den gradvis øgede motion.

Der kan læses mere om problematikken i denne rapport:
Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Oslo Universitets Sygehus skriver således om emnet i deres Veileder i forbindelse med utredning av pasienter der man mistenker Myalgisk encefalopati (ME)/ Kronisk utmattelsessyndrom (CFS) i allmennpraksis:
"Studier der kognitiv atferdsterapi (CBT) og gradert treningsterapi (GET) er beynttet har vist effekt. Disse studiene er alle gjort på pasientgrupper som er inkludert med kriterier som inkluderer to til tre ganger så mange pasienter som kriteriene beskrevet i denne veilederen. Pasientene som skulle delta måtte være frisk nok til å reise til og fra det stedet der de skulle få behandling/opplæring, noe som betyr at de må tilhøre gruppen med en mild til moderat grad av sykdommen. Få studier hadde objektive effektmål og der slike fantes var effekten begrenset. Det er derfor usikkert om disse resutlatene kan overføres på pasienter som diagnostiseres etter et strengere kriteriesett. Men klinisk erfaring kan tyde på at pasienter som i en periode på noen måneder har vært i stabil bedring kan ha utbytte av en gradert opptrapping. Hos svært dårlige, sengeliggende pasienter kan det være viktig å motivere de til å løfte hodeenden av sengen noen få cm f.eks. to ganger daglig 5 minutter, for å bedre den ortostatiske toleransen. Hvis det tolereres kan man prøve å øke både tid og vinkel forsiktig."

Oslo Universitets Sygehus skriver også om det optimale aktivitetsniveau for ME patienter i deres brochure
Aktivitetsavpasning og energiøkonomisering/energibesparende metoder:
”Det er viktig å ikke bruke mer energi enn du har! Du bør helst ikke bruke mer enn 70% av energien du opplever å ha; det vil si å ta en pause når du begynner å bli sliten for å unngå at slitenhet går over i utmattelse.”
”Det anbefales å legge opp til et jevnt aktivitetsnivå fra dag til dag og ikke øke aktivitetsnivået noe særlig på gode dager. Først når symptomene har blitt mindre og harholdt seg på et lavt nivå over tid kan du gradvis begynne å øke aktivitetsnivået uten at det fører til forverring.”

I USA benyttes de samme anbefalinger under begreberne "energy envelope" og "pacing". Direkte oversat betyder "energi kuvert" og pace betyder "tempo", så det er at sætte tempoet. Det centrale ved at benytte disse metoder er, at ME patienter skal rationalisere med energien, så sygdomsforværring undgåes. Den forværring som ME patienterne oplever kaldes på engelsk "post-exertional-malaise" (PEM). Det kan oversættes "efter-anstrengelse-sygdomsfølelse."

Der er masser af engelsksproget materiale og videnskabelige artikler om emnet:

Research1st har lavet en glimrende oversigt med links til flere gode artikler, og bemærk, at der også er en video "Pacing Yourself Through the Holidays". Du finder det hele ved at klikke her.  Og her har research1st et webinar "Top 10 Things You Need to Know about Post-Exertion Relapse".

En række amerikanske ME forskere fremlagde under afholdelse af en videnskabsdag i oktober 2010 deres arbejde for US Department of Health and Human Services. Disse præsentationer kan findes her:

Cardiopulmonary Exercise Testing (CPET) & Evaluating Functional Capacity
I præsentationen (side 25) vises det typiske ME fænomen: at ved motionstest og efterfølgende gen-test 24 timer senere afsløres en forværring af i peak af VO₂ (=konditallet) hos ME patienter. Dette kendetegn er så særegen for ME, at det er foreslået som diagnosekriterie.

Biological and Non-Biological Indices of Disability & Change
I præsentationen (side 63-65) ses det, at når ME patienter forbliver inden for deres "energy envelope" opnåes forbedringer.

Genetic and Genomic markers of CFS risk, progression and prognosis
I præsentationen (side 20) ses det, at den forværring som ME patienter oplever efter kortvarig motion kan måles fysisk, og fremgår meget tydeligt af det viste blokdiagram.

Eye problems in ME

Most ME patients report sensitivity to light. Dry eyes and “red eyes” are also common. I have tried to look into the subject, but there is not much literature on the subject. I found this from the CFIDS Association:
Visual Dysfunction in Chronic Fatigue Syndrome.

And this article Pathology of the organ of vision in chronic fatigue syndrome:
"218 patients were examined and the chronic fatigue syndrome (CFS) was diagnosed in them on the basis of clinical-and-immunologic data. 126 somatically healthy persons of the same age and sex were in the control group. Vascular pathology of the vision organ was found in 153 (70.2%) persons, and dystrophic pathology was found in 115 (52.8%) persons. A combination of vascular and dystrophic pathologies of the vision organ was diagnosed in 46 (21.1%) patients. The detection of vision pathology in the CFS patients essentially exceeded the morbidity of similar pathology in the controls. No reliable differences of refraction anomalies were found between the CFS patients and the controls."

But research is coming up. In the 2012 spring issue from ME research UK, a research project is described:
“People with ME/CFS often have problems with their vision; in fact, around three-quarters of the 2,073 consecutive patients described in the Canadian Consensus Document 2003 specifically reported sensitivity to light and dullness of vision to be significant problems.

ME Research UK and the Irish ME Trust have jointly funded a one-year pilot study that aims to determine quantitatively and objectively the main visual symptoms that people with ME/CFS experience. The study will also determine their rate of occurrence and establish whether the types and extent of visual symptoms experienced can be correlated with the severity of the condition and the specificity of other (non-visual) symptoms.”

At Phoenix Rising  you can read about a patient donating a tear sample to the CFI pathogen study. This study will be testing for new and novel pathogens in various body fluids (tears, saliva, urine and rectal swab), including blood.

Then I wondered…are Epstein Barr Virus or other viruses involved in eye problems? I did a search:

Ocular disease associated with Epstein-Barr virus infection
"Epstein-Barr virus (EBV) is a ubiquitous DNA virus of the herpesvirus genus with a high prevalence rate for antibody (about 90%) in the adult population. It is the most common causative agent of infectious mononucleosis syndrome. During recent years an increasing number of ocular disease entities have been reported to be linked to EBV infection. These entities include oculoglandular syndrome, conjunctivitis, dry eye, keratitis, uveitis, choroiditis, retinitis, papillitis and ophthalmoplegia. While EBV-specific serologic tests can now document recent and past primary infection with EBV and also identify patients manifesting atypical immunologic reactions to EBV, the lack of an animal model, the absence of clear-cut response to therapy and the paucity of documentation by culture render the pathogenesis uncertain or the association questionable in many of these cases."

Epstein-Barr virus (types 1 and 2) in the tear film in Sjogren's syndrome and HIV infection
"Evidence of Epstein-Barr virus (EBV) shedding in the saliva and tear film has been sought to explain the pathogenesis of the oral and ocular features of Sjogren's syndrome. Patients with human immunodeficiency virus (HIV) infection are purported to have a higher incidence of keratoconjunctivitis sicca. Twenty patients with definite Sjogren's syndrome (primary and secondary), 19 with HIV infection, and 15 normal controls were recruited and studied. Human herpes viruses (EBV 1 and 2, CMV, HZV, and HSV-1) in tear film were detected by polymerase chain reaction of DNA extracted from Schirmer strips. HSV-1, VZV, and CMV were not detected in any tear samples. EBV-1 DNA was found in the tear film of 4 patients with Sjogren's syndrome, which was not significantly different from the control group (P = 0.18). Twelve patients with HIV infection had evidence of EBV-1 in their tears, which was significantly different from controls (P = 0.0002) and patients with Sjogren's syndrome (P = 0.014). EBV-2 was found in 3 patients with HIV and in 1 patient with secondary Sjogren's syndrome, and was always found as a co-infection with EBV-1 (P = 0.01). This represents the first report examining EBV types 1 and 2 in the tear film and also EBV in the tear film of patients with HIV. Shedding of EBV in the tear film was not related to the presence of keratoconjunctivitis sicca in Sjogren's syndrome. EBV-2 co-infection with EBV-1 has not been previously reported in the tear film. EBV infection is abnormally regulated in Sjogren's syndrome and HIV, and it is likely that the presence of EBV in the tear film is related to the patients' altered immune status."

Multiplex detection of herpesviruses in tear fluid using the "stair primers" PCR method: prospective study of 93 patients
"Human herpesviruses can infect the eye and be excreted subsequently in tears. The aim of the present study was to use a multiplex PCR to detect herpesviruses (HSV-1, -2, VZV, CMV, EBV, HHV-6) in tears from normal subjects and from patients with pathological conditions (acute herpes, zoster, papillary conjunctivitis, and dry eye). Schirmer test strips were used to collect tear fluid from 93 patients, sampling both eyes. DNA was then extracted from the 186 samples by chromatography, and viral DNA amplified using a commercialised multiplex "stair primer" method. Thirty-four samples (18.3%) contained Taq inhibitors. The multiplex test gave positive results for HSV and VZV in tear fluid from patients with acute dendritic keratitis (3 patients) and acute ocular zoster (4 patients) and was, therefore, considered effective in testing samples from patients with acute lesions. HSV-1 and HSV-2 were found in two samples from patients with metaherpetic corneal scarring. Among 28 cases of dry eye, two were positive for HHV-6, the latter being associated with EBV in one patient. HHV-6 was also found in 4 out of 54 cases of papillary conjunctivitis. This raised occurrence of HHV-6 in dry eye or papillary conjunctivitis, suggests new clinical patterns for HHV-6 latency or reactivation. Detection of EBV in 1 out of 80 healthy eyes confirms previous evidence that lacrimal glands constitute potentially a site for latent-phase EBV.”

And then I wondered…are TLRs involved in eye problems? Purinergic signalling? Vasoactive peptides? (all subjects mentioned in previous posts) The answer is:

Toll-like receptors in ocular surface diseases: overview and new findings
“On the ocular surface, the early response against noxious stimuli is provided by innate immunity, which represents a non-specific surveillance system and promotes adaptive immune responses. The evidence discussed in the present review highlights the emerging roles of TLRs in regulating innate immune responses during ocular surface infectious and non-infectious inflammatory conditions. In addition, increasing evidence shows that TLRs play an important role in the pathogenic mechanisms of autoimmune and allergic ocular diseases, modulating the adaptive immune responses.”

Expression of toll-like receptor (TLR) 4 contributes to corneal inflammation in experimental dry eye disease
"Purpose. To investigate the corneal expression of toll-like receptor (TLR) 4 and determine its contribution to the immunopathogenesis of dry eye disease (DED).Methods. Seven to 8 week old female C57BL/6 mice were housed in a controlled environment chamber and administered scopolamine to induce experimental DED. Mice received intravenous TLR4 inhibitor (Eritoran) to block systemic TLR4-mediated activity. The expression of TLR4 by the corneal epithelium and stroma was evaluated using real-time polymerase chain reaction and flow cytometry. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease severity. The corneal expression of proinflammatory cytokines (IL-1?, IL-6, TNF, and CCL2), corneal infiltration of CD11b+ antigen-presenting cells, and lymph node frequency of mature MHC-IIhi CD11b+ cells were assessed.Results. The epithelial cells of normal corneas expressed TLR4 intracellularly; however, DED significantly increased the cell surface expression of TLR4. Similarly, flow cytometric analysis of stromal cells revealed a significant increase in the expression of TLR4 proteins by DED-induced corneas as compared to normal corneas. DED increased the mRNA expression of TLR4 in corneal stromal cells, but not epithelial cells. TLR4 inhibition decreased the severity of CFS and significantly reduced the mRNA expression of IL-1?, IL-6, and TNF. Furthermore, TLR4 inhibition significantly reduced the corneal infiltration of CD11b+ cells and the lymph node frequency of MHC-IIhi CD11b+ cells.Conclusions. These results suggest that DED increases the corneal expression of TLR4 and that TLR4 participates in the inflammatory response to ocular surface desiccating stress."

The role of purinergic receptors in retinal function and disease
"Extracellular ATP acts as a neurotransmitter in the central and peripheral nervous systems. In this review, the role of purinergic receptors in neuronal signaling and bi-directional glial-neuronal communication in the retina will be considered. There is growing evidence that a range of P2X and P2Y receptors are expressed on most classes of retinal neurons and that activation of P2 receptors modulates retinal function. Furthermore, neuronal control of glial function is achieved through neuronal release of ATP and activation of P2Y receptors expressed by Müller cells. Altered purinergic signaling in Müller cells has been implicated in gliotic changes in the diseased retina and furthermore, elevations in extracellular ATP may lead to apoptosis of retinal neurons."

Professor Don Staines who has written about a role for autoimmunity and vasoactive neuropeptides in ME, has written this about ophthalmology:

Vasoactive neuropeptides in clinical ophthalmology: An association with autoimmune retinopathy?
“The mammalian eye is protected against pathogens and inflammation in a relatively immune-privileged environment. Stringent mechanisms are activated that regulate external injury, infection, and autoimmunity. The eye contains a variety of cells expressing vasoactive neuropeptides (VNs), and their receptors, located in the sclera, cornea, iris, ciliary body, ciliary process, and the retina. VNs are important activators of adenylate cyclase, deriving cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Impairment of VN function would arguably impede cAMP production and impede utilization of ATP. Thus VN autoimmunity may be an etiological factor in retinopathy involving perturbations of purinergic signaling. A sound blood supply is necessary for the existence and functional properties of the retina. This paper postulates that impairments in the endothelial barriers and the blood-retinal barrier, as well as certain inflammatory responses, may arise from disruption to VN function. Phosphodiesterase inhibitors and purinergic modulators may have a role in the treatment of postulated VN autoimmune retinopathy.”

Is it all somehow connected: pathogens, TLRs, mimicry, autoimmunity, purinergic signalling, vasoactive peptides…?

Internationale forskere undersøger autoimmunitet i ME

Frit oversat fra Invest in ME:

"Medicinske og videnskabelige eksperter fra hele verden mødtes i London den 30. og 31. maj 2012 for at drøfte den seneste videnskabelige udvikling i forståelsen af Myalgic Encephalomyelitis/Chronic Fatiuge Syndrome (ME/CFS).

”Med-formand” for den kliniske autoimmunitet arbejdsgruppe for ME/CFS, Professor Dr. Don Staines erklærede: ”De norske forskeres opdagelse, at anti-CD20 B-celle-nedbrydende stof giver en markant forbedring i behandlingen af ME/CFS har sendt et klart signal til forskere og læger rundt om i verden, at denne sygdom kan have en autoimmun oprindelse”.

Mens de klinikere, der gjorde opdagelsen, Dr Øystein Fluge, Dr. Olav Mella og medarbejdere bliver ”overvåget” for at drage uberettigede konklusioner fra undersøgelsen, der er offentliggjort i tidskriftet PLoS i slutningen af sidste år, er yderligere undersøgelser nu planlagt i håb om at udvide forsøget til flere klinikker og øge antallet af patienter i undersøgelserne.

Dr. Staines sagde yderligere: "Resultaterne som lægerne Fluge, Mella og deres medarbejdere frembragte er i overensstemmelse med tidligere offentliggjorte teorier: At ME/CFS kan være en autoimmun sygdom. På trods af overbevisende dokumentation for, at denne sygdom er epidemiologisk knyttet til infektion, og sygdommen muligvis er en post-infektion forstyrrelse af immunsystemet, er få midler doneret til studier af autoimmunitet. Det er helt klart en multi-system sygdom, der er blevet dårligt forvaltet af den eksisterende dagsorden i forskningsverden. "

Tilmeldte eksperter til mødet var en lang række dygtige, internationale forskere. Bl.a. Professor Noel Rose, direktør for Autoimmune Disease Research fra det meget anerkendte John Hopkins Hospital i USA, Professor Hugh Perry, formanden for UK Medical Research Council Neurosciences and Mental Health Board og selvfølgelig Olav Mella og Øystein Fluge. Hele listen over deltagere er her:

Dr Amolak Bansal MD

Dr. James N Baraniuk MD

Dr Monica Carson PhD

Professor Simon Carding PhD

Dr Abhijit Chaudhuri MD PhD

Dr Mario Delgado PhD

Dr Øystein Fluge MD PhD

Dr Ian Gibson PhD

Dr Konstance Knox PhD

Dr Andreas Kogelnik MD PhD

Dr Richard Kwiatek MBBS FRACP

Professor Stephen D. Miller PhD

Dr Sonya Marshall-Gradisnik PhD

Professor Olav Mella MD PhD

Dame Bridget Ogilvie AC, DBE, FRS

Professor Hugh Perry PhD

Dr Daniel Peterson MD

Professor Noel Rose MD PhD

Dr Katherine Rowe MD MBBS FRACP MPH DipEd

Dr Rosamund Vallings MD

Professor Tom Wileman PhD

VIP and PACAP

Professor Don Staines has for several years worked on a hypothesis, that the development of ME is based on loss of immunological tolerance to vasoactive neuropeptides (VIP and PACAP) or their receptor binding sites:

Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?
“All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation.”

Professor Don Staines and colleagues have elaborated the theory in this article:
Novel pathomechanisms in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Do purinergic signalling perturbations and gliosis play a role?

But let us take a closer look on these neuropeptides to better understand the ME articles:

VIP = Vasoactive Intestinal Peptide
PACAP = Pituitary Adenylate Cyclase Activating Polypeptide
PACAP-27, PACAP-38 = two forms of PACAP, respectively a 27 and a 38 amino acid peptide
VIPR1 = VPACR1 = VPAC₁  receptor = Vasoactive Intestinal Peptide Receptor 1
VIPR2 = VPACR2 = VPAC₂  receptor = Vasoactive Intestinal Peptide Receptor 2
ADCYAP1R1 = PAC1R = PAC₁ receptor = Adenylate Cyclase Activating Polypeptide 1 (pituitary) receptor

VPAC₁ receptor responds to VIP and PACAP with comparable affinity.
VPAC₂ receptor also responds to VIP and PACAP with comparable affinity.
PAC₁ receptor recognises PACAP-27 and PACAP-38 with much higher potency than VIP.

VIP is a vasodilator and has many other actions as a neuroendocrine hormone, putative neurotransmitter and cytokine. The presence of VIP and specific VIP binding sites in defined pathways in the brain indicate that it may play an important role in central nervous system function. VIP is now widely accepted as a co-transmitter, with nitric oxide and carbon monoxide, of nonadrenergic, noncholinergic relaxation of both vascular and nonvascular smooth muscle. VIP stimulates prolactin secretion from the pituitary and catecholamine release from the adrenal medulla. In the immune system, VIP regulates T cell traffic and inhibits mitogen-activated proliferation of T cells by inhibiting interleukin-2 production. Other actions of VIP include stimulation of electrolyte secretion and protection against oxidant injury.

PACAP and the mRNA encoding its precursor are most abundant in the hypothalamus, with lower levels in many other brain regions. PACAP is also present in a number of peripheral tissues, including the gastrointestinal tract, adrenal gland and testis. PACAP is expressed in sympathetic neurons and in the cholinergic innervation of the adrenal medulla, where it is thought to facilitate prolonged secretion of catecholamines under conditions of high stress. PACAP is also thought to regulate exocrine and endocrine secretion from the pancreas.
Reference: IUPHAR Database. VIP and PACAP receptors: Introduction

I had hoped to find an abundance of articles with measurements of VIP, PACAP and expression of their receptors – but all I could find was this:

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
“This is the first study to show significantly higher levels of VPACR2 receptors, CD4+CD25+Tregs and FoxP3 +Treg expression in CFS/ME patients compared to healthy controls.”

But I found something else interesting. At Glostrup Hospital in Denmark researchers have shown that PACAP-38 provokes a significant headache, while VIP only gives a small headache. Danish reference  
Poster in English about PACAP and headache

Further reading about VIP and PACAP:
VIP and PACAP. Recent insights into their functions/roles in physiology and disease from molecular and genetic studies

Immunomodulation of innate immune responses by vasoactive intestinal peptide (VIP): its therapeutic potential in inflammatory disease

Emerging roles of vasoactive intestinal peptide: a new approach for autoimmune therapy

MicroRNA and ME

What is microRNA?

MiRNA (microRNA) is a large group of about 1000 different, very small RNA molecules, that regulate, how the information in the genes is translated into proteins in the cells. Here the proteins determine, how the cells work and develop. Another type of RNA molecules, mRNA (messengerRNA) determines, which proteins are expressed in the cell, while miRNAs determines the extent to which the proteins are expressed. Danish reference.

MiRNAs have the potential to be used as biomarker for a lot of diseases. They are widely used in cancer research. Exiqon, a company in Denmark, are experts in miRNA technology. You can learn more from their website. Danish readers can learn more from Biokemisk Forening.

In miRBase: the microRNA database you can search for information about any micro-RNA.

MicroRNAs as biomarker for ME

Shown by this paper, Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, micro-RNAs can maybe also be used as a biomarker for ME:

"There was a significant reduction in the expression levels of miR-21, in both the NK and CD8(+)T cells in the CFS/ME sufferers.

Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 was significantly decreased in NK cells of CFS/ME patients in comparison to the non-fatigued controls.

Collectively these miRNAs have been associated with apoptosis, cell cycle, development and immune function. Changes in miRNAs in cytotoxic cells may reduce the functional capacity of these cells and disrupt effective cytotoxic activity along with other immune functions in CFS/ME patients."

MicroRNA, TLR, EBV and immune-mediated diseases

In my last post I wrote about TLR, LPS and ME. And now we can learn from the following abstracts, that microRNA, TLR and LPS are somehow connected. Epstein Bar Viruses also push the microRNAs around, likewise microRNAs are involved in all immune-mediated diseases:


A trio of microRNAs that control Toll-like receptor signalling
"Several miRNAs have been shown to be up-regulated in response to TLR ligands, and many directly target components of the TLR signalling system, revealing a whole extra level of control of TLR signalling which is being extensively researched. The dysregulation of miRNAs may be involved in many inflammatory diseases and cancers and thus merits further investigation. In this review, we focus in on a trio of miRNA which have proven to be key in many immune and inflammatory pathways; miR-155, miR-21 and miR-146."

MicroRNA in TLR signaling and endotoxin tolerance
"Toll-like receptors (TLRs) in innate immune cells are the prime cellular sensors for microbial components. TLR activation leads to the production of proinflammatory mediators and thus TLR signaling must be properly regulated by various mechanisms to maintain homeostasis. TLR4-ligand lipopolysaccharide (LPS)-induced tolerance or cross-tolerance is one such mechanism, and it plays an important role in innate immunity. Tolerance is established and sustained by the activity of the microRNA miR-146a, which is known to target key elements of the myeloid differentiation factor 88 (MyD88) signaling pathway, including IL-1 receptor-associated kinase (IRAK1), IRAK2 and tumor-necrosis factor (TNF) receptor-associated factor 6 (TRAF6). In this review, we comprehensively examine the TLR signaling involved in innate immunity, with special focus on LPS-induced tolerance. The function of TLR ligand-induced microRNAs, including miR-146a, miR-155 and miR-132, in regulating inflammatory mediators, and their impact on the immune system and human diseases, are discussed. Modulation of these microRNAs may affect TLR pathway activation and help to develop therapeutics against inflammatory diseases."

Differential regulation of miR-21 and miR-146a by Epstein-Barr virus-encoded EBNA2
"The discovery of microRNA (miR) represents a novel paradigm in RNA-based regulation of gene expression and their dysregulation has become a hallmark of many a tumor. In virally associated cancers, the host-pathogen interaction could involve alteration in miR expression. Epstein-Barr virus (EBV)-encoded EBNA2 is indispensable for the capacity of the virus to transform B cells in vitro. Here, we studied how it affects cellular miRs. Extensive miR profiling of the virus-infected and EBNA2-transfected B lymphoma cells revealed that oncomiR miR-21 is positively regulated by this viral protein. Conversely, Burkitt's lymphoma (BL) cell lines infected with EBNA2 lacking P3HR1 strain did not show any increase in miR-21. EBNA2 increased phosphorylation of AKT and this was directly correlated with increased miR-21. In contrast, miR-146a was downregulated by EBNA2 in B lymphoma cells. Low miR-146a expression correlates with an elevated level of IRAK1 and type I interferon in EBNA2 transfectants. Taken together, the present data suggest that EBNA2 might contribute to EBV-induced B-cell transformation by altering miR expression and in particular by increasing oncomiR-like miR-21 and by affecting the antiviral responses of the innate immune system through downregulation of its key regulator miR-146a."

MicroRNAs: emerging regulators of immune-mediated diseases
"Recently, the role of miRNAs in the development of immune cells and the maintenance of immune system homeostasis gained attention and the involvement of miRNAs in the pathogenesis of several immune system diseases has emerged. This review focuses on the role of miRNAs in autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis) and inflammatory pathologies of distinct organ (atherosclerosis, osteoarthritis, atopic eczema) and/or systemic locations such as allergy. The role of miRNAs, their predicted and known mRNA targets and description of their actions in physiological immune reactions and in the pathological processes ongoing in immune-mediated human disorders will be discussed. Finally, miRNA-based diagnostics and therapeutic potentials will be highlighted."

Pieces of puzzles: ME after EBV infection, activated TLRs, downregulated microRNAs, translocated LPS, changed mRNA in purinergic signalling and TLR4 after exercise, reduced NK cytotoxic activity, Rituximab that helps some ME patients…are the scientists about to solve the puzzle?

Toll like receptors (TLR) and ME

Basic knowledge about TLR

The innate immune system is the first line of defence against invading microorganisms. The system consists of cells: neutrophils, monocytes/macrophages, dendritic cells and natural killer cells, and of soluble elements such as cytokines and components of the complement system. Detection of these microorganisms is mediated by pattern recognition receptors (PRR) expressed on the cells of the innate immune system. The most important components of PRR are Toll-like receptors (TLR). TLR recognize structures common to many pathogens, the so-called pathogen associated molecular patterns (PAMP). PAMP are part of endotoxins, peptidoglycans and other microbial molecules of clinical relevance in infectious diseases.  Danish Reference

There are 12 known TLRs – named TLR1-TLR12. Each TLR recognize a different structure. Some of them are (look in Wikipedia for a complete list):
TLR1/TLR2:   Lipopeptides from bacteria
TLR3:             Double-strandend RNA from viruses
TLR4:             Lipopolysaccharide (LPS) from gramnegative bacteria
TLR5:             Flagellin from bacteria
TLR6:             Multiple diacyl lipopeptides from Mycoplasma
TLR7/TLR8:  Small synthetic compounds, single-stranded RNA
TLR9:             Unmethylated CpG Oligodeoxynucleotide DNA

Agonists and antagonists respectively activate and de-activate receptors. TLR agonists have the ability to turn on the immune system, and TLR antagonists have the potential to be immunosuppressive and anti-inflammatory.

TLRs and ME

From the Whittemore Petersons website you can read:
The microbial pattern recognition receptors, Toll-like receptors (TLRs) 3 and 4, are activated by pathogen-derived dsRNA and LPS, respectively, to produce these proinflammatory cytokines. This system is tightly regulated; however, in patients with ME/CFS, it is constitutively active. The focus of this research project is to better understand the mechanism of this dysregulation.

Light et al also mention TLR4: After a sustained moderate exercise test, CFS patients showed greater increases than control subjects in gene expression for metabolite detecting receptors ASIC3, P2X4, and P2X5, for SNS receptors alpha-2A, beta-1, beta-2, and COMT and IS genes for IL10 and TLR4 lasting from 0.5 to 48 hours (P < .05). Reference

Maes et al have several times referred to LPS translocation as part of ME (and I presume that must activate TLR4):
The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients. Reference

Ampligen/Rintatolimod used for ME is a TLR3 agonist. Reference

Some ME patients have tried Naltrexone, which is a TLR 4 antagonist.

TLR and other diseases

Is there more to learn about ME and TLRs? Let us look for inspiration in other diseases:

Toll-like receptor signaling in neural plasticity and disease
TLR signaling in immune cells, glia and neurons can play roles in the pathogenesis of stroke, Alzheimer's disease (AD) and multiple sclerosis (MS). Recent findings suggest that TLR signaling also influences multiple dynamic processes in the developing and adult central nervous system including neurogenesis, axonal growth and structural plasticity. In addition, TLRs are implicated in the regulation of behaviors including learning, memory and anxiety. This review describes recently discovered and unexpected roles for TLRs in neuroplasticity, and the implications of these findings for future basic and translational research studies.

Toll-like receptors in rheumatic diseases: are we paying a high price for our defense against bugs?
In the last decade Toll-like receptor (TLR) research has led to new insights in the pathogenesis of many rheumatic diseases. In autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis TLR signaling is likely to be involved in tolerance breakthrough and chronic inflammation via combined Fc gamma receptors and TLR recognition of immune complexes. Furthermore, inflammatory diseases like psoriatic arthritis and gout also show more and more evidence for TLR involvement. In this review we will discuss the involvement of TLR signaling in several rheumatic diseases and stress their similarities and differences based on recent findings.


Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management
Toll-like receptors (TLR) are important innate immune proteins for the identification and clearance of invading pathogen. TLR signal through adaptor proteins, most commonly myeloid differentiation primary response gene 88 (MyD88). Inappropriate response of specific TLR has been implicated in certain autoimmune diseases, such as multiple sclerosis (MS). Activation of TLR2, TLR4, TLR7 and TLR9 plays a role in experimental allergic encephalomyelitis (EAE), a murine model of MS, while TLR3 activation protects from disease. Therefore, TLR-modulation could be an important adjuvant to current treatments. Here, we focus on TLR involved in EAE and MS pathogenesis highlighting specific components targeting TLR that might offer further therapeutic possibilities.


The Emerging Role of TLR and Innate Immunity in Cardiovascular Disease
Cardiovascular disease is a complex disorder involving multiple pathophysiological processes, several of which involve activation of toll-like receptors (TLRs) of the innate immune system. As sentinels of innate immunity TLRs are nonclonally germline-encoded molecular pattern recognition receptors that recognize exogenous as well as tissue-derived molecular dangers signals promoting inflammation. In addition to their expression in immune cells, TLRs are found in other tissues and cell types including cardiomyocytes, endothelial and vascular smooth muscle cells. TLRs are differentially regulated in various cell types by several cardiovascular risk factors such as hypercholesterolemia, hyperlipidemia, and hyperglycemia and may represent a key mechanism linking chronic inflammation, cardiovascular disease progression, and activation of the immune system. Modulation of TLR signaling by specific TLR agonists or antagonists, alone or in combination, may be a useful therapeutic approach to treat various cardiovascular inflammatory conditions such as atherosclerosis, peripheral arterial disease, secondary microvascular complications of diabetes, autoimmune disease, and ischemia reperfusion injury. In this paper we discuss recent developments and current evidence for the role of TLR in cardiovascular disease as well as the therapeutic potential of various compounds on inhibition of TLR-mediated inflammatory responses.

TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients
Chronic systemic inflammation links periodontal disease and diabetes to increased incidence of serious comorbidities. Activation of TLRs, particularly TLR2 and TLR4, promotes chronic systemic inflammation. Human B cells have been generally thought to lack these TLRs. However, recent work showed that an increased percentage of circulating B cells from inflammatory disease patients express TLR2 and TLR4, and that TLR engagement on B cells resulted in unexpected changes in gene expression. New data show that B cells from inflammatory disease patients secrete multiple cytokines in response to different classes of TLR ligands. Furthermore, the B cell response to combinations of TLR ligands is cytokine- and ligand-specific. Some cytokines (IL-1beta and IL-10) are predominantly regulated by TLR4, but others (IL-8 and TNF-alpha) are predominantly regulated by TLR2, due in part to TLR-dictated changes in transcription factor/promoter association. TLR2 and TLR9 also regulate B cell TLR4 expression, demonstrating that TLR cross-talk controls B cell responses at multiple levels. Parallel examination of B cells from periodontal disease and diabetes patients suggested that outcomes of TLR cross-talk are influenced by disease pathology. We conclude that disease-associated alteration of B cell TLR responses specifically regulates cytokine production and may influence chronic inflammation.


EBV Latent Membrane Protein 2A Induces Autoreactive B Cell Activation and TLR Hypersensitivity
TLR signaling has been suggested to be important to the activation of autoreactive B cells in autoimmunity…
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by the production of autoantibodies and multiorgan inflammatory damage. Both genetic and environmental factors contribute to the etiology of SLE, but a clear understanding of how these factors contribute to disease is still lacking. Among the environmental risk factors, EBV is the most closely associated with SLE. SLE patients have higher titers of anti-EBV Abs than control populations, and EBV infection is more common among juvenile and adult SLE patients than among control populations. Some cases of SLE appear to directly result from acute EBV infection or reactivation of EBV. In addition, SLE patients have a 40-fold higher EBV viral load in peripheral blood leukocytes than control populations due to poor cytotoxic T cell (CTL) responses and a higher frequency of infected B cells….
Since EBV-encoded latent membrane protein 2A (LMP2A) interferes with normal B cell differentiation and function, we sought to determine its effect on B cell tolerance…..
LMP2A induces a heightened sensitivity to TLR ligand stimulation, resulting in increased proliferation or antibody-secreting cell differentiation or both. Thus, we propose a model whereby LMP2A induces hypersensitivity to TLR stimulation, leading to activation of anti-Sm B cells through the BCR/TLR pathway..
These data further implicate TLRs in the etiology of SLE and suggest a mechanistic link between EBV infection and SLE…
We have focused on an SLE-specific autoantigen, but since this mechanism could act on B cells of specific for autoantigens targeted in other autoimmune diseases, EBV could have a role in the etiology of multiple autoimmune diseases such as Sjögren’s syndrome, rheumatoid arthritis, multiple sclerosis, and autoimmune hepatitis.

Toll-Like Receptor Agonists Synergistically Increase Proliferation and Activation of B Cells by Epstein-Barr Virus
Epstein-Barr virus (EBV) efficiently drives proliferation of human primary B cells in vitro, a process relevant for human diseases such as infectious mononucleosis and posttransplant lymphoproliferative disease. Human B-cell proliferation is also driven by ligands of Toll-like receptors (TLRs), notably viral or bacterial DNA containing unmethylated CpG dinucleotides, which triggers TLR9. Here we quantitatively investigated how TLR stimuli influence EBV-driven B-cell proliferation and expression of effector molecules. CpG DNA synergistically increased EBV-driven proliferation and transformation, T-cell costimulatory molecules, and early production of interleukin-6. CpG DNA alone activated only memory B cells, but CpG DNA enhanced EBVmediated transformation of both memory and naive B cells. Ligands for TLR2 or TLR7/8 or whole bacteria had a weaker but still superadditive effect on B-cell transformation. Additionally, CpG DNA facilitated the release of transforming virus by established EBV-infected lymphoblastoid cell lines. These results suggest that the proliferation of EBV-infected B cells and their capability to interact with immune effector cells may be directly influenced by components of bacteria or other microbes present at the site of infection.

Toll-like receptor 4 in CNS pathologies
Because microglial activation is widely controlled by pathogen recognition receptors (PRRs), TLR4 is implicated in the microglia-mediated neurotoxicity that occurs in many brain pathologies….
,,, If the TLR4 pathway is erroneously activated, or if a signal is amplified out of control, the cytokine response may have deleterious effects on the nervous system….
…Mice lacking functional TLR4 expression in CNS are exempt from long-term progressive neuron loss. This example illustrates the paradoxical nature of TLR4 signaling: it is necessary for defense, yet it invokes a powerful cascade that can be toxic. The stakes are high in the CNS, where subtle modifications can tip TLR4 signaling over the neurotoxic edge…
…Recent reports of TLR4 activation by endogenous ligands link TLR4 to autoimmunity as well as legitimate inflammation…
…Microglia, the immunocompetent cells of the CNS, are important contributors to chronic pain pathologies (Milligan and Watkins 2009). The TLR4 receptor is one avenue through which microglia can be activated and primed for the pain response. TLR4 influences the CNS pain response, invoking the production of pro-inflammatory cytokines and reactive oxygen species…
…LPS induces glial activation, and this activation can be ameliorated by naloxone administration (Wu et al. 2006). Based on the ability of naloxone to interfere with LPS signaling, the TLR4 pathway is implicated as a mediator of non-classical opioid responses…
…Consistent with the ability of naltrexone to reduce chronic pain symptoms, opioid
antagonists were found to inhibit TLR4 signaling and the production of pro-inflammatory substances. TLR4 inhibition was proportional to morphine analgesia effectiveness….
…Altogether, innate immunity and the responses coordinated by PRRs are extremely powerful modulators of the CNS environment…


Painful pathways induced by TLR stimulation of dorsal root ganglion neurons 
…TLR ligands upregulated the expression of a nociceptive receptor, transient receptor potential vanilloid type 1 (TRPV1), and enhanced calcium flux by TRPV1-expressing DRGNs. Using a tumor-induced temperature sensitivity model, we showed that in vivo administration of a TLR9 antagonist, known as a suppressive oligodeoxynucleotide, blocked tumor-induced temperature sensitivity. Taken together, these data indicate that stimulation of peripheral neurons by TLR ligands can induce nerve pain…

Emerging role of Toll-like receptors in the control of pain and itch
... In particular, primary sensory neurons, such as nociceptors, express TLRs (e.g., TLR4 and TLR7) to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch...

Systemic challenge with the TLR3 agonist poly I:C induces amplified IFNalpha/beta and IL-1beta responses in the diseased brain and exacerbates chronic neurodegeneration
The role of inflammation in the progression of neurodegenerative disease remains unclear. We have shown that systemic bacterial insults accelerate disease progression in animals and in patients with Alzheimer's disease. Disease exacerbation is associated with exaggerated CNS inflammatory responses to systemic inflammation mediated by microglia that become 'primed' by the underlying neurodegeneration. The impact of systemic viral insults on existing neurodegenerative disease has not been investigated. Polyinosinic:polycytidylic acid (poly I:C) is a toll-like receptor-3 (TLR3) agonist and induces type I interferons, thus mimicking inflammatory responses to systemic viral infection. In the current study we hypothesized that systemic challenge with poly I:C, during chronic neurodegenerative disease, would amplify CNS inflammation and exacerbate disease. Using the ME7 model of prion disease and systemic challenge with poly I:C (12 mg/kg i.p.) we have shown an amplified expression of IFN-alpha and beta and of the pro-inflammatory genes IL-1beta and IL-6. Similarly amplified expression of specific IFN-dependent genes confirmed that type I IFNs were secreted and active in the brain and this appeared to have anti-inflammatory consequences. However, prion-diseased animals were susceptible to heightened acute sickness behaviour and acute neurological impairments in response to poly I:C and this treatment also accelerated disease progression in diseased animals without effect in normal animals. Increased apoptosis coupled with double-stranded RNA-dependent protein kinase (PKR) and Fas transcription suggested activation of interferon-dependent, pro-apoptotic pathways in the brain of ME7+poly I:C animals. That systemic poly I:C accelerates neurodegeneration has implications for the control of systemic viral infection during chronic neurodegeneration and indicates that type I interferon responses in the brain merit further study.

Chronic ethanol increases systemic TLR3 agonist-induced neuroinflammation and neurodegeneration
Increasing evidence links systemic inflammation to neuroinflammation and neurodegeneration. We previously found that systemic endotoxin, a TLR4 agonist or TNFalpha, increased blood TNFalpha that entered the brain activating microglia and persistent neuroinflammation. Further, we found that models of ethanol binge drinking sensitized blood and brain proinflammatory responses. We hypothesized that blood cytokines contribute to the magnitude of neuroinflammation and that ethanol primes proinflammatory responses. Here, we investigate the effects of chronic ethanol on neuroinflammation and neurodegeneration triggered by toll-like receptor 3 (TLR3) agonist poly I:C.
Poly I:C increased blood and brain TNFalpha that peaked at three hours. Blood levels returned within one day, whereas brain levels remained elevated for at least three days. Escalating blood and brain proinflammatory responses were found with ethanol, poly I:C, and ethanol-poly I:C treatment. Ethanol pretreatment potentiated poly I:C-induced brain TNFalpha (345%), IL-1beta (331%), IL-6 (255%), and MCP-1(190%). Increased levels of brain cytokines coincided with increased microglial activation, NOX gp91phox, superoxide and markers of neurodegeneration (activated caspase-3 and Fluoro-Jade B). Ethanol potentiation of poly I:C was associated with ethanol-increased expression of TLR3 and endogenous agonist HMGB1 in the brain. Minocycline and naltrexone blocked microglial activation and neurodegeneration.
Ethanol potentiation of TLR3 agonist responses is consistent with priming microglia-monocytes and increased NOX, ROS, HMGB1-TLR3 and markers of neurodegeneration. These studies indicate that TLR3 agonists increase blood cytokines that contribute to neurodegeneration and that ethanol binge drinking potentiates these responses.

Apparently TLRs are involved in many conditions and diseases - so this is one topic more to keep an eye on.

Diagnosticering og behandling af ME

Myalgic encephalomyelitis bliver også kaldt for Chronic Fatigue Syndrome eller for kronisk træthedssyndrom.

I Sundhedsstyrelsens SKS browser for diagnosekoder har ME diagnosekoden DG933A og kaldes "Benign myalgisk encefalomyelitis."

Til diagnosticering af ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) anvendes et sæt diagnosekriterier. Der har igennem tiden været benyttet flere forskellige kriterier:

Oxford Definition
Fukuda Definition
The Canadien Consensus Document
Myalgic encephalomyelitis International Consensus Criteria

Årsagen til at man har ændret i kriterierne er, at forskerne søger at gøre definitionen på ME så skarp og entydig som overhovedet mulig, så patienter med andre diagnoser ikke fejlagtigt får diganosen ME.

I det norske Dagens Medisin er det vurderet, at hvis Oxford kriterierne anvendes, er der 25.000 - 47.000 ME patienter i Norge. Og hvis de Canadiske kriterier anvendes, er tallet nede på 9.000 -17.000 ME patienter.

Det norske helsedirektorat anbefaler de nye internationale diagnosekriterier. Og Oslo Universitetssygehus har en udmærket  vejledning til udredning af patienter, som er under observation for ME.

Ved Infektionsmedicinsk afdeling, Århus Universitetshospital, refereres der til den ældre Fukuda definition i denne instruks: Instruks 1.18.1 Kronisk træthedssyndrom.

I instruksen nævnes kognitiv terapi (CBT) som behandlingsmulighed. Sundhedsstyrelsen anbefaler også kognitiv terapi under henvisning til NICE guidelines. På side 190 i denne guidelines står der: 

"CBT or psychological approaches to CFS/ME do not imply that symptoms are psychological, "made up" or in the patient's head. CBT is used as part of overall management for many conditions, including cardiac rehabilitation, diabetes and chronic pain."

oversat:

"CBT eller psykologiske tilgange til CFS/ME betyder ikke, at symptomer er psykologiske, "opdigtede" eller i patientens hoved. CBT bruges som en del af den overordnede håndtering af mange tilstande, herunder hjerterehabilitering, diabetes og kroniske smerter."

Det er også værd at bemærke, at der på side 256 står, at antidepressiv medicin ikke virker:

“No benefit was found in patients with CFS/ME from treatment with anticholinergic agents, antidepressants, antihypertensives or growth hormone.”

Imidlertid kan lave doser af tri-cykliske antidepressiva anvendes ved smerter og søvnbesvær, fra side 278:

"Prescribing of low-dose tricyclic antidepressants, specifically amitriptyline, should be considered for people with CFS/ME who have poor sleep or pain."

At ME er en alvorlig sygdom anerkender NICE guidelines ved at skrive dette på side 68:

"Chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (or encephalopathy) (ME) is a relatively common illness. The physical symptoms can be as disabling as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, congestive heart failure and other chronic conditions."

oversat:

"Chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (eller  encephalopathy) (ME) er en relativ almindelig sygdom. De fysiske symptomer kan være lige så invaliderende som multipel sclerose, systemisk lupus erythematosus, rheumatoid arthritis, kongestiv hjertesvigt og andre kroniske tilstande."

Kogntiv terapi og ligeledes gradueret fysisk træning (GET), som NICE Guidelines også anbefaler, er meget omdiskuteret som egnet behandlingsform til ME. Dette fremgår bl.a. af Tom Kindlon's rapport:
"Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome."

Histamine Intolerance

Some ME patients report, that they benefit from a diet low in histamine.

Quote from Histamine and Histamine Intolerance:

"Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines."

If plasma histamine concentrations are very high, you will experience symptoms of histamine poisoning. But if plasma concentrations are less elevated, you may only observe elevated gastric acid secretion and elevated heart rate, - and therefore maybe not get a suspicion to histamine intolerance. 

In videos from Dr. Janice Vickerstaff Joneja you can learn more about histamine intolerance.

Histamine is involved in the immune system and also act as a neurotransmitter. I found this interesting paper about histamine's impact on the immune system: Histamine Potently Suppresses Human IL-12 and Stimulates IL-10 Production via H2 Receptors

Quote:

"IL-12 and IL-10, respectively, stimulate Th1 and Th2 immune responses. The development of some allergic reactions, infections,and tumors are associated with excessive histamine production and a shift toward Th2 responses"...."Thus, histamine, via stimulation of H2 receptors on peripheral monocytes and subsequent elevation of cAMP, suppresses IL-12 and stimulates IL-10 secretion, changes that may result in a shift of Th1/Th2 balance toward Th2-dominance. This may represent a novel mechanism by which excessive secretion of histamine potentiates Th2-mediated allergic reactions and contributes to the development of certain infections and tumors normally eliminated by Th1-dependent immune mechanisms."

For Danish readers - Til danske læsere:
Region Midtjylland har udgivet en pjece om histamin intolerance: Madens mulige betydning ved histamin intolerance