Links om blodprøver, analyser og medicin

På Københavns Praktiserende Lægers Laboratoriums hjemmeside kan du søge viden om blodprøver og undersøgelser. KPLL

Når du er inde på KPLL kan du klikke på linket analysefortegnelse, hvor du kan søge efter din blodprøve.
Analysefortegnelse

Statens Serum Institut foretager analyser for bakterier, virus, parasitter, hormoner og en lang række autoimmune stoffer. SSI

Søgning direkte på analyser hos SSI sker her. Diagnostisk Håndbog

Rigshospitalets laboratorievejledninger

Under Labka analyseoversigten er der over 3000 analyser beskrevet. Labka

Rigshospitalets andre vejledninger. Rigshospitalet vejledninger

Århus universitetshospitals analysefortegnelse

Region midtjylland har en omfattende samling af medicinske vejledninger. E dok

Dansk Lægemiddelinformation har en side, hvor du kan finde alle informationer om din medicin.

På interaktionsdatabasen kan du taste din medicin ind og se om du må tage de forskellige medicinpræparater samtidig.  Interaktionsdatabasen

Faglige vejledninger Herlev Hospital. Endoherlev

Institut for Rationel Farmakoterapi er også et godt sted af finde forskellige oplysninger. IRF


Engelsksprogede links:

Labtestonline er et virkelig godt sted at slå dine blodprøver op og lære mere om dem. Labtestonline

Quest Diagnostics har mange analyser. Quest

Her er selve guiden til analyserne. Quest test

Labcorp har ligeledes mange analyser. Labcorp

Hvis du har lyst til at lede efter videnskabelige artikler kan du kigge her. Pubmed

Der er også U S Library of Medicine at søge i. Library

Database over kliniske afprøvninger. Clinicaltrial

Medicinsk leksikon. Medilexicon

Og så slutter vi med en af mine favoritter. Små film, der kort beskriver forskellige medicinske emner. F.eks. er der glimrende, overskuelige forklaringer om de forskellige dele, som immunforsvaret består af.

Handwrittentutorials

Ofatumumab (Arzerra) for B-cells related disease

Rituximab (Rituxan, MabThera) is a chimeric monoclonal antibody against the CD20 molecule found on the surface of B cells.

Ofatumumab (Arzerra) is a human monoclonal antibody which targets an epitope in the CD20 molecule.

It is called a chimeric monoclonal antibody because the metod used to produce the antibody yields an animal. When mice is used for this purpose, these murine monoclonal antibodies can, when injected into humans, provoke an adverse reaction.

Therefore scientists are trying to develop fully human monoclonal antibodies to avoid side effects from the chimeric antibodies. More about monoclonal antibodies.

Ofatumumab was developed by Genmab. It is a biotechnology company, founded in Denmark in 1999. The company is specializing in the creation and development of differentiated human antibody therapeutics. Ofatumumab is being investigated for use in oncology and autoimmune diseases. More information here. 

Genmab uses patented UltiMAb® transgenic mouse technology to produce monoclonal human antibodies. More information here.

GlaxoSmithKline about Ofatumumab:
The binding of ofatumumab to the membrane-proximal epitope of the CD20 molecule induces recruitment and activation of the complement pathway at the cell surface, leading to complement-dependent cytotoxicity and resultant lysis of tumour cells.  Ofatumumab has been shown to induce appreciable lysis of cells with high expression levels of complement defence molecules.  Ofatumumab has also been shown to induce cell lysis in both high and low CD20 expressing cells and in rituximab-resistant cells.  In addition, the binding of ofatumumab allows the recruitment of natural killer cells allowing the induction of cell death through antibody-dependent cell-mediated cytotoxicity.

An article on Ofatumumab from 2009 informs: 

A number of anti-CD20 mAbs are under development or are already on the market. Compared to the marketed product anti-CD20 product rituximab, ofatumumab has demonstrated greater cytotoxic potential in killing B-cells though CDC (complement-dependent cytotoxicity) pathways. Thus, ofatumumab may offer alternative therapy for patients who are resistant to rituximab. Other anti-CD20 mAbs are in clinical development, including afutuzumab (Hoffmann-LaRoche/Biogen Idec), veltuzumab (Immuomedics) and ocrelizumab (Genentech/Biogen Idec). These candidates have also shown positive results in clinical trials, and are expected to enrich the pipeline of mAb therapy for B-cells related disease.

Forstyrrelser i immunforsvaret hos ME patienter

Bloggen Phoenix Rising omtaler meget rosende PHANU gruppen (Population Health and Neuroimmunology Unit) fra Bond Universitet i Australien. Forskere herfra med Dr. Sonya Marshall-Gradisnik og Dr. Donald Staines i spidsen har gjort store fremskridt i forskningen i forstyrrelser i ME/CFSs patienters immunforsvar.

Disse to forskere fremlagde deres og kollegers resultater på invest in ME konferencen i juni 2012. Man kan se deres præsentationer (på engelsk) på DVD'erne fra konferencen. DVD'erne kan købes på invest in MEs hjemmeside her.

Jeg vil i det følgende kort gennemgå én af deres artikler:

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Forskerne har undersøgt forskellige parametre i immunforsvaret hos 95 ME/CFS patienter (Fukuda kriterier fra 1994) og sammenlignet med 50 raske kontrolpersoner.

Hos ME/CFS patienter blev der fundet

• nedsat cytotoksisk aktivitet af Natural Killer Celler (NK)
• nedsat cytotoksisk aktivitet af CD8⁺T celler 
• nedsat antal af CD56^bright NK celler

CD betyder Cluster of Differentiation og er en måde at identificere immuncellernes overflademolekyler (receptor eller ligand) på. En immuncelle har således forskellige egenskaber afhængig af overflademolekylerne.

Natural Killer celler er en del af det innate (medfødte) immunforsvar. Natural Killer celler bekæmper virus og tumorer.

CD8⁺T celle er en T celle med en CD8 receptor, der kan genkende overfladen på en virusinficeret celle og dræbe den. CD8⁺T celler dræber også cancerceller eller celler der er beskadiget på anden vis.

CD56^bright NK celler producerer cytokiner og har også immunoregulatoriske egenskaber. CD56^bright NK celler er henholdvis op- og nedreguleret i en række sygdomme. F.eks. er de også nedreguleret i juvenil rheumatoid arthritis.

Disse resultater bekræfter en nedsættelse i immunfunktionen, der gør ME/CFS patienter sårbare over for infektioner.

Forskerne viste samtidig, at ME/CFS patienterne havde en opregulering af

• IL-10
• IFN- γ
• TNF-α
• CD4⁺ CD25⁺  T-celler 
• FoxP3 ekspression
• VPACR2 ekspression

IL-10 er et anti-inflammatorisk interleukin, mens INF- γ og TNF-α er proinflammatoriske cytokiner.

CD4⁺ CD25⁺  T-celler er regulatoriske celler, hvis opgave er at "tilbageregulere" immunforsvaret efter, at det har været aktiveret i forbindelse med infektion. De regulatoriske T celler skal også forhindre autoimmunitet.

Ekspression af FoxP3 anses for overordnet at styre de T regulatoriske celler. På engelsk kaldes FoxP3 for "master-regulator".

VPACR2 er en Vasoactive Intestinal Peptide Receptor, som jeg har skrevet om i en tidligere blog-post. VPACR2 er en G koblet protein receptor, der reagerer på neuropeptider og som er involveret i adenylate cyclase aktivitet.

Forskerne skriver i deres diskussion/konklusion:

"Dette er den første undersøgelse, der viser betydeligt højere niveauer af VPACR2 receptorer, CD4⁺  CD25⁺ T-regs og FoxP3 Treg ekspression i CFS/ME patienter sammenlignet med raske kontrolpersoner. Derudover havde CFS/ME patienter signifikant højere niveauer af anti-inflammatoriske cytokin IL-10 og pro-inflammatoriske cytokiner IFN-γ og TNF-α. Denne profil afspejler en væsentlig og vigtig immunologiske dysregulation, der kunne forklare nogle af de kliniske symptomer, for eksempel den vedvarende sygdomsfølelse, som af CFS/ME patienter har.

Disse resultater viser en alvorlig kompromitteret immunmodulation mekanisme i CFS/ME, hvor forsøg på at regulere eller genoprette immun homøostase synes at være svækket. Disse resultater tyder på, at visse immunologiske biomarkører, som påvist i denne undersøgelse, kan være unikke for CFS/ME."

Jeg synes, at man skal være opmærksom på et par ting i forbindelse med denne artikel. Der er anvendt Fukuda kriterier, som af mange forskere nu anses for forældede, fordi de kan medtage patienter med andre sygdomme end ME. Problemet er, at de nye skarpe ICC-kriterier endnu ikke ligger til grund for artikler. Forsøg, skrivning af artikler og udgivelse er en langsommelig affære, så der går nok noget tid endnu inden, der kommer artikler med ICC kriterierne som udgangspunkt.

Ydermere skal man være opmærksom på inkonsistens i resultater af cytokinprofiler fra forskellige forsøg. Et nyere forsøg af samme forskere viser f.eks. at IL-10 hos samme gruppe af ME/CFS patienter både kan være højere og lavere end hos kontrolpersoner målt på forskellige tidspunkter.

Nedsætttelse af NK-cellers cytotoksiske aktivitet hos ME/CFS patietner er derimod påvist i flere uafhængige forsøg, og er også vist at være konsistent over tid i sidstnævnte forsøg.

Ønsker man mere baggrundsviden om immunforsvaret og regulatoriske immunceller kan jeg anbefale disse to artikler:

Immunsystemet ved kronisk inflammation

CD4+CD25+-regulatoriske T-celler og deres betydning for sygdomme hos mennesker

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