Tuesday, 27 January 2015

ClinicSpeak: Helicobacter pylori infection might prove the hygiene hypothesis in MS

How convinced are you by the hygiene hypothesis? #MSBlog #MSResearch #ClinicSpeak

"There is a theory that MS, and other putative autoimmune diseases, are due to excessive hygiene. The cleaner the environment you grow up in, the less infections you get as a child, the less your immune system gets educated by infections, the more likely it is your immune system will go awry when you are older, the more likely you are to get MS. The hygiene hypothesis has its many proponents; I am yet to be convinced as the data is inconsistent. The study below shows that MSers are less likely to be infected with the bacteria Helicobacter, which causes peptic (high acid) ulcers in the stomach and duodenum (upper small intestine). This study supports the hygiene hypothesis."

"A large component of the hygiene hypothesis relates to parasitic infections; there is data showing that the prevalence of MS is inversely proportional to prevalence of parasite infections in the population. This and other data have led to several clinical trials of worm therapy in MS; if you are infected with worms it changes your immune function that suppresses MS disease activity."

"Is it not amazing that we can go from bone marrow transplantation, or haemopoietic stem cell transplantation (HSCT), one day as means of rebooting your immune system to deliberate parasitic infections to subtly tweak your immune system as treatments for MS? How disparate can these two scenarios be. The difference with the parasite infection lobby is that they are doing randomised, double-blind, placebo-controlled trials to generate data to prove or disprove their hypothesis (Trichuris Suis Ova (TSO) in Recurrent Remittent Multiple Sclerosis and Clinically Isolated Syndrome (TRIOMS); NCT01413243). In comparison, the HSCT lobby simply want us to accept the evidence based on open-label observational studies that this treatment works and everyone should have access to the treatment because they know best and are prepared to take the risk. Either we accept the scientific process or we don't. If we don't set a very high-bar of scientific evidence for HSCT we are going to have all the same problems we have seen with other fringe therapies in MS and it will end-up condemning HSCT as a potentially very effective treatment for MS and open it up to abuse from unscrupulous clinics and clinicians wanting to make money out of desperate MSers and their families. It is important that the HSCT lobby take the MS community along with them; the only way this will be achieved is by a deliberate and well thought out public engagement campaign underpinned by due scientific process."

"Is anyone out there keen to help design a clinical trial to raise the level of evidence for HSCT above what it is at the moment? It is not just about whether HSCT works, but about its safety and durability and how it stacks up against existing licensed therapies."

"Back to this post. What is Helicobacter? It is a bacteria which infects up to 50% of the human population. Some strains of this bacterium cause disease in particular peptic ulcers, chronic gastritis, duodenitis, and stomach cancer. Helicobacter species are able to thrive in the very acidic mammalian stomach by producing large quantities of the enzyme urease, which locally raises the pH from about 2 to a more compatible range of 6 to 7. Helicobacter are usually susceptible to antibiotics. There is an amazing story behind the discovery of Helicobacter as a cause of peptic ulcer disease that eventually led to a Nobel prize. I would recommend reading about how Marshall and Warren came to win the 2005 Nobel Prize in Medicine; science does not get more inspiring than this. The Helicobacter story is not too dissimilar to countless others, whenever there is a paradigm shift in a field the community rejects it. I touched on this a few weeks ago when I discussed Zur Hausen, HPV and cervical cancer. I would not be surprised if a similar story is waiting in the wings for MS. Please remember Arthur Schopenhauer’s Dictum; all truth passes through three stages: (1) It is ridiculed, (2) it is violently opposed and (3) it is finally accepted as self-evident. Are we anywhere near this with the autoimmune MS theory or is there a black swan circling?"

Epub: Fabis et al. Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females.J Neurol Neurosurg Psychiatry. 2015 Jan 19. pii: jnnp-2014-309495. doi: 10.1136/jnnp-2014-309495.

BACKGROUND: In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results.

OBJECTIVE: To determine the association between the H. pylori infection and MS.

METHODS: 550 MSers were included in the study and were matched by gender and year of birth to 299 controls. MSers were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups.

RESULTS: H. pylori seropositivity was found to be lower in MSers than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate.

CONCLUSIONS: Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life.

Getting rid of hot microglia

Airas L, Dickens A, Elo P, Marjamäki PM, Johansson J, Eskola O, Jones P, Trigg W, Solin O, Haaparanta-Solin M, Anthony D, Rinne J. In vivo Positron Emission Tomography Imaging Demonstrates Diminished Microglial Activation after Fingolimod Treatment in an Animal Model of Multiple Sclerosis. J Nucl Med. 2015 Jan 8. pii: jnumed.114.149955. [Epub ahead of print]

There is a great need for the monitoring of microglial activation surrounding multiple sclerosis lesions as this is thought to be driving the widespread neuronal damage. Recently, 'second generation' positron emission tomography (PET) radioligands have been developed which can reveal the extent of microglial activation by quantifying the increased expression of the 18 kDa translocator (TSPO) protein. Here, we investigate whether PET imaging can be used to demonstrate the reduction in microglial activation surrounding a chronic focal multiple sclerosis (MS)-like lesion following treatment with fingolimod, an established MS therapy.
METHODS: Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotaxic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund's adjuvant. This results in a delayed type hypersensitivity (DTH)-like EAE-lesion. The extent of neuroinflammation surrounding the lesion was measured using 18F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/day po, 28 days) or vehicle as a control. In addition to this, autoradiography and immunohistochemistry experiments were performed to verify the in vivo results.
RESULTS:The chronic DTH-EAE lesion led to increased ligand binding in the ipsilateral compared to contralateral hemisphere when PET imaging was performed with the TSPO-binding radioligand 18F-GE180. Treatment with fingolimod led to highly significant reduction in the binding potential, which could be demonstrated using both in vivo and ex vivo imaging (fingolimod vs. vehicle treatment, p<0.0001). The area of increased 18F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry.
CONCLUSION:PET-imaging, unlike magnetic resonance imaging (MRI), can be used to visualise the microglial activation surrounding a chronic DTH-EAE lesion. Importantly, treatment effect of fingolimod can be monitored in vivo by measuring the degree of microglial activation surrounding the chronic DTH-EAE lesion. This work gives promise for introduction of new outcome measures applicable in treatment studies of progressive MS.

This study suggests that we have a tool to measure hot microglia it is a short-activing radioactive tracer,in this can it is a 8 kDa translocator (TSPO) protein, another previously used is the benzodiazapine receptor. In this study the hot microglia were blocked by fingolimod. This will block the inflammatory penubra and blockinflammatory lesion formation,but what we need to block is the microglial inflammation in progressive disease. Can fingolimod do this in progressive MS, apparently not based on the recent failings in PPMS or are hot microglia a  smokescreen, I somehow suspect not. Could this be useful in humans

Image reveals higher levels of inflammation-associated translocator protein (orange/red) in the thalamus and other brain regions of chronic pain patients.

I guess so as images have now just been shown in humans in pain in the thalamus. Maybe this can be used to monitor progression in MS.