The Possible Role of Mycobacterium avium subspecies paratuberculosis (MAP) in Multiple Sclerosis

 

The cause of multiple sclerosis is currently unknown. Researchers have proposed a variety of causes, and there are certain risk factors that make the disease more likely in certain populations.  However, the initial cause of MS has been elusive.

The leading hypothesis is that MS is a disease caused by genetic vulnerabilities combined with environmental factors, such as infectious agents. Recently, it has been shown that multiple sclerosis patients have genetic vulnerabilities which make them susceptible to mycobacterial infection. Additionally, some pathogens are able to trigger an immune response by cross-reactivity or molecular mimicry.

• Cross-reactivity occurs when an antibody created by one bacterial species attacks a similar bacterial species.
• Molecular mimicry is when an infectious agent, such as MAP, displays antigenic elements similar to something in the host. Due to this similarity, the infectious agent causes the immune system to respond by attacking the body’s own cells instead of the infectious agent.

Some researchers have hypothesized that MAP is the infectious agent that triggers MS.

One interesting case which may show an association of MAP with MS is in Iceland. Iceland was MAP free until 1938, when 20 sheep were imported from Germany. Since then, the incidence of MS has been increasing, as evidenced by this 100 year population study.

 

Research on MAP and Multiple Sclerosis in the Sardinian Population

The strongest correlation between MAP and MS is in the Sardinian population. Sardinia is an ideal area to study MS since it has one of the highest rates of MS in the world, which cannot be attributed solely to a limited gene pool. Due to the geographical isolation of this island nation, the search for an environmental trigger may be made easier. MAP infection is epidemic in the sheep and cattle populations in Sardinia as well.

A dedicated group of researchers conducting research in Sardinia has consistently shown that MAP is found in a significantly higher percentage of MS patients than in healthy controls. The presence of MAP DNA has been identified in 15.6-42% of MS patients, as compared to 7-12.5% in healthy controls. Likewise, MAP antibodies have been found in 32-36% of MS patients, but only 2-3% of healthy controls.

These researchers have observed an extremely high  immune response against a MAP protein that is comparable human mylin. Sardinian MS patients also had a significantly higher immune response to a specific heat shock protein found in both humans and MAP (23% in MS vs. 6.5% in controls),  which indicates that MAP could play a role in MS.

Additionally, the Sardinian population might be susceptible to developing an autoimmune disease like MS due to mutations in the SLC11A1 gene, which is important in the immune response against intracellular bacteria such as MAP. In another genetic study, a significantly lower presence of MAP antibodies were found in MS patients who had at least one the protective HLA gene. This indicates that a protective HLA type may protect against MAP and MS.

 

Additional research discussing the role of MAP in MS

Research on the role of MAP in MS on patients outside of Sardinia has been conducted as well. Like the research from Sardinia, MAP was present in a significantly higher percentage of MS patients as compared to healthy controls. MAP antibodies have been found in 30-63% of non-Sardinian MS patients, but only 18-36% of healthy controls or patients with non-inflammatory neurological disorders.

Both the Epstein-Barr virus (EBV) and MAP are thought to be potential pathogenic triggers in the onset of multiple sclerosis, and it has been hypothesized that pathogens such as MAP and EBV could act synergistically in genetically susceptible patients to cause disease.

One research group has studied B lymphocyte activating factor (BAFF) levels in MS patients before and after interferon-β therapy and measured the MAP antibody response to see if it was related to increased BAFF levels. While the researchers found that interferon-β therapy increased BAFF levels, there was no change in the MAP antibody levels. The researchers concluded that interferon-β therapy does not alter the immune response to MAP in MS patients.

For detailed descriptions and links to the research articles which discuss MAP in MS, see the Multiple Sclerosis Core Research Pack.

 

Treatment Applications for MAP-driven Multiple Sclerosis

There are many studies suggesting antibiotics may be beneficial in multiple sclerosis. The most commonly discussed pathogens associated with MS are Chlamydia Pneumonia, and the Lyme disease bacteria B. burgdorferi. Antibiotics sometimes prescribed for multiple sclerosis include Minocycline, Doxycycline, Azithromycin, and Metronidazole.

In 2005, a pilot study was conducted on 8 newly diagnosed relapsing-remitting MS patients which had Chlamydia Pneumonia in the spinal fluid. 4 patients were given a combination of rifampin and azithromycin for 6 months, and the other 4 were given a placebo. The antibiotic group showed significantly lower brain atrophy, as measured by brain parenchymal fraction loss, and had cleared the pathogen from their spinal fluid by 12 months.

While this research is of interest, Human Para will focus only on the treatment of MAP in MS.

In December 2016, RedHill Biopharma completed their Phase IIa proof of concept study (CEASE-MS) to test the safety and effectiveness of RHB-104 as an add-on therapy to interferon beta-1a in relapsing-remitting multiple sclerosis. RHB-104 is a proprietary antibiotic combination therapy, in oral capsule formulation, with potential intracellular, anti-mycobacterial and anti-inflammatory properties. Originally developed by Prof. Thomas Borody, it’s based on increasing evidence which supports the hypothesis that MAP plays a critical role in the multiple sclerosis disease process in certain susceptible patients. Per the ClinicalTrials.gov site, the RHB-104 contains clofazimine, Rifabutin and clarithromycin. RedHill gradually increases the dosage, with each capsule containing 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine. Eventually, the patient will take 5 capsules, twice a day for a total dosage of 950 mg. of clarithromycin, 450 mg. of rifabutin, and 100 mg. of clofazimine. Patrick McLean, is the RHB-104 Product Manager at RedHill Biopharma.

The CEASE-MS study, which was begun in 2013 and completed in 2016 in Israel, recently released positive final results. Although the primary goal of the study was to assess the safety of RHB-104 in MS patients, the treatment showed preliminary effectiveness as well. 18 patients were enrolled and received treatment with RHB-104 for 24 weeks, in addition to the standard interferon beta-1a therapy. They were then assessed for an additional 24 weeks after discontinuing RHB-104 while remaining on interferon beta-1a therapy. The interim results released in March 2016 showed a 0% relapse rate at 24 weeks in the per-protocol patient population, which was comparatively better than the published relapse rates of the interferon beta-1a therapies Avonex and Rebif from the EVIDENCE trial. Additionally, RHB-104 was found to be safe and well tolerated.

The final results, released in December 2016, are consistent with the interim results, and the impact of RHB-104 treatment seems to remain even after it is discontinued. 100% of the per protocol patients and 93% of the modified ITT patients were relapse free at 48 weeks. Additionally, a reduction of T2 lesion volume was noted, which suggests that disease burden decreased. RHB-104 was safely tolerated with no relevant adverse events. “Further analysis will drive next steps in the development path of RHB-104 for MS.”

 

The BCG (tuberculosis) Vaccine in Multiple Sclerosis

Researchers in Italy have completed a Stage II trial using the BCG vaccine as a therapy in early-stage multiple sclerosis patients. 73 patients who had experienced a single clinical episode suggestive of MS were given either the BCG vaccine or a placebo injection. (With no intervention, about half of patients who experience a single clinical episode will develop MS within 2 years.) After 6 months, all patients were given beta interferon therapy for an additional 12 months. Results showed that the BCG group had less disease activity, measured by fewer MS lesions found in MRIs at 6, 12 and 18 months. At 5 years, there was a significant different in MS disease onset between the two groups; 57.6% of the BCG group had not converted to MS by 5 years while only 30% of the placebo group remained MS free. Additionally, patients who were not on any therapy were more frequent in the BCG group. Phase III trials on BCG and MS have recently begun in Italy.

How is this connected to MAP? The BCG vaccine is made with a non-disease causing form of Mycobacterium bovis. It provides some immunity against TB (a different mycobacterial species) by stimulating the body’s immune system to recognize mycobacteria as a threat. Later on, when the body is exposed to TB or another mycobacterial species, the immune system more easily recognizes the pathogen and destroys it before it produces disease. The BCG vaccine is 50-80% effective against tuberculosis, which varies by location. Studies have also indicated that it is 26-41% effective against Mycobacterium leprae, the pathogen which causes leprosy. This cross-reactivity between the BCG vaccine and mycobacterial species may apply to MAP as well, and could lend support to the theory that MAP is involved in the development of MS.

The researchers in the study mention that the effectiveness of the BCG vaccine in preventing MS onset may be explained by the Hygiene Hypothesis. The Hygiene Hypothesis seeks to explain the rapidly increasing rate of allergies and immune diseases found in Western countries. It theorizes that the decreased exposure to microbes (both helpful and harmful) in early childhood suppresses the normal development of the immune system, leading to defects in immune tolerance. This “old friends theory” argues that it’s the lack of exposure to persistent and latent infections, such as TB, cholera and typhoid, that hinder the full development of the immune system. Animal studies support a conclusion that mycobacteria are important candidates in the hygiene hypothesis. Without early exposure to mycobacterial species, the innate immune system may not develop the ability to recognize and destroy them.

Exposure to mycobacteria is also critical to the proper development and function of regulatory T cells (Tregs.) The function of Tregs is to stop the immune system once a pathogen has been eliminated, and to maintain immune tolerance. They distinguish between what is “self” and what is “foreign” in the body. These distinctions are critical for preventing autoimmune disease, which is when the immune system attacks the body’s own tissue thinking it is foreign. In MS, the line between “self” and “foreign” gets blurred, and malfunctioning Tregs allow mylin destruction, thinking it is a foreign substance. A ubiquitous, and previously harmless, species like MAP could be viewed by the immune system as a pathogen per the Old Friends theory, and may trigger a dysfunctional Treg response in MS and other immune conditions.