Article Index

Immunological abnormalities in ME

Dr. Don Staines (Gold coast, Australia) then presented an update on the work by Sonya Marshall-Grasilnik, who was unable to attend the meeting. He outlined the new research being undertaken at Griffith University, where there is a dedicated ME research facility, which includes a 3 bed unit for 24 hour stay.  He stressed the importance of  getting immunological and molecular markers for this multi-system disease.  He outlined natural killer cell (NK) function showing the release of lytic proteins: perforins and granzymes (A and B).

Studies show that NK-cell function declines over time in ME.  CD107a is a NK marker for lysis, and granzyme B is down in ME. 

Several dimensions show impaired function in the immune system in this illness such as: CD56 (bright) down, CD8 lysis down++, reduced respiratory burst in neutrophils and high levels of HNA2. There are also a number of significant differences in microRNA in ME. mRNA CD8 cells show consistent abnormalities.

He asked the question—is ME an autoimmune disease? Other abnormal results from their lab included upregulation of T-reg cells in the adaptive immune system—this could be a potential biomarker, and helps to suppress inflammatory mechanisms. No differences were found in gamma-delta cells, but this will be redone.

B-cell phenotypes showed reduced immature cells, despite increased memory and increased plasma levels. Plasmacytoid dendritic cells were elevated. Conceptual paradigms were outlined in the innate and adaptive immune systems, whose components are initiated in response to an adaptive pathogen.

Results indicate potential hallmarks of autoimmunity. There are clear derangements in the immune system, and he reiterated the fact that such major changes will never be fixed by “exercise”!

It is important to note that severe patients were included in these studies by going into patients’ homes to take the blood.

B-cell abnormalities

Clinical immunology and research on B-cell abnormalities in ME was discussed by Dr Amolak Bansal  (Surrey, UK). He talked about immune dysfunction and autoimmunity. He looked at a long list of potential causes of ME, with interaction of the various systems, and a list of predisposing factors. He showed that 10-15% patient do have joint hypermobility. There is a slight familial tendency and relationships to personality and race. Fibromyalgia, IBS and MCS all can co-exist.

There is often a past history of mood disorders. Triggers can include infection, stress, vaccinations, injury, major life events etc. Factors which adversely affect the illness include sleep abnormality, over-activity, infections, anxiety and depression, inactivity, iatrogenic illness, illness beliefs, pessimism and loss of confidence.

He said that persistent stress can have an adverse effect on the immune system, stimulates the hypothalamo-pituitary axis and increases cortisol levels.  Stress raises the predisposition for autoimmunity, upregulates the Th2 mechanism and downregulates TH-1 and T-regs.

Many symptoms occur associated with viruses and ME, but there is no evidence of overt antibody, complement or neutrophil change. There is NK-cell immunodeficiency. There have been very few useful studies looking at the immune abnormalities in ME.

There are no abnormalities on routine tests. Occasionally increased atypical lymphocytes are seen. CRP is usually normal. Altered NK function is not always found.

There are many inconsistencies. This may be due to use of different criteria, varying severity of illness, roles of exercise, sleep and stress, different methods and technologies used and the timing of tests.

Bansal asked several questions: What is the role of exaggerated receptor solubilisation, and cytokine/cytokine receptor autoimmunity in this illness? Are patients generating antibodies?  He had looked at many immune parameters for antibodies and all were negative. However, transitional B-cells were elevated in ME patients, plasmablasts reduced and naïve B-cells increased. Some cytokines were abnormal and there were some T-cell subset abnormalities.

His conclusions were:

1) B-cells not being regulated properly

2) No evidence of autoimmunity to presently recognised organ specific and neuronal antigens

3) Reduced antiviral cytokines

4) Impaired T lymphocytes

5) Increased T viral effector cell numbers.

There is possible B-cell dysregulation initiated by a virus, the B-cells may produce autoantibodies, which can contribute to arousal mechanisms. They may target the mitochondrial proteins, leading to post-exertional malaise. Removing the autoantibodies reduces symptoms, but there is need to suppress the activity of the viruses, which encourage survival of autoreactive B-cells. Antivirals such as acyclovir and valcyte may be useful. He summarised by reiterating that this is a very complex disease.

Immunological basis of ME

The immunological basis of ME was addressed by Professor Carmen Scheibenbogen (Berlin, Germany). She explained how we are looking for the missing pieces of the jigsaw. There is evidence for immune mediated disease in the clinical picture, the laboratory finding and the efficacy of immunological treatment with drugs such as rituximab, ampligen, immunoglobulins and interferon alpha. There are controversial phenotypes immunologically in ME. Elevated T-regs and low NK toxicity are reproducible.

There is some immune activation and some immunodeficiency. She discussed cytokine analysis undertaken by Luminex. In further studies, 50% of patients were found to have elevated T-cell function with a TH-1 to TH-2 shift. Phenotyping was done by flow cytometry and there was T-cell activation in 2/3 of the patients. There was lymphopenia in a subset of the patients.

Polyclonal immunoglobulin was elevated in 25% of patients and there was evidence for immunodeficiency in a further 25%. There was MBL deficiency in 15% (and 7% in controls)—making these patients more prone to infection. There was evidence for ongoing infections with herpes viruses. A subset of patients (those with onset associated with EBV and those with recurrent herpes lesions) who improved on valaciclovir.  She recommends trying a course in these patients. Some patients may have ongoing EBV activation. The data is controversial as there may be enhanced or diminished EBV responses. The team had done EBV sero-array and measured antibody response against more than 2000 peptides from EBV. There was significant difference between patients and controls.

The conclusion was that there are some distinct entities corresponding to different types of the illness. There is evidence for activation, deficiency and non-immune ME.

B-cell lymphocyte depletion in ME has previously been reported by Dr Oystein Fluge and Professor Olav Mella (Bergen, Norway) and as yet there is an embargo on disseminating their further research as it is awaiting publication. A further report on their findings will be added following journal publication.

They described again the studies undertaken up until 2011, when initially 3 lymphoma patients with ME had responded to the B-cell depleting drug rituximab. 2 infusions had been given 2 weeks apart (500mg/m2). A further study was then undertaken with 30 subjects (15 patients and 15 controls). 67% of patients had positive results and only 13% of controls. No major toxicity or adverse events were described. Duration of response was 8-44 weeks, with 2 patients having no relapse to date.  In the majority of patients relapse occurred over time.

Further studies to be  reported in the literature very soon include 26 patients being followed over 28 months using rituximab with a different drug regimen, and a further 8 very severely ill patients.

Towards the end of the proceedings, Ellen Piro (Oslo, Norway) presented Invest in ME with a special award acknowledging all the effort in organising these conferences, bringing together so many distinguished researchers  and clinicians from around the world, encouraging collaborative research and enabling patient participation.

An award was also given to Professor Malcolm Hooper for his great efforts over the years. I would like to add my thanks to all these people, and in particular to both Invest in ME and the Alison Hunter Memorial Foundation. I must also thank ANZMES for giving me the opportunity to attend such a wonderful event.

Rosamund Vallings MNZM, MB BS
Auckland, NZ

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