Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME

Abstract

Introduction: Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases.

Methods: 10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry.

Results: IgG levels dropped to median 0.73 g/l (normal 7-16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6-12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening.

Conclusions: IA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

Conflict of interest statement

Competing Interests: This trial was supported with a grant by Fresenius Medical Care. Harald Heidecke is employed by CellTrend GmbH who also provided support in the measurement of autoantibodies. A patent application for the diagnostic use of antibodies against ß1 and ß2 adrenergic receptors in CFS/ME was filed (patent publication No WO 2016/188979 A1, applicants CellTrend (H.H.) and Charité (C.S). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. IgG and specific antibody levels during treatment.

Total and specific ß1, ß2, M3 and M4 IgG in the serum before and during IA. The levels are depicted as x-fold change to day -1 level for each single patient days +1 (day after 1st IA cycle) up to day +4 (day after the 4th IA cycle).

Fig 2. IgG and specific antibody levels follow-up.

ß1, ß2, M3 and M4 IgG, total IgG, tetanus IgG, and pneumococcal IgG in the serum before and after 3 and 6 months of IA. The values are shown for each single patient. The course of ß1 and ß2 values of patients 4 and 5 with long term response are indicated by a line. In patient 9 ß2 antibodies were elevated at screening 3 months prior to study inclusion, but below the upper normal value (8.5 U) at the day before IA.

Fig 3. Patients condition before treatment.

Symptom scores before IA. Symptoms are indicated as 0 (absent) to 10 (most severe).

Fig 4. Development of symptoms.

Symptom scores for fatigue, cognitive score, muscle pain and immune score during IA (A), and after 1 to 12 months of IA (B) are shown for each patient (3 unchanged, 4 slight, 5 marked improvement, 6 complete disappearance, 2 slight increase, 1 marked increase). The line indicates level 3 for unchanged symptoms.

Fig 5. Fact score follow-up.

FACT-F score assessing fatigue before and after 1 to 12 months of IA for each patient. The line indicates the individual pretreatment FACT-F score.

Fig 6. Patients mobility.

Mean daily number of steps counted during one week before and thereafter monthly after IA for 7 patients (patients 1, 2, 4, 5, 6, 7 and 10).

Fig 7. B cell subset analysis.

Frequencies of CD19 total B cells, CD19+CD27+ memory B cells, CD19+CD27+IgM negative class switched (CS) B cells, plasmablasts (PB) and CD86+ plasmablasts before IA (day -1) and after the 4th IA (day -4).