Immune Dysfunction and Autoimmunity
1 Loebel et al. 2016 — Autoantibodies to Adrenergic and Muscarinic Receptors
Full Citation:: Loebel M, Grabowski P, Heidecke H, et al. Antibodies to beta adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. 2016;52:32–39. (Loebel et al. 2016) DOI:: 10.1016/j.bbi.2015.09.013 Key Findings::
- Elevated autoantibodies against GPCR (beta-adrenergic and muscarinic receptors) in CFS
- Suggests autoimmune mechanism targeting autonomic signalingRelevance to Part V:: Key evidence for autoimmune sub-models within the immune system modeling chapter.
2 Bynke et al. 2020 — GPCR Autoantibodies: Swedish Validation
[/ Full Citation:: Bynke A, Julin P, Gottfries C-G, Heidecke H, Scheibenbogen C, Bergquist J. Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients—A validation study in plasma and cerebrospinal fluid from two Swedish cohorts. Brain, Behavior, & Immunity – Health. 2020;7:100107. (Bynke et al. 2020)], DOI:: 10.1016/j.bbih.2020.100107 Key Findings::
- Validated GPCR autoantibody findings in independent Swedish cohorts
- Detected in both plasma and cerebrospinal fluidRelevance to Part V:: Replication evidence strengthening autoantibody model parameters in immune system models.
3 Sotzny et al. 2021 — GPCR Autoantibodies Correlate with Symptom Severity
Full Citation:: Freitag H, Szklarski M, Lorenz S, Sotzny F, et al. Autoantibodies to Vasoregulative G-Protein-Coupled Receptors Correlate with Symptom Severity, Autonomic Dysfunction and Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Clinical Medicine. 2021;10(16):3675. (Freitag et al. 2021) DOI:: 10.3390/jcm10163675 Key Findings::
- GPCR autoantibody levels correlate with symptom severity and autonomic dysfunction
- Supports dose–response relationship between autoantibody titre and clinical impairmentRelevance to Part V:: Provides quantitative dose–response data for autoantibody–symptom coupling in integrated models.
4 Fluge et al. 2011 — Rituximab Phase II RCT
Full Citation:: Fluge Ø, Bruland O, Risa K, Storstein A, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome: a double-blind and placebo-controlled study. PLOS ONE. 2011;6(10):e26838. (Fluge et al. 2011) DOI:: 10.1371/journal.pone.0026838 Key Findings::
- Phase II RCT ($n$=30): 67% response to rituximab vs 13% placebo at 12 months
- Delayed response pattern (3–8 months) suggested autoimmune mechanismRelevance to Part V:: Temporal response dynamics inform B-cell depletion kinetics in immune system models.
5 Fluge et al. 2015 — Rituximab Maintenance RCT
Full Citation:: Fluge Ø, Mella O, Bruland O, et al. B-lymphocyte depletion in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine. 2015;162(6):401–410. (Fluge et al. 2015) DOI:: 10.7326/M14-1083 Key Findings::
- Maintenance rituximab protocol; continued B-cell depletion
- Response patterns consistent with autoimmune pathogenesis hypothesisRelevance to Part V:: Extended treatment kinetics data for modeling sustained immune modulation.
6 Fluge et al. 2019 — RituxME: Definitive Negative Trial
Full Citation:: Fluge Ø, Rekeland IG, Lien K, et al. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of Internal Medicine. 2019;170(9):585–593. (Fluge et al. 2019) DOI:: 10.7326/M18-1451 Key Findings::
- Larger definitive trial showed no significant benefit of rituximab over placebo
- Refuted earlier positive phase II findingsRelevance to Part V:: Critical negative result constraining autoimmune model predictions; demonstrates importance of replication in model validation.
7 Hardcastle et al. 2016 — Mast Cell Phenotypes in ME/CFS
Full Citation:: Hardcastle SL, Brenu EW, Johnston S, et al. Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients. BMC Immunology. 2016;17(1):Article 30. (Hardcastle et al. 2016) DOI:: 10.1186/s12865-016-0167-z Key Findings::
- Altered mast cell phenotypes in peripheral blood of ME/CFS patients
- Suggests mast cell involvement in ME/CFS immune dysfunctionRelevance to Part V:: Immune cell phenotyping data for mast cell sub-model parameterisation.
8 Frioni et al. 2024 — Mast Cell Activation Syndrome: Systematic Review
Full Citation:: Frioni T, Leonardi S, Ricciardi L, Cianferoni A, Novembre E, Bernardini R. Mast cell activation syndrome: A systematic review. Clinical and Molecular Allergy. 2024;22(1):1. (Frioni et al. 2024) DOI:: 10.1186/s12948-023-00211-1 Key Findings::
- Systematic review of MCAS diagnosis, pathophysiology, and management
- Provides diagnostic framework for MCAS as comorbidityRelevance to Part V:: MCAS diagnostic criteria inform mast cell activation modeling in immune system and integrated models.
9 Folkerts et al. 2020 — Butyrate Inhibits Mast Cell Activation
Full Citation:: Folkerts J, Redegeld F, Folkerts G, et al. Butyrate inhibits human mast cell activation via epigenetic regulation of Fc\(\varepsilon\)RI-mediated signaling. Allergy. 2020;75(8):1966–1978. (Folkerts et al. 2020) DOI:: 10.1111/all.14254 Key Findings::
- Butyrate and propionate achieved up to 90% inhibition of mast cell degranulation via HDAC inhibition
- Downregulated BTK, SYK, and LAT kinases; mechanism independent of GPR41/GPR43 receptorsRelevance to Part V:: Mechanistic data for gut–immune coupling models linking SCFA production to mast cell regulation.