DecodeME genet OLFM4 styrer en del af balancen i immunforsvaret

DecodeME artiklen (1) udpegede en række gener, der kan være involveret i ME sygdomsmekanismen. Dette er beskrevet her: DecodeME studiet afslører variationer i DNAet fra ME patienter

Et af generne er OLFM4 - olfactomedin 4.

DecodeME artiklen oplyser følgende om OLFM4 (1):

"Olfactomedin-4 (OLFM4) suppresses antibacterial and inflammatory responses by binding to neutrophil cationic proteins and neutralises their ability to kill bacteria and form immunogenic complexes with DNA (61)."

Denne viden om OLFM4 er fra artiklen (2):

OLFM4 regulates the antimicrobial and DNA binding activity of neutrophil cationic proteins

De neutrofile udgør en del af immunforsvaret. En undergruppe af de neutrofile udskiller OLFM4. 

Aktiverede neutrofile udskiller en lang række proteiner. Disse proteiner kan være:

• positivt ladede (kationer)
• negativt ladede (anioner)
• neutrale

Figur 1A og 1B fra ovennævnte artikel (2) viser en oversigt over disse proteiner:

De positivt ladede proteiner hedder på engelsk, Neutrophil Cationic Proteins (NCPs). NCPs kan via deres positive ladning interagere med mikroorganismer og skade dem. OLFM4 kan via sin negative ladning dæmpe processen. Herved holdes immunforsvaret i balance. 

OLFM4 er opreguleret i mange virale og bakterielle infektioner. OLFM4 anses for at være en biomarkør for, hvor alvorligt infektionen udvikler sig. Højt niveau af OLFM4 er forbundet med højere dødelighed ved livstruende infektioner (3).

Det store spørgsmål er, hvordan en mulig DNA variation i OLFM4 genet påvirker ME sygdomsmekanismen? Her må vi vent på mere forskning. I mellemtiden kan vi se, hvad det norske studie af proteiner i serum fra ME patienter viser. 

Artiklen over studiet findes som et prerprint (4):

Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights

Der var ikke nedsat niveau af neutrofile, men der var nedsat niveau af proteiner, som de neutrofile kan udskille. Det tyder på udmattelse eller nedsat aktivitet af neutrofile. Citat fra side 13 artiklen (4):

"Regarding the reduction of bone marrow proteins, decreased protein release from neutrophils appears to be a plausible explanation. Many of the granulocyte-related proteins found to be decreased in the patients are associated with neutrophil granules, stimulated secretion, and NETs, suggesting that changes in neutrophil maturation and/or activation states occur in ME/CFS (59). These cells release DNA and proteins such as MPO, BPI, histones, and granular proteins when activated upon infection. The release of these proteins is not restricted to the NET process, and other aspects of neutrophil activity and phenotypes may be involved (60). Since standard clinical blood cell counts did not indicate detectable abnormalities in the circulating numbers of the main leukocyte classes in the ME/CFS patients, the proteomics data may suggest that functional changes are present, which may include exhaustion or suppression of neutrophil activity. This represents a mechanistic element that also is likely to involve other immune cell types, as well as cells in the blood vessel walls (61)."

Går man ind i supplerende tabel 2 og søger på OLFM4 ser man, at der ikke er forskel på niveauet af OLFM4 i serum fra ME patienter og raske kontrol personer. 

Man skal være opmærksom på, at OLFM4 også findes i knoglemarv, tarm og prostata. Kan OLFM4 spille en rolle i tarmen i ME sygdomsmekanismen? Det bliver spændende at se, hvad ME forskerne finder ud af.


Mere viden om OLFM4:

Olfactomedin-4 in digestive diseases: A mini-review

OLFM4 modulates intestinal inflammation by promoting IL-22+ILC3 in the gut

Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression

Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells

Blocking OLFM4/HIF-1α axis alleviates hypoxia-induced invasion, epithelial–mesenchymal transition, and chemotherapy resistance in non-small-cell lung cancer

Referencer:

1) Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
https://www.medrxiv.org/content/10.1101/2025.08.06.25333109v1
Genetics Delivery Team, Thibaud Boutin, Andrew D. Bretherick, Joshua J. Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L. Samms, Veronique Vitart, Project and Cohort Delivery Team, Øyvind Almelid, Tom Baker, Malgorzata Clyde, Anne Connolly, Diana Garcia, Shona M. Kerr, Claire Tripp, Jareth C. Wolfe, Patient and Public Involvement, Jackie Goold, Gemma Hoyes, Sian Leary, Simon J. McGrath, Julie Milton, Anna Redshaw, Jim M. Wilson, Marketing and Communications Team, Helen Baxter, Danielle Boobyer, Claire Dransfield, Daphne Lamirel, Isabel Lewis, Nina Muirhead, Ella Ponting, Charles Shepherd, Alice Turner, University of Edinburgh Team, Sumy V. Baby, Sjoerd Beentjes, John Ireland, Ava Khamseh, Ewan McDowall, David Perry, Joshua Slaughter, Genetic Epidemiology of ME/CFS Consortium, Erik Abner, Cindy G. Boer, Estonian Biobank Research Team, Sarah Finer, Genes & Health Research Team, Hele Haapaniemi, Hanna M. Ollila, Beth Pollack, Judith Rosmalen, Erika Romppanen, Sirine Saafi, Richa Saxena, Nasa Sinnott-Armstrong, Anniina Tervi, Lea Urpa, Jesse Valliere, David A. van Heel, Management Team, Sonya Chowdhury, Andy Devereux-Cooke, Chris P. Ponting
medRxiv 2025.08.06.25333109; doi: https://doi.org/10.1101/2025.08.06.25333109
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

2) Vandenberghe-Dürr S, Gilliet M, Di Domizio J. OLFM4 regulates the antimicrobial and DNA binding activity of neutrophil cationic proteins. Cell Rep. 2024 Oct 22;43(10):114863. doi: 10.1016/j.celrep.2024.114863. Epub 2024 Oct 11. PMID: 39396234.

https://pubmed.ncbi.nlm.nih.gov/39396234/

3) Liu W, Rodgers GP. Olfactomedin 4 Is a Biomarker for the Severity of Infectious Diseases. Open Forum Infect Dis. 2022 Feb 8;9(4):ofac061. doi: 10.1093/ofid/ofac061. PMID: 35291445; PMCID: PMC8918383.
https://pubmed.ncbi.nlm.nih.gov/35291445/

4) Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights

August Hoel, Fredrik Hoel, Sissel Elisabeth Furesund Dyrstad, Henrique Chapola, Ingrid Gurvin Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Karl Albert Brokstad, Hans-Peter Marti, Olav Mella, Øystein Fluge, Karl Johan Tronstad

medRxiv 2025.05.28.25328245; doi: https://doi.org/10.1101/2025.05.28.25328245

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

https://www.medrxiv.org/content/10.1101/2025.05.28.25328245v1