IL-18 associated with lung lymphoid aggregates drives IFNγ production in severe COPD

Background: Increased interferon gamma (IFNγ) release occurs in Chronic Obstructive Pulmonary Disease (COPD) lungs. IFNγ supports optimal viral clearance, but if dysregulated could increase lung tissue destruction. Methods: The present study investigates which mediators most closely correlate with IFNγ in sputum in stable and exacerbating disease, and seeks to shed light on the spatial requirements for innate production of IFNγ, as reported in mouse lymph nodes, to observe whether such microenvironmental cellular organisation is relevant to IFNγ production in COPD lung. Results: We show tertiary follicle formation in severe disease alters the dominant mechanistic drivers of IFNγ production, because cells producing interleukin-18, a key regulator of IFNγ, are highly associated with such structures. Interleukin-1 family cytokines correlated with IFNγ in COPD sputum. We observed that the primary source of IL-18 in COPD lungs was myeloid cells within lymphoid aggregates and IL-18 was increased in severe disease. IL-18 released from infected epithelium or from activated myeloid cells, was more dominant in driving IFNγ when IL-18-producing and responder cells were in close proximity. Conclusions: Unlike tight regulation to control infection spread in lymphoid organs, this local interface between IL-18-expressing and responder cell is increasingly supported in lung as disease progresses, increasing its potential to increase tissue damage via IFNγ.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Lungmedicin och allergi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Respiratory Medicine and Allergy hsv//eng
Chronic obstructive pulmonary disease
Interferon gamma
Interleukin-18
Lymphocytes
Lymphoid aggregates
Tertiary follicles

Ferguson, G. JohnMedImmune Limited, Cambridge (författare)
Mori, MichikoLund University,Lunds universitet,Luftvägsinflammation,Forskargrupper vid Lunds universitet,Airway Inflammation and Immunology,Lund University Research Groups(Swepub:lu)med-mhm (författare)
Damera, GautamMedImmune, Inc. (författare)
Stephenson, KatherineUniversity of Nottingham,MedImmune Limited, Cambridge (författare)
Karp, Natasha A.AstraZeneca, UK (författare)
Sethi, SanjayThe State University of New York (författare)
Ward, Christine KMedImmune, Inc.,Bristol-Myers Squibb (författare)
Sleeman, Matthew A.MedImmune Limited, Cambridge,Regeneron Pharmaceuticals, Inc. (författare)
Erjefält, Jonas S.Lund University,Lunds universitet,Luftvägsinflammation,Forskargrupper vid Lunds universitet,Airway Inflammation and Immunology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)mphy-jer (författare)
Finch, Donna K.MedImmune Limited, Cambridge (författare)
Agenus LtdMedImmune Limited, Cambridge (creator_code:org_t)

Ingår i:Respiratory Research: Springer Science and Business Media LLC18:11465-99211465-993X

Av författaren/redakt...: Briend, Emmanuel; Ferguson, G. Joh ...; Mori, Michiko; Damera, Gautam; Stephenson, Kath ...; Karp, Natasha A.; visa fler...; Sethi, Sanjay; Ward, Christine ...; Sleeman, Matthew ...; Erjefält, Jonas ...; Finch, Donna K.; visa färre...

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