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Evaluating the Impact of Dysregulated Complement Activation on Monocytes in alpha-1 anti-trypsin Deficiency

thesis
posted on 11.03.2022, 15:39 authored by Ciara Gough

The term alpha one anti-trypsin deficiency (AATD) refers to any qualitative or quantitative deficiency of alpha one anti-trypsin (AAT) protein. AATD represents a major cause of early onset emphysema and liver failure and is frequently under-diagnosed. AAT acts as a binding partner of complement protein C3. Cleavage of C3 by proteases represents the final common step of all 3 described pathways of complement activation.

High levels of the complement fragment C3d has been previously identified in the plasma and airways of those with ZZ AATD suggestingdysregulated activation of the complement cascade in AATD. The aim of this study was to explore what kind of effect C3d was likely to have on monocytes in ZZ AATD and healthy MM controls.

The receptor for C3d, CR2 was identified on the surface of ZZ and MM monocytes. Findings were confirmed using a combination of reverse transcription polymerase chain reaction (RT PCR), Flow cytometry, western blotting (WB) and confocal microscopy (CM). Multi colour flow cytometry was used to identify CR2 on the surface of leucocyte subsets in the airways. Treatment of MM and ZZ monocytes resulted in significant increases in the levels of matrix metalloproteinase 9 (MMP-9), proteinase 3 (PR3) and soluble CD14 (sCD14) detectable in monocyte supernatants. This raises questions about the role C3d signalling through monocytes and monocyte-derived macrophages plays in the pathogenesis of AATD lung disease.

In conclusion, this study confirms the presence of the C3d receptor CR2 on the surface of monocytes. Results presented facilitate the generation of hypotheses that expand our understanding of the role monocytes play in the pathogenesis of ZZ AATD

History

First Supervisor

Prof. Noel Gerry McElvaney

Second Supervisor

Dr Emer Reeves

Comments

Submitted for the Award of Doctor of Medicine to the Royal College of Surgeons in Ireland, 2021.

Published Citation

Gough C. Evaluating the Impact of Dysregulated Complement Activation on Monocytes in alpha-1 anti-trypsin Deficiency. [MD Thesis] Dublin: Royal College of Surgeons in Ireland; 2021

Degree Name

Doctor of Medicine (MD)

Date of award

31/05/2021

Programme

  • Doctor of Medicine (MD)