Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Mechanisms underlying pulmonary neutrophilia versus eosinophilia in fungal allergy

Fei, Mingjian (2011) Mechanisms underlying pulmonary neutrophilia versus eosinophilia in fungal allergy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (10MB) | Preview


Aspergillus fumigatus (A. fumigatus) is commonly associated with allergic bronchopulmonary aspergillosis (ABPA), which represents one of the most extreme manifestations of fungal allergy. Eosinophils are considered to be effector cells mediating lung dysfunction, but there is increasing appreciation that pulmonary neutrophilia also contributes to ABPA pathology. In our efforts to recapitulate this fungal allergic condition, we found that persistent exposure to A. fumigatus resulted in neutrophil and eosinophil-biased responses in BALB/c and C57BL/6 mice,respectively, and that the former mimicked the inflammation pattern observed in ABPA. By performing a comparative study, we found substantially higher lung TNF-á levels in neutrophil-rich BABL/c mice compared to C57BL/6 mice. TNF-á blockade or deficiency in BALB/c miceswitched the response from neutrophilia to eosinophilia, implicating TNF-á as the key mediator. We identified CD11c+CD11b+Ly6C+ inflammatory dendritic cells (DCs) and macrophages as the primary sources of TNF-á, and that depletion of these CD11c+ cells in CD11c-DTR BALB/cmice dramatically reduced lung TNF-á levels. Importantly, BALB/c DCs demonstrated a stronger TNF-á-producing capacity than C57BL/6 DCs, strongly suggesting that this was the basis for the strain-associated TNF-á difference. As compared to TNF-áhigh BALB/c DCs, TNF-á low C57BL/6 DCs contained more repressive NF-êB p50 homodimers at the TNF-á promoter at early time points following A. fumigatus infection, and expressed notably less pattern recognition receptors, in particular TLR2 following persistent fungal exposure. These differences explained the strain-specific differential TNF-á production by DCs. In addition, TNF-á deficiency itselfblunted the accumulation of Ly6c+CD11b+ DCs, implicating a positive feedback loop to amplify the cellular sources of TNF-á. Functionally, higher amounts of IL-5 in C57BL/6 and TNF-á-/-mice were associated with higher eosinophil counts, while collaboration between TNF-á and IL-17A triggered significantly higher levels of the neutrophil chemoattractants KC and MIP-2 in the BALB/c mice. In summary, our study identifies that TNF-á, acting as a molecular switch, orchestrates a sequence of events in DCs and CD4+ T cells and promotes pulmonary neutrophilia.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Fei, Mingjianmif23@pitt.eduMIF23
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRay, Anuradharaya@pitt.eduRAYA
Committee MemberKolls, Jay
Committee MemberKalinski, Pawelkalinskip@upmc.eduPAK5
Committee MemberKhader, Shabaana
Committee MemberOury, Tim D.tdoury@pitt.eduTDOURY
Date: 2 June 2011
Date Type: Completion
Defense Date: 7 April 2011
Approval Date: 2 June 2011
Submission Date: 1 June 2011
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Aspergillus; DC; Lung; neutrophils; T; TNF
Other ID:, etd-06012011-151409
Date Deposited: 10 Nov 2011 19:46
Last Modified: 19 Dec 2016 14:36


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item