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Abstract Number: 46

Organic Dust Inhalants Shift Immune Responses and Extracellular Matrix Balance between Synovium and Lung in the Collagen-Induced Arthritis Mouse Model

Michael J. Duryee1, Jill Poole2, Amy Nelson3, Katherine Janike2, Lynell W. Klassen4, James R. O'Dell4, Bryant R. England5, Ted R. Mikuls6 and Geoffrey M. Thiele7, 1Internal Medicine Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE, 2Medicine, University of Nebraska Medical Center, Omaha, NE, 3Department of Medicine, University of Nebrasa Medical Center, Omaha, NE, 4Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 5Rheumatology, VA Nebraska-Western Iowa Health Care System & University of Nebraska Medical Center, Omaha, NE, 6Internal Medicine, Division of Rheumatology, VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE, 7University of Nebraska Medical Center, Omaha, NE

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Arthritis, Collagen, inflammation and lung injury, Synovial Immune Biology

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Session Information

Date: Sunday, October 21, 2018

Session Title: Rheumatoid Arthritis – Animal Models Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:   Emerging evidence suggests that the lungs may be an initiating site of autoimmunity leading to RA with organic inhalant exposures such as those from cigarette smoking acting as a trigger. To study the impact of organic inhalant exposures in RA pathogenesis, we previously developed a novel mouse model by exposing mice with collagen induced arthritis to repeated organic dust extract (ODE). Our objective in the present study was to evaluate autoantibody responses and tissue expression of extracellular matrix proteins (ECM) that have been implicated in RA pathogenesis and that may be involved in articular and lung responses in this model. 

Methods:   Male DBA/1J mice were injected with chicken collagen type II with Freund’s complete adjuvant (CIA) or saline on day 1 and 21.  ODE or saline was instilled by intranasal inhalation daily for 5 weeks. Groups are identified as: 1) Saline, 2) ODE, 3) CIA, and 4) ODE + CIA.  Anti-citrullinated protein antibody (ACPA) and IgG antibody to malondialdehyde-acetaldehyde (MAA) were measured in serum. Synovial and lung tissues were collected and stained for the presence of MAA, collagen II, fibronectin and vimentin. Confocal microscopy was used to assess tissue expression of ECM and MAA.  Coloc 2 plugin (ImageJ) was used to quantify correlations between the tissue expression of ECM and MAA.

Results:   Serum ACPA concentrations were significantly increased (p<0.05) in mice treated with ODE + CIA compared to all other treatment groups.  Anti-MAA levels were increased in the ODE exposed mice compared to Saline or CIA (p<0.0001) and decreased with the addition of ODE + CIA (p<0.02).  ECM and MAA expression mean pixel density in lung and joint tissues are shown in the Table 1. Paralleling enhanced arthritis and attenuated lung disease previously reported in ODE + CIA, differential colocalization of MAA with both collagen II and vimentin was observed in both synovium and lung (p<0.001) in ODE + CIA (Figure 1).  In contrast, fibronectin + MAA colocalization was similarly predominate in the lung in all groups.  

Conclusion:   Increased ACPA and decreased anti-MAA levels in the ODE + CIA treated group suggests a shift in the immune response with dual exposures. Likewise, ECM protein expression was markedly altered between synovium and lung in the combined ODE + CIA model. Our study importantly characterizes alterations in immune responses and ECM proteins that may explain the compartmentalized response of increase in inflammatory arthritis with the simultaneous attenuation of pulmonary disease previously observed in CIA mice exposed to ODE.

Table 1

Joint Tissue Mean Pixel Density

Lung Tissue Mean Pixel Density

Saline

CIA

ODE

ODE + CIA

Saline

CIA

ODE

ODE + CIA

MAA

1.39

±

0.25

16.3*

±

1.85

33.25*#

±

1.48

20.2*

±

4.5

8.4

±

0.4

17.7

±

1.6

28.62*

±

6.0

21.1*

±

4.9

Collagen II

(CII)

5.50

±

1.32

4.45

±

1.23

5.54

±

1.46

59.3*

±

15.7

2.56

±

0.42

59.6*

±

17.7

0.48

±

0.03

0.19

±

0.044

Fibronectin

3.6

±

0.9

12.8

±

1.50

35.8*#

±

8.9

24.9*

±

2.4

0.02

±

0.004

0.04

±

0.006

1.91*#

±

0.31

2.80*#

±

0.736

Vimentin

15.9

±

3.46

46.5*#

±

5.03

2.8$

±

0.92

49.1*#

±

7.0

35.4

±

16.9

68.7$

±

9.2

0.47*

±

0.19

4.0*

±

1.0

Significance

Increased (*p<0.05) compared to saline

MAA increase (#p<0.05) compared to CIA  

CII increase (*p<0.01) compared to all groups

Fibronectin increase (*p<0.05) compared to saline

Fibronectin increase (#p<0.04) compared to CIA

Vimentin Increase ($p<0.04) compared to ODE

Note: All values shown are 105 units

MAA increase (*p<0.01) compared to saline

CII increase (*p<0.01) compared to all groups

Fibronectin increase (*p<0.05) compared to saline

Vimentin Decreased (*p<0.01) compared to saline

Vimentin Decreased ($p<0.05) compared to CIA

Note: All values shown are 105 units


Disclosure: M. J. Duryee, None; J. Poole, None; A. Nelson, None; K. Janike, None; L. W. Klassen, None; J. R. O'Dell, Medac, 5; B. R. England, None; T. R. Mikuls, BMS, Ironwood, Horizon, 2,Pfizer, Inc., 5; G. M. Thiele, None.

To cite this abstract in AMA style:

Duryee MJ, Poole J, Nelson A, Janike K, Klassen LW, O'Dell JR, England BR, Mikuls TR, Thiele GM. Organic Dust Inhalants Shift Immune Responses and Extracellular Matrix Balance between Synovium and Lung in the Collagen-Induced Arthritis Mouse Model [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/organic-dust-inhalants-shift-immune-responses-and-extracellular-matrix-balance-between-synovium-and-lung-in-the-collagen-induced-arthritis-mouse-model/. Accessed December 14, 2019.
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