Anti-Citrullinated Heat Shock Protein 90 Antibodies Identified in Bronchoalveolar Lavage Fluid Are a Marker of Lung-Specific Immune Responses

Lisa Harlow¹, Bernadette Gochuico², Ivan Rosas³, Tracy Doyle⁴, Juan Osorio⁴, Timothy Travers⁵, Carlos Camacho⁶, Chester V. Oddis⁷ and Dana P. Ascherman⁸, ¹Rheumatology and Clinical Immunology, University of Miami Miller School of Medicine, Miami, FL, ²Medical Genetics Branch, National Institutes of Health, Bethesda, MD, ³Medicine/Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, ⁴Medicine/Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, ⁵Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, ⁶Compuational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, ⁷Rheum/Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, ⁸Medicine/Rheumatology, University of Miami Miller School of Medicine, Miami, FL

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Anti-citrullinated protein/peptide antibodies (ACPA) and rheumatoid arthritis (RA), Lung Disease

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose . Previous work has demonstrated an association between serum anti-citrullinated HSP90 antibodies and rheumatoid arthritis-associated interstitial lung disease (RA-ILD). To further investigate this potential pathogenic relationship, we assessed anti-citrullinated HSP90 antibody profiles in bronchoalveolar lavage fluid (BALF) isolated from RA patients with and without ILD.

Methods . BALF and corresponding serum samples were collected from a well-defined cohort of RA patients with various stages of ILD. Specimens obtained from these subjects were then subjected to enzyme-linked immunosorbent assays (ELISAs) using recombinant HSP90 isoforms and derivative peptides as substrate antigens. While comparison of resulting BALF-associated antibody profiles to those identified in healthy controls and patients with idiopathic pulmonary fibrosis (IPF) permitted assessment of disease specificity, evaluation of matching serum specimens provided insight regarding relative antibody production in lung and extra-pulmonary tissue compartments.

Results . 9/21 RA-derived BALF specimens demonstrated either IgG or IgA antibodies targeting citrullinated HSP90 proteins/peptides, highlighting disease specific immune responses (with a predilection for RA-ILD) that did not occur in IPF patients (0/5) or healthy control subjects (0/5). Discordance between these antibody responses and BALF anti-CCP2 reactivity (IgG, IgA) provided clear evidence of antigen specificity (as only 3/21 BALF samples possessed antibodies recognizing both CCP2 and citrullinated HSP90 derivatives). Furthermore, comparison of antibody profiles between BALF and matching serum specimens revealed several different recognition patterns favoring predominant production of anti-citrullinated HSP90 antibodies within the lung microenvironment.

Conclusion . IgG and IgA anti-citrullinated HSP90 antibodies occur preferentially in BALF derived from patients with RA-ILD, supporting the connection between this antibody specificity and parenchymal lung disease. Moreover, qualitative as well as quantitative differences in anti-citrullinated HSP90 profiles between BALF and serum indicate that the lung plays a direct role in shaping the immune repertoire of RA/RA-ILD.

Disclosure:

L. Harlow,
None;

B. Gochuico,
None;

I. Rosas,
None;

T. Doyle,
None;

J. Osorio,
None;

T. Travers,
None;

C. Camacho,
None;

C. V. Oddis,
None;

D. P. Ascherman,
None.

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