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Abstract Number: 0778

Bacterial Families Lachnospiraceae/Ruminococcaceae Are Immunologically Targeted in Individuals At-risk for RA and a Specific Strain Is Arthritogenic in Monocultured Gnotobiotic Mice

Meagan Chriswell1, Jennifer Seifert2, Lisa Blum3, Michelle Bloom3, Marie Feser4, M Kristen Demoruelle5, Jill Norris6, Kevin D. Deane7, Eddie James8, Jane Buckner8, William Robinson3, V. Michael Holers5 and Kristine Kuhn9, 1UC Denver SOM, Denver, CO, 2UC Denver, Littleton, CO, 3Stanford University, Palo Alto, CA, 4Division of Rheumatology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA, Colorado, 5University of Colorado, Denver, CO, 6Colorado School of Public Health, Aurora, CO, 72 Division of Rheumatology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA, Colorado, 8Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, 9University of Colorado Anschutz Medical Campus, Aurora, CO

Meeting: ACR Convergence 2020

Keywords: Anti-CCP, B-Lymphocyte, immunology, Mouse Models, RA, rheumatoid arthritis

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Session Information

Date: Saturday, November 7, 2020

Session Title: RA – Etiology & Pathogenesis Poster

Session Type: Poster Session B

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

Background/Purpose: Circulating autoantibodies, including anti-CCP and RF, develop years before physical manifestations of rheumatoid arthritis (RA), with several lines of evidence suggesting that these autoantibodies may be driven in part by microbial-mucosal interactions. We hypothesized that discrete bacterial strains in the gut may drive autoantibody generation, inducing a systemic breach of tolerance in the autoantibody positive preclinical RA period that leads to the future development of joint inflammation.

Methods: Human fecal samples were obtained from 16 healthy controls (HC), 12 at-risk individuals (AR) (serum anti-CCP+ in the absence of current or prior arthritis), and 13 individuals with early RA (< 1 year duration). Antibody-seq was performed by flow sorting bacteria endogenously coated with human IgA, followed by 16S rRNA sequencing. Plasmablasts (PB) were isolated from 4 additional AR individuals, defined by serum CCP+ (83%) and/or RF+ (83%), and from 2 individuals with early RA (CCP+). Subdomains of the antigen binding region from PB-produced antibodies were selected by sequence analysis for their origin in a dual IgA/IgG isotype family, cloned onto a mouse IgG2a framework and expressed as monoclonal antibodies (mAbs). 94 mAbs were chosen for further study based on recombinant antibody reactivity with synovial antigens. Lachno(spiraceae)/Rumino(coccaceae) strains were isolated from the feces of an AR subject. After culture in anaerobic media, 7 strains of interest were identified by 16S sequencing.

Results: The closely related families Lachno/Rumino were expanded in AR and RA compared to HC. This expansion was accompanied by increased IgA coating of Lachno/Rumino in AR when compared to family abundance.  62% of 94 PB-derived mAbs that bound synovial antigens also targeted intestinal bacteria, specifically Lachno/Rumino. Together these suggest altered mucosal responses to these families and cross-reactivity between Lachno/Rumino bacterial and host self-antigens in RA joints. To analyze phenotypic effects of these families, primary human bacterial strain isolates within Lachno/Rumino were verified as targeted by representative PB-derived mAbs. Germ-free DBA/1j mice were mono-colonized with Lachno/Rumino strain isolates, Prevotella copri, or culture media. Within 14 days arthritis, characterized by joint swelling and bone loss, was observed in mono-colonized mice receiving one Lachno/Rumino strain.

Conclusion: In a cohort of AR and RA individuals, we identified altered mucosal and systemic immunity to Lachno/Rumino. Germ-free mice mono-colonized with a strain derived from an AR individual developed arthritis. Although the full mechanism has not been fully elucidated, the observed cross-recognition of Lachno/Rumino and joint derived antigens by AR and early RA PB-derived mAbs, and induction of joint inflammation by such bacteria in mono-colonized mice, suggests that bacterial antigens and/or arthritogenic factors derived from these families drive a breach in tolerance during human preclinical RA and contribute centrally to the development of arthritis and classified RA.


Disclosure: M. Chriswell, None; J. Seifert, None; L. Blum, None; M. Bloom, None; M. Feser, None; M. Demoruelle, Pfizer Inc., 2; J. Norris, None; K. D. Deane, None; E. James, Pfizer, 2, Janssen, 2, Sanofi, 2, Novartis, 2; J. Buckner, Bristol-Myers Squibb, 2, 5, Janssen, 2; W. Robinson, None; V. Holers, None; K. Kuhn, None.

To cite this abstract in AMA style:

Chriswell M, Seifert J, Blum L, Bloom M, Feser M, Demoruelle M, Norris J, D. Deane K, James E, Buckner J, Robinson W, Holers V, Kuhn K. Bacterial Families Lachnospiraceae/Ruminococcaceae Are Immunologically Targeted in Individuals At-risk for RA and a Specific Strain Is Arthritogenic in Monocultured Gnotobiotic Mice [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/bacterial-families-lachnospiraceae-ruminococcaceae-are-immunologically-targeted-in-individuals-at-risk-for-ra-and-a-specific-strain-is-arthritogenic-in-monocultured-gnotobiotic-mice/. Accessed May 16, 2022.
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