Commensal Microbiota Influence Systemic Autoimmune Responses

Jens Van Praet¹, Erin Donovan², Michael Drennan¹, Fons Van de Loo³, Sylvie Rabot⁴, Jeroen Raes⁵, Tom Van De Wiele⁶, Carl Ware⁷ and Dirk Elewaut⁸, ¹Department of Rheumatology, Ghent University Hospital, Ghent, Belgium, ²department of Rheumatology, Ghent University Hospital, ghent, Belgium, ³Rheumatology, Raboud University Medical Center, Utrecht, Netherlands, ⁴AgroParisTech, Micalis,, Jouy-en-Josas, France, ⁵Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium, ⁶Laboratory of Microbial Ecology and Technology, Ghent University Hospital, Ghent, Belgium, ⁷Infectious and Inflammatory Disease Center,, Sanford-Burnham Medical Research Institute, La Jolla, CA, ⁸Rheumatology, Department of Rheumatology Ghent University Hospital, Ghent, Belgium

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: ANA, autoantibodies, lymph node and mucosal T cells

Session Information

Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose Antinuclear antibodies are a hallmark feature of generalized autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis. However, the processes underlying the loss of tolerance, particularly the role of lymphoid organs, against nuclear self constituents remains largely unresolved.

Methods: We generated mice lacking all secondary lymphoid organs including spleen by intercrossing lymphotoxin beta receptor deficient mice with HOX11 deficient animals. LTbR-Fc was administered intrauterine and postnatally at various stages of development . Ltb^−/−, T-Ltb^−/−, B-Ltb^−/− and Rorγt-Ltb^-/- were generated by crossing LTβ-floxed mice with CD4-cre, mb1-cre, RORgt-cre mice respectively. Thymi were isolated from newborn LTbR^-/-or wildtype mice and transplanted under the kidney capsule of adult nude mice. 16S rRNA profiling and analysis was conducted on mucosal, luminal and faecal samples. Germfree versus conventionalized mice were treated with LTbR-Fc intrauterine and postnatally. Germfree mice were monocolonized with SFB or E. Coli species and treated with LTbR-Fc. We screened for autoantibodies using a validated immunodetection system for a broad range of ANA, including anti-U1RNP, anti-Sm, anti Scl70/Topoisomerase-I, anti-Centromere protein B, anti-SSA/Ro52 and anti-Jo1 (INNO‐LIA ANA Update, Innogenetics NV).

Results: We found that approximately 25% of mice lacking secondary lymphoid organs spontaneously develop specific antinuclear antibodies. Interestingly, we find this phenotype is not caused by a defect in central tolerance. Rather, cell-specific deletion and in vivo lymphotoxin blockade link these systemic autoimmune responses to the formation of gut associated lymphoid tissue in the neonatal period of life. We further demonstrate antinuclear antibody production is influenced by the presence of commensal gut flora, in particular increased colonisation with segmented filamentous bacteria, IL-17 receptor signalling, and IgA production, which appears to have a protective role against autoantibody formation.

Conclusion: Together, these data indicate that neonatal colonization of gut microbiota influences generalized autoimmunity in adult life.

Disclosure:

J. Van Praet,
None;

E. Donovan,
None;

M. Drennan,
None;

F. Van de Loo,
None;

S. Rabot,
None;

J. Raes,
None;

T. Van De Wiele,
None;

C. Ware,
None;

D. Elewaut,
None.

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