Antigenic responses are hallmarks of fibrotic interstitial lung diseases independent of underlying etiologies.

Summary

Interstitial lung diseases (ILD) are heterogeneous conditions that may lead to progressive fibrosis and death of affected individuals. Despite diversity in clinical manifestations, enlargement of lung-associated lymph nodes (LLN) in fibrotic ILD patients predicts worse survival. Herein, we revealed a common adaptive immune landscape in LLNs of all ILD patients, characterized by highly activated germinal centers and antigen-activated T cells including regulatory T cells (Tregs). In support of these findings, we identified serum reactivity to 17 candidate auto-antigens in ILD patients through a proteome-wide screening using phage immunoprecipitation sequencing. Autoantibody responses to actin binding LIM protein 1 (ABLIM1), a protein highly expressed in aberrant basaloid cells of fibrotic lungs, were correlated with LLN frequencies of T follicular helper cells and Tregs in ILD patients. Together, we demonstrate that end-stage ILD patients have converging immune mechanisms, in part driven by antigen-specific immune responses, which may contribute to disease progression.

Competing Interest Statement

M.E. Strek received grants from editorial assistance from Boehringer Ingelheim and personal fees from Fibrogen. A. Adegunsoye received grants and personal fees from Boehringer Ingelheim, Roche, Inogen, and Medscape. P. J. Wolters received grants from Roche, Sanofi, Pliant, Boehringer Ingelheim, and personal fees from Sanofi, Boehringer Ingelheim, and Blade Therapeutics. M. Anderson owns stock in Medtronic and Merck and has consulted for Sana and Imcyse. J.L. Derisi is a paid scientific consultant for The Public Health Company, Inc., Allen & Co., and Delve Bio. There is no direct overlap between the current study and these consulting duties. These authors have no additional financial interests. The other authors have no conflicting financial interests.

Funding Statement

This work was supported by National Institute of Health grants: U19 AI162310 (A.I. Sperling), R01 HL13079 (I. Noth), T32 AI007090-44 (Y. Yoon), K08HL165106 (V. Upadhyay), R01AI68299 (A.K. Shum), U19 AI082724 (M.R. Clark), T32 HL007605 (K.C. Selvan), K23 HL146942 (A. Adegunsoye), F31 HL156659 (M.K. Hollinger), The American Heart Association (T.E. Velez), The Pulmonary Fibrosis Foundation (C.T. Lee), The Nina Ireland Program for Lung Health at UCSF (P.J. Wolters), The UCSF Clinical Translational Sciences Institute (V. Upadhyay).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study is approved by Institutional Review Boards (University of Chicago IRB 14163A & IRB 14514A, UCSF IRB 10-02467 & IRB 10-01592), and all ILD patients included in the study gave informed consent. Samples from organ donors are IRB exempt as they are deceased upon donation.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors.

https://derisilab.ucsf.edu/

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