PreprintCC BYbioRxiv20 Oct 2026

Developmental and molecular features shaping broad and synergistic actions of human autoantibodies targeting interferon-α

K. Groen
J. A. Moritz
S. Vasquez
A. A. Rubio
R. Kuratli
D. Jones
D. Grafl
M. Motta
S. Fontana
J. Manning
S. Costagli
L. Simonelli

14 more authors

R. Thakur
D. Jarrossay
C. Tran
Y. E. Lee
I. A. Abela
A. Calmy
C. Hirzel
D. E. Kaufmann
Swiss HIV Cohort Study
H. F. Günthard
R. D. Kouyos
C. O. Barnes
D. F. Robbiani
B. G. Hale¹

¹University of Zurich, Switzerland

Abstract

Neutralizing autoantibodies against interferon- (IFN) are associated with severe viral infections but may improve outcomes in IFN-driven autoimmunity. How these antibodies emerge, mature, and function at the molecular level remains unclear. Here, we tracked development of plasma neutralizing activity against all 12 IFNs in multiple human donors over years. Plasma neutralization frequently initiates with narrow IFN specificity, often IFN8, but increases in breadth and potency with individual kinetics. Monoclonal antibody analyses reveal that affinity maturation generates epitope-specific antibody classes, highlighting parallel emergence of subtype-restricted and broadly-reactive antibodies. Biophysical and structural characterization of human antibody-IFN complexes uncovers determinants of initial specificity and breadth development. Strikingly, antibodies engaging non-competing, neutralizing epitopes can act co-operatively to block IFN signaling, and some combinations trigger Fc-effector functions via cell surface IFN:IFNAR2 interactions that may eliminate IFN-responsive cells. Our findings reveal features shaping anti-IFN autoantibody repertoires and unappreciated synergistic mechanisms that amplify their potency and pathogenic potential.

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BibTeX

@misc{groen2026developmental,
  title = {{Developmental and molecular features shaping broad and synergistic actions of human autoantibodies targeting interferon-α}},
  author = {K. Groen and J. A. Moritz and S. Vasquez and A. A. Rubio and R. Kuratli and D. Jones and D. Grafl and M. Motta and S. Fontana and J. Manning and S. Costagli and L. Simonelli and R. Thakur and D. Jarrossay and C. Tran and Y. E. Lee and I. A. Abela and A. Calmy and C. Hirzel and D. E. Kaufmann and Swiss HIV Cohort Study and H. F. Günthard and R. D. Kouyos and C. O. Barnes and D. F. Robbiani and B. G. Hale},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.20.760426},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760426v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Developmental and molecular features shaping broad and synergistic actions of human autoantibodies targeting interferon-α
AU  - K. Groen
AU  - J. A. Moritz
AU  - S. Vasquez
AU  - A. A. Rubio
AU  - R. Kuratli
AU  - D. Jones
AU  - D. Grafl
AU  - M. Motta
AU  - S. Fontana
AU  - J. Manning
AU  - S. Costagli
AU  - L. Simonelli
AU  - R. Thakur
AU  - D. Jarrossay
AU  - C. Tran
AU  - Y. E. Lee
AU  - I. A. Abela
AU  - A. Calmy
AU  - C. Hirzel
AU  - D. E. Kaufmann
AU  - Swiss HIV Cohort Study
AU  - H. F. Günthard
AU  - R. D. Kouyos
AU  - C. O. Barnes
AU  - D. F. Robbiani
AU  - B. G. Hale
PY  - 2026
DA  - 2026/10/20
PB  - bioRxiv
DO  - 10.64898/2026.10.20.760426
UR  - https://www.biorxiv.org/content/10.64898/2026.10.20.760426v1
AB  - Neutralizing autoantibodies against interferon- (IFN) are associated with severe viral infections but may improve outcomes in IFN-driven autoimmunity. How these antibodies emerge, mature, and function at the molecular level remains unclear. Here, we tracked development of plasma neutralizing activity against all 12 IFNs in multiple human donors over years. Plasma neutralization frequently initiates with narrow IFN specificity, often IFN8, but increases in breadth and potency with individual kinetics. Monoclonal antibody analyses reveal that affinity maturation generates epitope-specific antibody classes, highlighting parallel emergence of subtype-restricted and broadly-reactive antibodies. Biophysical and structural characterization of human antibody-IFN complexes uncovers determinants of initial specificity and breadth development. Strikingly, antibodies engaging non-competing, neutralizing epitopes can act co-operatively to block IFN signaling, and some combinations trigger Fc-effector functions via cell surface IFN:IFNAR2 interactions that may eliminate IFN-responsive cells. Our findings reveal features shaping anti-IFN autoantibody repertoires and unappreciated synergistic mechanisms that amplify their potency and pathogenic potential.
ER  -

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