AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies

Steffen Meyer; Martin Woodward; Christina Hertel; Philip Vlaicu; Yasmin Haque; Jaanika Kärner; Annalisa Macagno; Shimobi C. Onuoha; Dmytro Fishman; Hedi Peterson; Kaja Metsküla; Raivo Uibo; Kirsi Jäntti; Kati Hokynar; Anette S. B. Wolff; Antonella Meloni; Nicolas Kluger; Eystein S. Husebye; Katarina Trebusak Podkrajsek; Tadej Battelino; Nina Bratanic; Aleksandr Peet; Kai Krohn; Annamari Ranki; Pärt Peterson; Kai Kisand; Adrian Hayday

doi:10.1016/j.cell.2016.06.024

AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies

Steffen Meyer, Martin Woodward, Christina Hertel, Philip Vlaicu, Yasmin Haque, Jaanika Kärner, Annalisa Macagno, Shimobi C. Onuoha, Dmytro Fishman, Hedi Peterson, Kaja Metsküla, Raivo Uibo, Kirsi Jäntti, Kati Hokynar, Anette S. B. Wolff, Antonella Meloni, Nicolas Kluger, Eystein S. Husebye, Katarina Trebusak Podkrajsek, Tadej BattelinoNina Bratanic, Aleksandr Peet, Kai Krohn, Annamari Ranki, Pärt Peterson, Kai Kisand^*, Adrian Hayday

^*Corresponding author for this work

Peter Gorer Department of Immunobiology

Research output: Contribution to journal › Article › peer-review

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Abstract

APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.

Original language	English
Pages (from-to)	582-595
Number of pages	14
Journal	Cell
Volume	166
Issue number	3
Early online date	14 Jul 2016
DOIs	https://doi.org/10.1016/j.cell.2016.06.024
Publication status	Published - 28 Jul 2016

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Meyer, S., Woodward, M., Hertel, C., Vlaicu, P., Haque, Y., Kärner, J., Macagno, A., Onuoha, S. C., Fishman, D., Peterson, H., Metsküla, K., Uibo, R., Jäntti, K., Hokynar, K., Wolff, A. S. B., Meloni, A., Kluger, N., Husebye, E. S., Podkrajsek, K. T., ... Hayday, A. (2016). AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies. Cell, 166(3), 582-595. https://doi.org/10.1016/j.cell.2016.06.024

@article{e3f59f28c5ed44438284e86ea013f708,

title = "AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies",

abstract = "APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.",

author = "Steffen Meyer and Martin Woodward and Christina Hertel and Philip Vlaicu and Yasmin Haque and Jaanika K{\"a}rner and Annalisa Macagno and Onuoha, {Shimobi C.} and Dmytro Fishman and Hedi Peterson and Kaja Metsk{\"u}la and Raivo Uibo and Kirsi J{\"a}ntti and Kati Hokynar and Wolff, {Anette S. B.} and Antonella Meloni and Nicolas Kluger and Husebye, {Eystein S.} and Podkrajsek, {Katarina Trebusak} and Tadej Battelino and Nina Bratanic and Aleksandr Peet and Kai Krohn and Annamari Ranki and P{\"a}rt Peterson and Kai Kisand and Adrian Hayday",

year = "2016",

month = jul,

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doi = "10.1016/j.cell.2016.06.024",

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Meyer, S, Woodward, M, Hertel, C, Vlaicu, P, Haque, Y, Kärner, J, Macagno, A, Onuoha, SC, Fishman, D, Peterson, H, Metsküla, K, Uibo, R, Jäntti, K, Hokynar, K, Wolff, ASB, Meloni, A, Kluger, N, Husebye, ES, Podkrajsek, KT, Battelino, T, Bratanic, N, Peet, A, Krohn, K, Ranki, A, Peterson, P, Kisand, K & Hayday, A 2016, 'AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies', Cell, vol. 166, no. 3, pp. 582-595. https://doi.org/10.1016/j.cell.2016.06.024

TY - JOUR

T1 - AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies

AU - Meyer, Steffen

AU - Woodward, Martin

AU - Hertel, Christina

AU - Vlaicu, Philip

AU - Haque, Yasmin

AU - Kärner, Jaanika

AU - Macagno, Annalisa

AU - Onuoha, Shimobi C.

AU - Fishman, Dmytro

AU - Peterson, Hedi

AU - Metsküla, Kaja

AU - Uibo, Raivo

AU - Jäntti, Kirsi

AU - Hokynar, Kati

AU - Wolff, Anette S. B.

AU - Meloni, Antonella

AU - Kluger, Nicolas

AU - Husebye, Eystein S.

AU - Podkrajsek, Katarina Trebusak

AU - Battelino, Tadej

AU - Bratanic, Nina

AU - Peet, Aleksandr

AU - Krohn, Kai

AU - Ranki, Annamari

AU - Peterson, Pärt

AU - Kisand, Kai

AU - Hayday, Adrian

PY - 2016/7/28

Y1 - 2016/7/28

N2 - APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.

AB - APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.

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U2 - 10.1016/j.cell.2016.06.024

DO - 10.1016/j.cell.2016.06.024

M3 - Article

SN - 0092-8674

VL - 166

SP - 582

EP - 595

JO - Cell

JF - Cell

IS - 3

ER -

AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies

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