Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)

Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2) Publisher Pubmed

Gruber C ; Ramba M ; Debnath B ; Cuollo L ; Neehus A L ; Lee A ; Buta S ; Martin Fernandez M ; Rosain J ; Berteloot L ; Drabent P ; Le Voyer T ; Soudee C ; Peel J Show All Authors

Gruber C
Ramba M
Debnath B
Cuollo L
Neehus A L
Lee A
Buta S
Martin Fernandez M
Rosain J
Berteloot L
Drabent P
Le Voyer T
Soudee C
Peel J
Seeleuthner Y
Puel A
Zhang S Y
Ciancanelli M J
Arango Franco C A
Migaud M
Fremond M L
Renaldo F
Boespflug Tanguy O
Dorboz I
Dubern B
Fonteneau T
Parvaneh N
Molatefi R
Shahrooei M
Duffy D
Bondet V
Rice G I
Crow Y J
Molina T J
Boddaert N
Casanova J L
Houdouin V
Melki I
Hadchouel A
Bustamante J
Bogunovic D

Source: The Journal of experimental medicine Published:2026

Abstract

Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP. © 2026 Gruber et al.

Style	Citing Format
MLA	Gruber C, et al.. "Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)." The Journal of experimental medicine, vol. 223, no. 8, 2026, pp. -.
APA	Gruber C, Ramba M, Debnath B, Cuollo L, Neehus A L, Lee A, Buta S, Martin Fernandez M, Rosain J, Berteloot L, Drabent P, Le Voyer T, Soudee C, Peel J, Seeleuthner Y, Puel A, Zhang S Y, Ciancanelli M J, Arango Franco C A, ... Bogunovic D (2026). Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2). The Journal of experimental medicine, 223(8), -.
Chicago	Gruber C, Ramba M, Debnath B, Cuollo L, Neehus A L, Lee A, Buta S, et al.. "Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)." The Journal of experimental medicine 223, no. 8 (2026): -.
Harvard	Gruber C et al. (2026) 'Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)', The Journal of experimental medicine, 223(8), pp. -.
Vancouver	Gruber C, Ramba M, Debnath B, Cuollo L, Neehus A L, Lee A, et al.. Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2). The Journal of experimental medicine. 2026;223(8):-.
BibTex	@article{ author = {Gruber C and Ramba M and Debnath B and Cuollo L and Neehus A L and Lee A and Buta S and Martin Fernandez M and Rosain J and Berteloot L and Drabent P and Le Voyer T and Soudee C and Peel J and Seeleuthner Y and Puel A and Zhang S Y and Ciancanelli M J and Arango Franco C A and Migaud M and Fremond M L and Renaldo F and Boespflug Tanguy O and Dorboz I and Dubern B and Fonteneau T and Parvaneh N and Molatefi R and Shahrooei M and Duffy D and Bondet V and Rice G I and Crow Y J and Molina T J and Boddaert N and Casanova J L and Houdouin V and Melki I and Hadchouel A and Bustamante J and Bogunovic D}, title = {Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)}, journal = {The Journal of experimental medicine}, volume = {223}, number = {8}, pages = {-}, year = {2026} }
RIS	TY - JOUR AU - Gruber C AU - Ramba M AU - Debnath B AU - Cuollo L AU - Neehus A L AU - Lee A AU - Buta S AU - Martin Fernandez M AU - Rosain J AU - Berteloot L AU - Drabent P AU - Le Voyer T AU - Soudee C AU - Peel J AU - Seeleuthner Y AU - Puel A AU - Zhang S Y AU - Ciancanelli M J AU - Arango Franco C A AU - Migaud M AU - Fremond M L AU - Renaldo F AU - Boespflug Tanguy O AU - Dorboz I AU - Dubern B AU - Fonteneau T AU - Parvaneh N AU - Molatefi R AU - Shahrooei M AU - Duffy D AU - Bondet V AU - Rice G I AU - Crow Y J AU - Molina T J AU - Boddaert N AU - Casanova J L AU - Houdouin V AU - Melki I AU - Hadchouel A AU - Bustamante J AU - Bogunovic D TI - Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2) JO - The Journal of experimental medicine VL - 223 IS - 8 SP - EP - PY - 2026 ER -

Style

Citing Format

MLA

Gruber C, et al.. "Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)." The Journal of experimental medicine, vol. 223, no. 8, 2026, pp. -.

APA

Gruber C, Ramba M, Debnath B, Cuollo L, Neehus A L, Lee A, Buta S, Martin Fernandez M, Rosain J, Berteloot L, Drabent P, Le Voyer T, Soudee C, Peel J, Seeleuthner Y, Puel A, Zhang S Y, Ciancanelli M J, Arango Franco C A, ... Bogunovic D (2026). Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2). The Journal of experimental medicine, 223(8), -.

Chicago

Gruber C, Ramba M, Debnath B, Cuollo L, Neehus A L, Lee A, Buta S, et al.. "Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)." The Journal of experimental medicine 223, no. 8 (2026): -.

Harvard

Gruber C et al. (2026) 'Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)', The Journal of experimental medicine, 223(8), pp. -.

Vancouver

Gruber C, Ramba M, Debnath B, Cuollo L, Neehus A L, Lee A, et al.. Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2). The Journal of experimental medicine. 2026;223(8):-.

BibTex

@article{ author = {Gruber C and Ramba M and Debnath B and Cuollo L and Neehus A L and Lee A and Buta S and Martin Fernandez M and Rosain J and Berteloot L and Drabent P and Le Voyer T and Soudee C and Peel J and Seeleuthner Y and Puel A and Zhang S Y and Ciancanelli M J and Arango Franco C A and Migaud M and Fremond M L and Renaldo F and Boespflug Tanguy O and Dorboz I and Dubern B and Fonteneau T and Parvaneh N and Molatefi R and Shahrooei M and Duffy D and Bondet V and Rice G I and Crow Y J and Molina T J and Boddaert N and Casanova J L and Houdouin V and Melki I and Hadchouel A and Bustamante J and Bogunovic D}, title = {Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)}, journal = {The Journal of experimental medicine}, volume = {223}, number = {8}, pages = {-}, year = {2026} }

RIS

TY - JOUR
AU - Gruber C
AU - Ramba M
AU - Debnath B
AU - Cuollo L
AU - Neehus A L
AU - Lee A
AU - Buta S
AU - Martin Fernandez M
AU - Rosain J
AU - Berteloot L
AU - Drabent P
AU - Le Voyer T
AU - Soudee C
AU - Peel J
AU - Seeleuthner Y
AU - Puel A
AU - Zhang S Y
AU - Ciancanelli M J
AU - Arango Franco C A
AU - Migaud M
AU - Fremond M L
AU - Renaldo F
AU - Boespflug Tanguy O
AU - Dorboz I
AU - Dubern B
AU - Fonteneau T
AU - Parvaneh N
AU - Molatefi R
AU - Shahrooei M
AU - Duffy D
AU - Bondet V
AU - Rice G I
AU - Crow Y J
AU - Molina T J
AU - Boddaert N
AU - Casanova J L
AU - Houdouin V
AU - Melki I
AU - Hadchouel A
AU - Bustamante J
AU - Bogunovic D
TI - Familial Pulmonary Alveolar Proteinosis and Type I Interferonopathy by Mutation of Stat2 (Tims2)
JO - The Journal of experimental medicine
VL - 223
IS - 8
SP -
EP -
PY - 2026
ER -

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