(The Letter for the global important
reader)
//Background//---
Programmed cell death protein 1 (called PD-1)
is a surface-expressed protein on T and B cell that has a role in regulating
the immune function. Immune system is regulated as “a scale
balance”, and both promoting and suppressing function
are needed. It is said that PD-1 has suppressive function, so lack of this
function leads autoimmune system. On the other hand, when durable immune
function is needed, such as cancer treatment, we have choice that we
intentionally suppress this function through PD-1 blockade. However, this
control by the drug is difficult, and some of cancer patients receiving this
immunotherapy are prone to autoimmunity including pneumonitis(1).
Type
1 diabetes in which very little or no insulin is produced beta cell is
previously known as juvenile diabetes. This is one of the typical symptoms in
(congenital) autoimmune disease. In some cases, this immune dysfunction also
leads to tuberculosis due to previous infection of Mycobacterium tuberculosis.
The rate of this infection is about 25% globally(2). Therefore, the child
having inborn error of immunity needs to be careful of this infection and
tuberculosis. Generally, to prevent tuberculosis, BCG vaccination is taken.
However, this vaccine efficacy of the child with autoimmune disease is
unknown(1).
Masato
Ogishi, Rui Yang, Caner Aytekin et al. elucidate that genetically inherited
PD-1 deficiency and alloplasia underly tuberculosis and autoimmunity in a
child(1).
//Clinical condition of the child with
autoimmunity(1)//---
A child(Patient) born to consanguineous
Turkish parents.
At the age of 3 years.
(Diagnosed diseases)
Type 1 diabetes / Hypothyroidism / Juvenile
idiopathic arthritis /
Abdominal tuberculosis
(Diseases progression)
Hepatotoxicity due to antimycobacterial
therapy in 8 months
Dyspnea and respiratory failure after 2
months
Detected Autoantibody
Alpha 3 chain of type IV collagen,
Autoantigen underlying Goodpasture’s syndrome
Autoantibodies associated with autoimmune thyroiditis and T1D
Died due to alveolar hemorrhage only 3 months after respiratory
illness despite aggressive immunosuppressive therapy.
//Genetical, cellular and molecular
analysis for this patient(1)//---
A homozygous frameshift variant of PDCD1
PDCD1 encodes the immune checkpoint receptor
PD-1. Therefore, this gene variant is related to the dysfunction of PD-1 in the
child with autoimmune diseases. Actually, in HEK293T cell analysis with this
gene mutation from this patient, lack of expression or truncated expression of
PD-1 is confirmed.
This
dysfunction of PD-1 is related to impaired IFN-γ(type2
interferon).
(The immune cell confirmed IFN-γ deficiency)(1)(See Fig.3c-e)
B cell, T cell(CD8, CD4, iNK, DN, γδ), NK cell and MAIT cell
(The typical function of IFN-γ(type2 interferon))
*Promotion of Natural Killer cell activity
*Increase of antigen presentation and
lysosome activity of macrophages
*Activation of inducible nitric oxide
synthase (iNOS)
*Induction of the production of IgG2a and
IgG3 from activated plasma B cells
*Cause normal cells to increase the
expression of class I MHC molecules as well as II on antigen-presenting cells
Promotion of adhesion and binding of the
expression intrinsic defense factors
⇒Therefore, effector function and
activation of broad immune cell such as T cell, B cell and NK cell could be
suppressed by IFN-gamma deficiency.
(Upregulated immune cell due to immune
dysfunction)
RORγT+CD4-CD8-
double-negative αβT cell
Not helper(CD4), cytotoxic(CD8) function
Related gene: STAT3 upregulation
Related cytokine: IL-6, IL23
Lymphoproliferative
phenotypes, that is, becoming dominant in lymphocyte.
//The strategy of clinical treatment//---
*Tocilizumab, an anti-IL-6 receptor
monoclonal antibody
*Tofacitinib, a JAK1/3 inhibitor
*The gene therapy for STAT or PDCD1
*Autoantibody suppression through
suppressive binding to the key epitopes
*CAR-immune cell therapy (if possible, autogenous
transplantation) with normal PD-1 expression
//Contribution(1)//---
M.O., S.B.-D. and J.-L.C. designed the
study. M.O., R.Y., D.L., M.B., T.K., F.A.A., M.R., O.M.D., M.C., C.G., S.J.P.,
A.N.S., J.R., W.-T.L., S.D., G.R., C.S.M., Y.N., T.Y., K.C., S.C.W., J.-F.E.,
F. Rozenberg, G.A., M.S.G., D.B., N.M., L.D.N., S.G.T., T.H. and P.G. performed
experiments. M.O. and P.Z. analyzed the single-cell and bulk RNA-seq data.
P.Z., F. Rapaport, G.K. and L.A. assisted in the analysis of genetic data.
M.D.H., M.K.C., M.A., P.W. and J.D.W. collected data on patients treated with
anti-PD-1 monoclonal antibody. C.A., I.T., D.C., F.O.H., F.D., A.I., V.K.R.,
L.K., V.B. and J.B. collected clinical data and biological materials of
patients. S.D. assisted with the experiments and the writing of the case
report. M.O., S.B.-D. and J.-L.C. interpreted the data and wrote the manuscript
with the help of all co-authors. All authors reviewed the manuscript and
approved its submission. S.V., R.P.L., B.B., L.A., D.B., N.M., L.D.N., S.G.T.,
T.H. and P.G. are co-second-to-last authors contributing equally. S.B.-D. and
J.-L.C. are co-last authors who jointly supervised the study.
(Reference)
(1)
Masato Ogishi, Rui Yang, Caner Aytekin,
David Langlais, Mathieu Bourgey, Taushif Khan, Fatima Al Ali, Mahbuba Rahman,
Ottavia M. Delmonte, Maya Chrabieh, Peng Zhang, Conor Gruber, Simon J. Pelham,
András N. Spaan, Jérémie Rosain, Wei-Te Lei, Scott Drutman, Matthew D.
Hellmann, Margaret K. Callahan, Matthew Adamow, Phillip Wong, Jedd D. Wolchok,
Geetha Rao, Cindy S. Ma, Yuka Nakajima, Tomonori Yaguchi, Kenji Chamoto, Samuel
C. Williams, Jean-Francois Emile, Flore Rozenberg, Michael S. Glickman, Franck
Rapaport, Gaspard Kerner, Garrett Allington, Ilhan Tezcan, Deniz Cagdas, Ferda
O. Hosnut, Figen Dogu, Aydan Ikinciogullari, V. Koneti Rao, Leena Kainulainen,
Vivien Béziat, Jacinta Bustamante, Silvia Vilarinho, Richard P. Lifton,
Bertrand Boisson, Laurent Abel, Dusan Bogunovic, Nico Marr, Luigi D.
Notarangelo, Stuart G. Tangye, Tasuku Honjo, Philippe Gros, Stéphanie
Boisson-Dupuis & Jean-Laurent Casanova
Inherited PD-1 deficiency underlies
tuberculosis and autoimmunity in a child
Nature Medicine (2021)
ー
Author information
Author notes
These authors contributed equally: Silvia
Vilarinho, Richard P. Lifton, Bertrand Boisson, Laurent Abel, Dusan Bogunovic,
Nico Marr, Luigi D. Notarangelo, Stuart G. Tangye, Tasuku Honjo, Philippe Gros.
These authors jointly supervised this work:
Stéphanie Boisson-Dupuis, Jean-Laurent Casanova.
Affiliations
St. Giles Laboratory of Human Genetics of
Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY,
USA
Masato Ogishi, Rui Yang, Peng Zhang, Simon
J. Pelham, András N. Spaan, Wei-Te Lei, Scott Drutman, Franck Rapaport, Vivien
Béziat, Jacinta Bustamante, Bertrand Boisson, Laurent Abel, Stéphanie
Boisson-Dupuis & Jean-Laurent Casanova
The David Rockefeller Graduate Program,
Rockefeller University, New York, NY, USA
Masato Ogishi
Department of Pediatric Immunology, Dr.
Sami Ulus Maternity and Children’s Health and Diseases Training and Research
Hospital, Ankara, Turkey
Caner Aytekin
Department of Human Genetics, McGill
University, Montreal, Quebec, Canada
David Langlais
McGill University Genome Center, Montreal,
Quebec, Canada
Mathieu Bourgey
Department of Immunology, Research Branch,
Sidra Medicine, Doha, Qatar
Taushif Khan, Fatima Al Ali, Mahbuba Rahman
& Nico Marr
Immune Deficiency Genetics Section,
Laboratory of Host Defenses, Division of Intramural Research, National
Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD, USA
Ottavia M. Delmonte & Luigi D.
Notarangelo
Laboratory of Human Genetics of Infectious
Diseases, Necker Branch, INSERM U1163, Paris, France
Maya Chrabieh, Jérémie Rosain, Gaspard
Kerner, Vivien Béziat, Jacinta Bustamante, Bertrand Boisson, Laurent Abel, Stéphanie
Boisson-Dupuis & Jean-Laurent Casanova
University of Paris, Imagine Institute,
Paris, France
Maya Chrabieh, Jérémie Rosain, Gaspard
Kerner, Vivien Béziat, Jacinta Bustamante, Bertrand Boisson, Laurent Abel, Stéphanie
Boisson-Dupuis & Jean-Laurent Casanova
Department of Microbiology, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
Conor Gruber & Dusan Bogunovic
Department of Pediatrics, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
Conor Gruber & Dusan Bogunovic
The Mindich Child Health and Development
Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Conor Gruber & Dusan Bogunovic
Precision Immunology Institute, Icahn
School of Medicine at Mount Sinai, New York, NY, USA
Conor Gruber & Dusan Bogunovic
Department of Medicine, Sloan Kettering
Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Matthew D. Hellmann, Margaret K. Callahan
& Jedd D. Wolchok
Weill Cornell Medicine, New York, NY, USA
Matthew D. Hellmann, Margaret K. Callahan
& Jedd D. Wolchok
Immune Monitoring Core Facility, Memorial
Sloan Kettering Cancer Center, New York, NY, USA
Matthew Adamow & Phillip Wong
Parker Institute for Cancer Immunotherapy,
San Francisco, CA, USA
Matthew Adamow & Jedd D. Wolchok
Human Oncology and Pathogenesis Program,
Memorial Sloan Kettering Cancer Center, New York, NY, USA
Jedd D. Wolchok
Garvan Institute of Medical Research,
Darlinghurst, New South Wales, Australia
Geetha Rao, Cindy S. Ma & Stuart G.
Tangye
St Vincent’s Clinical School, Faculty of
Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia
Cindy S. Ma & Stuart G. Tangye
Department of Immunology and Genomic
Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University
Graduate School of Medicine, Kyoto, Japan
Yuka Nakajima, Tomonori Yaguchi, Kenji
Chamoto & Tasuku Honjo
Laboratory of Investigative Dermatology, Rockefeller
University, New York, NY, USA
Samuel C. Williams
Weill Cornell/Rockefeller/Sloan Kettering
Tri-Institutional MD-PhD Program, New York, NY, USA
Samuel C. Williams
Department of Pathology, Assistance
Publique-Hôpitaux de Paris, Ambroise Paré Hospital, Boulogne-Billancourt,
France
Jean-Francois Emile
Department of Virology, Cochin Hospital,
University of Paris, Paris, France
Flore Rozenberg
Immunology Program, Sloan Kettering
Institute, New York, NY, USA
Michael S. Glickman
Department of Genetics, Yale University
School of Medicine, New Haven, CT, USA
Garrett Allington, Silvia Vilarinho &
Richard P. Lifton
Section of Digestive Diseases, Departments
of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
Garrett Allington & Silvia Vilarinho
Department of Pathology, Yale University
School of Medicine, New Haven, CT, USA
Garrett Allington & Silvia Vilarinho
Department of Pediatric Immunology,
Hacettepe University Medical Faculty, Ankara, Turkey
Ilhan Tezcan & Deniz Cagdas
Department of Pediatric Gastroenterology,
Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and
Research Hospital, Ankara, Turkey
Ferda O. Hosnut
Department of Pediatric Immunology and
Allergy, Ankara University School of Medicine, Ankara, Turkey
Figen Dogu & Aydan Ikinciogullari
Laboratory of Clinical Immunology and
Microbiology, Division of Intramural Research, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
V. Koneti Rao
Department of Pediatrics and Department of
Medicine, Turku University Hospital, Turku, Finland
Leena Kainulainen
Study Center of Immunodeficiencies, Necker
Hospital for Sick Children, Paris, France
Jacinta Bustamante
Laboratory of Human Genetics and Genomics,
The Rockefeller University, New York, NY, USA
Richard P. Lifton
College of Health and Life Sciences, Hamad
Bin Khalifa University, Doha, Qatar
Nico Marr
McGill Research Centre on Complex Traits,
Montreal, Quebec, Canada
Philippe Gros
Department of Biochemistry, McGill
University, Montreal, Quebec, Canada
Philippe Gros
Howard Hughes Medical Institute, New York,
NY, USA
Jean-Laurent Casanova
ー
(2)
Houben, R. M. G. J. & Dodd, P. J.
The global burden of latent tuberculosis
infection: a re-estimation using mathematical modelling.
PLoS Med. 13, 1–13 (2016).
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