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Article ; Online: Ikaros is a principal regulator of Aire

Sin, Jun Hyung / Sucharov, Juliana / Kashyap, Sujit / Wang, Yi / Proekt, Irina / Liu, Xian / Parent, Audrey V / Gupta, Alexander / Kastner, Philippe / Chan, Susan / Gardner, James M / Ntranos, Vasilis / Miller, Corey N / Anderson, Mark S / Schjerven, Hilde / Waterfield, Michael R

Science immunology

2023 Volume 8, Issue 88, Page(s) eabq3109

Abstract: Mutations in the gene encoding the zinc-finger transcription factor Ikaros ( ...

Abstract	Mutations in the gene encoding the zinc-finger transcription factor Ikaros (
MeSH term(s)	Humans ; Mice ; Animals ; Central Tolerance ; Cell Differentiation ; Thymus Gland ; Transcription Factors ; Gene Expression Regulation
Chemical Substances	Transcription Factors
Language	English
Publishing date	2023-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abq3109
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Article ; Online: Insights into immune tolerance from AIRE deficiency.

Proekt, Irina / Miller, Corey N / Lionakis, Michail S / Anderson, Mark S

Current opinion in immunology

2017 Volume 49, Page(s) 71–78

Abstract: AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or ... ...

Abstract	AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or absent AIRE function have markedly variable phenotypes that include a range of autoimmune manifestations. Recent evidence suggests that this variability stems from cooperation of autoimmune susceptibilities involving both central and peripheral tolerance checkpoints. Here we discuss the broadening understanding of the factors that influence Aire expression, modify AIRE function, and the impact and intersection of AIRE with peripheral immunity. This rapidly expanding body of knowledge will force a reexamination of the definition and clinical management of APS-1 patients as well as provide a foundation for the development of immunomodulatory strategies targeting central tolerance.
MeSH term(s)	Animals ; Autoantigens/genetics ; Autoantigens/metabolism ; Gene Expression Regulation ; Humans ; Immune Tolerance/immunology ; Mice ; Phenotype ; Polyendocrinopathies, Autoimmune/immunology ; Thymus Gland/immunology ; Transcription Factors/genetics ; Transcription Factors/metabolism ; AIRE Protein
Chemical Substances	Autoantigens ; Transcription Factors
Language	English
Publishing date	2017-10-21
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2017.10.003
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Article ; Online: Validation of a murine proteome-wide phage display library for identification of autoantibody specificities.

Rackaityte, Elze / Proekt, Irina / Miller, Haleigh S / Ramesh, Akshaya / Brooks, Jeremy F / Kung, Andrew F / Mandel-Brehm, Caleigh / Yu, David / Zamecnik, Colin R / Bair, Rebecca / Vazquez, Sara E / Sunshine, Sara / Abram, Clare L / Lowell, Clifford A / Rizzuto, Gabrielle / Wilson, Michael R / Zikherman, Julie / Anderson, Mark S / DeRisi, Joseph L

JCI insight

2023 Volume 8, Issue 23

Abstract: Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide ... ...

Abstract	Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and μMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.
MeSH term(s)	Humans ; Animals ; Mice ; Autoantibodies ; Proteome ; Autoimmunity ; Peptides ; Mice, Inbred NOD ; Bacteriophages
Chemical Substances	Autoantibodies ; Proteome ; Peptides
Language	English
Publishing date	2023-12-08
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.174976
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Article: Validation of a murine proteome-wide phage display library for the identification of autoantibody specificities.

Rackaityte, Elze / Proekt, Irina / Miller, Haleigh S / Ramesh, Akshaya / Brooks, Jeremy F / Kung, Andrew F / Mandel-Brehm, Caleigh / Yu, David / Zamecnik, Colin / Bair, Rebecca / Vazquez, Sara E / Sunshine, Sara / Abram, Clare L / Lowell, Clifford A / Rizzuto, Gabrielle / Wilson, Michael R / Zikherman, Julie / Anderson, Mark S / DeRisi, Joseph L

bioRxiv : the preprint server for biology

2023

Abstract	Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq), to profile mouse autoantibodies. This system and library were validated using seven genetic mouse models across a spectrum of autoreactivity. Mice deficient in antibody production (
Language	English
Publishing date	2023-04-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.07.535899
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Article ; Online: Elevated BCR signaling and decreased survival of Lyn-deficient transitional and follicular B cells.

Gross, Andrew J / Proekt, Irina / DeFranco, Anthony L

European journal of immunology

2011 Volume 41, Issue 12, Page(s) 3645–3655

Abstract: The Src-family tyrosine kinase Lyn negatively regulates BCR signaling and also myeloid cell activity. Mice deficient in Lyn have substantially decreased numbers of peripheral B cells, despite spontaneously producing IgG anti-DNA antibodies. Here, we ... ...

Abstract	The Src-family tyrosine kinase Lyn negatively regulates BCR signaling and also myeloid cell activity. Mice deficient in Lyn have substantially decreased numbers of peripheral B cells, despite spontaneously producing IgG anti-DNA antibodies. Here, we examine the mechanism underlying the B-cell depletion in these mice. Lyn-deficient B cells were out-competed by WT B cells in mixed BM chimeras at two steps, at the T1 to T2 transitional maturation stage in the spleen and again between the T2 or T3 stage and the mature follicular B-cell population. Lyn-deficient T2 and follicular B cells expressed elevated levels of the pro-apoptotic factor Bim and deletion of Bim restored splenic B cells of Lyn-deficient mice to close to WT numbers. Lyn-deficient T2 and later stage B cells also had changes in cell surface phenotype consistent with increased in vivo BCR signaling. Similarly, an increased proportion of T2 and follicular B cells had elevated basal intracellular free calcium levels. Overall, these observations suggest that increased BCR signaling is responsible for increased death of weakly self-reactive Lyn-deficient B cells both at the T2 stage and additionally as these cells mature to follicular B cells.
MeSH term(s)	Animals ; Antibodies, Antinuclear/immunology ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/immunology ; Apoptosis Regulatory Proteins/metabolism ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Mice ; Mice, Inbred C57BL ; Oncogene Protein v-akt/immunology ; Oncogene Protein v-akt/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/immunology ; Receptors, Antigen, B-Cell/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology ; Spleen/immunology ; Spleen/metabolism ; src-Family Kinases/deficiency ; src-Family Kinases/genetics ; src-Family Kinases/immunology
Chemical Substances	Antibodies, Antinuclear ; Apoptosis Regulatory Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Receptors, Antigen, B-Cell ; lyn protein-tyrosine kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; Oncogene Protein v-akt (EC 2.7.11.1)
Language	English
Publishing date	2011-11-10
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201141708
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Article ; Online: Natural killer cells in NOD.NK1.1 mice acquire cytolytic function during viral infection and provide protection against cytomegalovirus.

Orr, Mark T / Beilke, Joshua N / Proekt, Irina / Lanier, Lewis L

Proceedings of the National Academy of Sciences of the United States of America

2010 Volume 107, Issue 36, Page(s) 15844–15849

Abstract: Resting natural killer (NK) cells in nonobese diabetic (NOD) mice have impaired immune functions compared with NK cells from other mouse strains. Here we investigated how NOD NK cells respond after mouse cytomegalovirus (MCMV) infection, using NOD mice ... ...

Abstract	Resting natural killer (NK) cells in nonobese diabetic (NOD) mice have impaired immune functions compared with NK cells from other mouse strains. Here we investigated how NOD NK cells respond after mouse cytomegalovirus (MCMV) infection, using NOD mice congenic for the protective NK gene complex from C57BL/6 mice. Compared with C57BL/6 mice congenic for the H2 gene complex from NOD mice (B6.g7), NOD.NK1.1 mice fail to control early infection with MCMV. After MCMV infection, however, NOD.NK1.1 NK cells demonstrate increased cytolytic function, associated with higher expression of granzyme B, and undergo robust expansion. One week after infection, NOD.NK1.1 NK cells control MCMV replication as effectively as B6.g7 NK cells, even in the absence of T cells and B cells. Thus, the impaired cytotoxic function of NK cells in NOD mice is alleviated by viral infection, which enables NOD NK cells to efficiently control MCMV infection.
MeSH term(s)	Animals ; Cytomegalovirus Infections/immunology ; Cytomegalovirus Infections/prevention & control ; Cytotoxicity, Immunologic ; Killer Cells, Natural/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD
Language	English
Publishing date	2010-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1010685107
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Article: Natural killer cells in NOD.NK1.1 mice acquire cytolytic function during viral infection and provide protection against cytomegalovirus

Orr, Mark T / Beilke, Joshua N / Proekt, Irina / Lanier, Lewis L

Proceedings of the National Academy of Sciences of the United States of America. 2010 Sept. 7, v. 107, no. 36

2010

Abstract	Resting natural killer (NK) cells in nonobese diabetic (NOD) mice have impaired immune functions compared with NK cells from other mouse strains. Here we investigated how NOD NK cells respond after mouse cytomegalovirus (MCMV) infection, using NOD mice congenic for the protective NK gene complex from C57BL/6 mice. Compared with C57BL/6 mice congenic for the H2 gene complex from NOD mice (B6.g7), NOD.NK1.1 mice fail to control early infection with MCMV. After MCMV infection, however, NOD.NK1.1 NK cells demonstrate increased cytolytic function, associated with higher expression of granzyme B, and undergo robust expansion. One week after infection, NOD.NK1.1 NK cells control MCMV replication as effectively as B6.g7 NK cells, even in the absence of T cells and B cells. Thus, the impaired cytotoxic function of NK cells in NOD mice is alleviated by viral infection, which enables NOD NK cells to efficiently control MCMV infection.
Keywords	Murid herpesvirus 1 ; T-lymphocytes ; cytotoxicity ; genes ; mice ; natural killer cells
Language	English
Dates of publication	2010-0907
Size	p. 15844-15849.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1010685107
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Article ; Online: LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity.

Proekt, Irina / Miller, Corey N / Jeanne, Marion / Fasano, Kayla J / Moon, James J / Lowell, Clifford A / Gould, Douglas B / Anderson, Mark S / DeFranco, Anthony L

The Journal of clinical investigation

2016 Volume 126, Issue 10, Page(s) 3758–3771

Abstract: Studies of the genetic factors associated with human autoimmune disease suggest a multigenic origin of susceptibility; however, how these factors interact and through which tolerance pathways they operate generally remain to be defined. One key ... ...

Abstract	Studies of the genetic factors associated with human autoimmune disease suggest a multigenic origin of susceptibility; however, how these factors interact and through which tolerance pathways they operate generally remain to be defined. One key checkpoint occurs through the activity of the autoimmune regulator AIRE, which promotes central T cell tolerance. Recent reports have described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmunity to a greater extent than previously thought. In families with these mutations, the penetrance of autoimmunity is incomplete, suggesting that other checkpoints play a role in preventing autoimmunity. Here, we tested whether a defect in LYN, an inhibitory protein tyrosine kinase that is implicated in systemic autoimmunity, could combine with an Aire mutation to provoke organ-specific autoimmunity. Indeed, mice with a dominant-negative allele of Aire and deficiency in LYN spontaneously developed organ-specific autoimmunity in the eye. We further determined that a small pool of retinal protein-specific T cells escaped thymic deletion as a result of the hypomorphic Aire function and that these cells also escaped peripheral tolerance in the presence of LYN-deficient dendritic cells, leading to highly destructive autoimmune attack. These findings demonstrate how 2 distinct tolerance pathways can synergize to unleash autoimmunity and have implications for the genetic susceptibility of autoimmune disease.
MeSH term(s)	Animals ; Antigen Presentation ; Autoantibodies/metabolism ; Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; Autoimmunity ; CD4-Positive T-Lymphocytes/immunology ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Eye Proteins/immunology ; Gastrointestinal Microbiome/immunology ; Mice, Inbred C57BL ; Mice, Transgenic ; Organ Specificity ; Retinol-Binding Proteins/immunology ; Transcription Factors/physiology ; Uveitis, Posterior/genetics ; Uveitis, Posterior/immunology ; src-Family Kinases/physiology ; AIRE Protein
Chemical Substances	Autoantibodies ; Eye Proteins ; Retinol-Binding Proteins ; Transcription Factors ; interstitial retinol-binding protein ; lyn protein-tyrosine kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2016-08-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI84440
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Article ; Online: Thymic regulatory T cells arise via two distinct developmental programs.

Nature immunology

2019 Volume 20, Issue 2, Page(s) 195–205

Abstract: The developmental programs that generate a broad repertoire of regulatory T cells ( ... ...

Abstract	The developmental programs that generate a broad repertoire of regulatory T cells (T
MeSH term(s)	Animals ; Autoantigens/immunology ; Cell Differentiation/immunology ; Colitis/immunology ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Freund's Adjuvant/administration & dosage ; Freund's Adjuvant/immunology ; Humans ; Immune Tolerance/immunology ; Interleukin-2 Receptor alpha Subunit/metabolism ; Lymphoid Progenitor Cells/physiology ; Lymphoid Progenitor Cells/transplantation ; Mice ; Mice, Transgenic ; Mycobacterium tuberculosis/immunology ; Myelin-Oligodendrocyte Glycoprotein/administration & dosage ; Myelin-Oligodendrocyte Glycoprotein/immunology ; Peptide Fragments/administration & dosage ; Peptide Fragments/immunology ; Signal Transduction ; Specific Pathogen-Free Organisms ; T-Lymphocytes, Regulatory/physiology ; Thymus Gland/cytology ; Thymus Gland/growth & development ; Thymus Gland/immunology
Chemical Substances	Autoantigens ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Il2ra protein, mouse ; Interleukin-2 Receptor alpha Subunit ; Myelin-Oligodendrocyte Glycoprotein ; Peptide Fragments ; myelin oligodendrocyte glycoprotein (35-55) ; Freund's Adjuvant (9007-81-2)
Language	English
Publishing date	2019-01-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-018-0289-6
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Article ; Online: Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq.

Vazquez, Sara E / Mann, Sabrina A / Bodansky, Aaron / Kung, Andrew F / Quandt, Zoe / Ferré, Elise M N / Landegren, Nils / Eriksson, Daniel / Bastard, Paul / Zhang, Shen-Ying / Liu, Jamin / Mitchell, Anthea / Proekt, Irina / Yu, David / Mandel-Brehm, Caleigh / Wang, Chung-Yu / Miao, Brenda / Sowa, Gavin / Zorn, Kelsey /

Chan, Alice Y / Tagi, Veronica M / Shimizu, Chisato / Tremoulet, Adriana / Lynch, Kara / Wilson, Michael R / Kämpe, Olle / Dobbs, Kerry / Delmonte, Ottavia M / Bacchetta, Rosa / Notarangelo, Luigi D / Burns, Jane C / Casanova, Jean-Laurent / Lionakis, Michail S / Torgerson, Troy R / Anderson, Mark S / DeRisi, Joseph L

eLife

2022 Volume 11

Abstract: Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood ... ...

Abstract	Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.
MeSH term(s)	Humans ; Autoantibodies ; Autoantigens/metabolism ; Autoimmune Diseases ; Autoimmunity ; Bacteriophages/metabolism ; COVID-19 ; Homeodomain Proteins ; Immunoprecipitation ; Proteome
Chemical Substances	Autoantibodies ; Autoantigens ; Homeodomain Proteins ; Proteome
Language	English
Publishing date	2022-10-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.78550
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