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Article ; Online: Effects of an FcγRIIA polymorphism on leukocyte gene expression and cytokine responses to anti-CD3 and anti-CD28 antibodies.

Stein, Michelle M / Hrusch, Cara L / Sperling, Anne I / Ober, Carole

2018 Volume 20, Issue 6, Page(s) 462–472

Abstract: The low affinity Fcγ receptor, FcγRIIA, harbors a common missense mutation, rs1801274 (G>A, Arg131His) that modifies binding affinity to human IgG2 and mouse IgG1 antibodies and is associated with increased risk of autoimmune disease. Despite the ... ...

Abstract	The low affinity Fcγ receptor, FcγRIIA, harbors a common missense mutation, rs1801274 (G>A, Arg131His) that modifies binding affinity to human IgG2 and mouse IgG1 antibodies and is associated with increased risk of autoimmune disease. Despite the important role of the Arg131His variant, little is understood about heterozygous genotype effects on global gene expression and cytokine production during an FcγR-dependent response. To address this gap in knowledge, we treated human whole-blood samples from 130 individuals with mouse IgG1 anti-CD3 and anti-CD28 antibodies and characterized the genome-wide gene expression profiles and cytokine production among individuals stratified by rs1801274 genotype. Our analysis revealed that the levels of four cytokines (IFNγ, IL-12, IL-2, TNFα) and global gene expression patterns differed between all three genotype classes. Surprisingly, the heterozygotes showed suboptimal T cell activation compared to cells from individuals homozygous for the higher-affinity FcγRIIA allele (GG; Arg/Arg). The results of this study demonstrate that IgG response varies among all rs1801274 genotype classes and results in profound differences in both cytokine responses and gene expression patterns in blood leukocytes. Because even heterozygotes showed dampened global responses, our data may provide insight into the heterogeneity of outcomes in cytokine release assays and immunotherapy efficacy.
MeSH term(s)	Adolescent ; Adult ; Aged ; Alleles ; Antibodies/pharmacology ; CD28 Antigens/antagonists & inhibitors ; CD28 Antigens/immunology ; CD3 Complex/antagonists & inhibitors ; CD3 Complex/immunology ; Child ; Genotype ; Heterozygote ; Homozygote ; Humans ; Interferon-gamma/blood ; Interferon-gamma/metabolism ; Interleukin-12/blood ; Interleukin-12/metabolism ; Interleukin-2/blood ; Interleukin-2/metabolism ; Leukocytes/immunology ; Leukocytes/metabolism ; Middle Aged ; Polymorphism, Genetic ; Receptors, IgG/genetics ; T-Lymphocytes/metabolism ; Transcriptome/immunology ; Tumor Necrosis Factor-alpha/blood ; Tumor Necrosis Factor-alpha/metabolism ; Young Adult
Chemical Substances	Antibodies ; CD28 Antigens ; CD3 Complex ; Fc gamma receptor IIA ; Interleukin-2 ; Receptors, IgG ; Tumor Necrosis Factor-alpha ; Interleukin-12 (187348-17-0) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2018-07-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2060566-3
ISSN	1476-5470 ; 1466-4879
ISSN (online)	1476-5470
ISSN	1466-4879
DOI	10.1038/s41435-018-0038-8
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Zs.A 5592: Show issues

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Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: IL-33-mediated Eosinophilia Protects against Acute Lung Injury.

Krishack, Paulette A / Hollinger, Maile K / Kuzel, Timothy G / Decker, Trevor S / Louviere, Tyler J / Hrusch, Cara L / Sperling, Anne I / Verhoef, Philip A

American journal of respiratory cell and molecular biology

2021 Volume 64, Issue 5, Page(s) 569–578

Abstract: Pneumonia-induced lung injury and acute respiratory distress syndrome can develop because of an inappropriate inflammatory response to acute infections, leading to a compromised alveolar barrier. Recent work suggests that hospitalized patients with ... ...

Abstract	Pneumonia-induced lung injury and acute respiratory distress syndrome can develop because of an inappropriate inflammatory response to acute infections, leading to a compromised alveolar barrier. Recent work suggests that hospitalized patients with allergies/asthma are less likely to die of pulmonary infections and that there is a correlation between survival from acute respiratory distress syndrome and higher eosinophil counts; thus, we hypothesized that eosinophils associated with a type 2 immune response may protect against pneumonia-induced acute lung injury. To test this hypothesis, mice were treated with the type 2-initiating cytokine IL-33 intratracheally 3 days before induction of pneumonia with airway administration of a lethal dose of
MeSH term(s)	Acute Lung Injury/etiology ; Acute Lung Injury/immunology ; Acute Lung Injury/microbiology ; Acute Lung Injury/prevention & control ; Animals ; Bronchoalveolar Lavage Fluid/chemistry ; Bronchoalveolar Lavage Fluid/cytology ; Diphtheria Toxin/pharmacology ; Disease Models, Animal ; Eosinophils/drug effects ; Eosinophils/immunology ; Female ; Gene Expression ; Humans ; Interleukin-33/genetics ; Interleukin-33/immunology ; Interleukin-33/pharmacology ; Interleukin-5/deficiency ; Interleukin-5/genetics ; Interleukin-5/immunology ; Leukocyte Count ; Leukocyte Reduction Procedures ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophils/drug effects ; Neutrophils/immunology ; Pneumonia, Staphylococcal/complications ; Pneumonia, Staphylococcal/immunology ; Pneumonia, Staphylococcal/microbiology ; Pneumonia, Staphylococcal/mortality ; Pulmonary Edema/complications ; Pulmonary Edema/immunology ; Pulmonary Edema/microbiology ; Pulmonary Edema/mortality ; Respiratory Distress Syndrome/etiology ; Respiratory Distress Syndrome/immunology ; Respiratory Distress Syndrome/microbiology ; Respiratory Distress Syndrome/prevention & control ; Staphylococcus aureus/immunology ; Staphylococcus aureus/pathogenicity ; Survival Analysis
Chemical Substances	Diphtheria Toxin ; Il33 protein, mouse ; Interleukin-33 ; Interleukin-5
Language	English
Publishing date	2021-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2020-0166OC
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Zs.A 2851: Show issues

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Article ; Online: Transcriptional programming and T cell receptor repertoires distinguish human lung and lymph node memory T cells.

Schoettler, Nathan / Hrusch, Cara L / Blaine, Kelly M / Sperling, Anne I / Ober, Carole

Communications biology

2019 Volume 2, Page(s) 411

Abstract: Antigen-specific memory T cells persist for years after exposure to a pathogen and provide effective recall responses. Many memory T cell subsets have been identified and differ in abundance throughout tissues. This study focused on CD4 and CD8 memory T ... ...

Abstract	Antigen-specific memory T cells persist for years after exposure to a pathogen and provide effective recall responses. Many memory T cell subsets have been identified and differ in abundance throughout tissues. This study focused on CD4 and CD8 memory T cells from paired human lung and lung draining lymph node (LDLN) samples and identified substantial differences in the transcriptional landscape of these subsets, including higher expression of an array of innate immune receptors in lung T cells which were further validated by flow cytometry. Using T cell receptor analysis, we determined the clonal overlap between memory T cell subsets within the lung and within the LDLN, and this was greater than the clonal overlap observed between memory T cell subsets compared across tissues. Our results suggest that lung and LDLN memory T cells originate from different precursor pools, recognize distinct antigens and likely have separate roles in immune responses.
MeSH term(s)	Biomarkers ; Cellular Reprogramming/genetics ; Gene Expression Profiling ; Gene Ontology ; Genes, T-Cell Receptor ; Humans ; Immunologic Memory ; Immunophenotyping ; Lung/immunology ; Lymph Nodes/immunology ; Reproducibility of Results ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Transcription, Genetic ; V(D)J Recombination
Chemical Substances	Biomarkers
Language	English
Publishing date	2019-11-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-019-0657-2
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Article ; Online: Gut microbiota modulates bleomycin-induced acute lung injury response in mice.

Yoon, Young Me / Hrusch, Cara L / Fei, Na / Barrón, Gabriel M / Mills, Kathleen A M / Hollinger, Maile K / Velez, Tania E / Leone, Vanessa A / Chang, Eugene B / Sperling, Anne I

Respiratory research

2022 Volume 23, Issue 1, Page(s) 337

Abstract: Background: Airway instillation of bleomycin (BLM) in mice is a widely used, yet challenging, model for acute lung injury (ALI) with high variability in treatment scheme and animal outcomes among investigators. Whether the gut microbiota plays any role ... ...

Abstract	Background: Airway instillation of bleomycin (BLM) in mice is a widely used, yet challenging, model for acute lung injury (ALI) with high variability in treatment scheme and animal outcomes among investigators. Whether the gut microbiota plays any role in the outcome of BLM-induced lung injury is currently unknown. Methods: Intratracheal instillation of BLM into C57BL/6 mice was performed. Fecal microbiomes were analyzed by 16s rRNA amplicon and metagenomic sequencing. Germ-free mice conventionalization and fecal microbiota transfer between SPF mice were performed to determine dominant commensal species that are associated with more severe BLM response. Further, lungs and gut draining lymph nodes of the mice were analyzed by flow cytometry to define immunophenotypes associated with the BLM-sensitive microbiome. Results: Mice from two SPF barrier facilities at the University of Chicago exhibited significantly different mortality and weight loss during BLM-induced lung injury. Conventionalizing germ-free mice with SPF microbiota from two different housing facilities recapitulated the respective donors' response to BLM. Fecal microbiota transfer from the facility where the mice had worse mortality into the mice in the facility with more survival rendered recipient mice more susceptible to BLM-induced weight loss in a dominant negative manner. BLM-sensitive phenotype was associated with the presence of Helicobacter and Desulfovibrio in the gut, decreased Th17-neutrophil axis during steady state, and augmented lung neutrophil accumulation during the acute phase of the injury response. Conclusion: The composition of gut microbiota has significant impact on BLM-induced wasting and death suggesting a role of the lung-gut axis in lung injury.
MeSH term(s)	Mice ; Animals ; Bleomycin/toxicity ; RNA, Ribosomal, 16S ; Mice, Inbred C57BL ; Acute Lung Injury/chemically induced ; Acute Lung Injury/pathology ; Lung/pathology ; Weight Loss
Chemical Substances	Bleomycin (11056-06-7) ; RNA, Ribosomal, 16S
Language	English
Publishing date	2022-12-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-993X
ISSN (online)	1465-993X
ISSN	1465-993X
DOI	10.1186/s12931-022-02264-7
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Article ; Online: IRF4 expression by lung dendritic cells drives acute but not Trm cell-dependent memory Th2 responses.

Camacho, Daniel F / Velez, Tania E / Hollinger, Maile K / Wang, Esther / Howard, Chanie L / Darnell, Eli P / Kennedy, Domenick E / Krishack, Paulette A / Hrusch, Cara L / Clark, Marcus R / Moon, James J / Sperling, Anne I

JCI insight

2022 Volume 7, Issue 21

Abstract: Expression of the transcription factor interferon regulatory factor 4 (IRF4) is required for the development of lung conventional DCs type 2 (cDC2s) that elicit Th2 responses, yet how IRF4 functions in lung cDC2s throughout the acute and memory allergic ... ...

Abstract	Expression of the transcription factor interferon regulatory factor 4 (IRF4) is required for the development of lung conventional DCs type 2 (cDC2s) that elicit Th2 responses, yet how IRF4 functions in lung cDC2s throughout the acute and memory allergic response is not clear. Here, we used a mouse model that loses IRF4 expression after lung cDC2 development to demonstrate that mice with IRF4-deficient DCs display impaired memory responses to allergen. This defect in the memory response was a direct result of ineffective Th2 induction and impaired recruitment of activated effector T cells to the lung after sensitization. IRF4-deficient DCs demonstrated defects in their migration to the draining lymph node and in T cell priming. Finally, T cells primed by IRF4-competent DCs mediated potent memory responses independently of IRF4-expressing DCs, demonstrating that IRF4-expressing DCs are not necessary during the memory response. Thus, IRF4 controlled a program in mature DCs governing Th2 priming and effector responses, but IRF4-expressing DCs were dispensable during tissue-resident memory T cell-dependent memory responses.
MeSH term(s)	Animals ; Mice ; Allergens ; Dendritic Cells ; Gene Expression Regulation ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Lung/pathology ; Memory T Cells/immunology ; Th2 Cells ; Immunologic Memory
Chemical Substances	Allergens ; Interferon Regulatory Factors
Language	English
Publishing date	2022-11-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.140384
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Article ; Online: The role of dendritic cells and monocytes in the maintenance and loss of respiratory tolerance.

Hrusch, Cara L / Tjota, Melissa Y / Sperling, Anne I

Current allergy and asthma reports

2014 Volume 15, Issue 1, Page(s) 494

Abstract: Promoting tolerance to inhaled antigens is an active area of study with the potential to benefit the millions of Americans currently suffering from respiratory allergies and asthma. Interestingly, not all individuals with atopy are symptomatic, arguing ... ...

Abstract	Promoting tolerance to inhaled antigens is an active area of study with the potential to benefit the millions of Americans currently suffering from respiratory allergies and asthma. Interestingly, not all individuals with atopy are symptomatic, arguing that sensitization alone does not lead to an allergic clinical phenotype. Respiratory dendritic cells (rDCs), classically associated with inducing inflammatory responses, can actively promote tolerance. Tolerance can be broken when inflammatory stimuli, including viral infections and other environmental exposures, inhibit rDC-mediated tolerance by allowing innocuous antigen to be presented to initiate type-2 immunity. Importantly, rDCs are composed of multiple subsets, each with a unique response to an inhaled antigen that can lead to either tolerance or inflammation. In this review, we will discuss how rDC subsets actively maintain tolerance or, alternatively, break tolerance in response to environmental cues.
MeSH term(s)	Animals ; Asthma/immunology ; Dendritic Cells/immunology ; Dermatitis, Atopic/immunology ; Humans ; Immune Tolerance/immunology ; Monocytes/immunology ; Phenotype
Language	English
Publishing date	2014-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2057370-4
ISSN	1534-6315 ; 1529-7322
ISSN (online)	1534-6315
ISSN	1529-7322
DOI	10.1007/s11882-014-0494-9
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Zs.A 5548: Show issues

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Article ; Online: T-cell phenotypes are associated with serum IgE levels in Amish and Hutterite children.

Hrusch, Cara L / Stein, Michelle M / Gozdz, Justyna / Holbreich, Mark / von Mutius, Erika / Vercelli, Donata / Ober, Carole / Sperling, Anne I

The Journal of allergy and clinical immunology

2019 Volume 144, Issue 5, Page(s) 1391–1401.e10

Abstract: Objectives: Amish children raised on traditional farms have lower atopy and asthma risk than Hutterite children raised on modern farms. In our previous study we established that the Amish environment affects the innate immune response to decrease asthma ...

Abstract	Objectives: Amish children raised on traditional farms have lower atopy and asthma risk than Hutterite children raised on modern farms. In our previous study we established that the Amish environment affects the innate immune response to decrease asthma and atopy risk. Here we investigated T-cell phenotypes in the same Amish and Hutterite children as in our earlier study to elucidate how this altered innate immunity affects adaptive T cells. Methods: Blood was collected from 30 Amish and 30 Hutterite age- and sex-matched children; cells were cryopreserved until analysis. Flow cytometry was used to analyze cell subsets. Atopy was determined based on allergen-specific and total IgE levels. Results: Children exposed to Amish farms had increased activated regulatory CD4 Conclusion: Amish children's blood leukocytes are not only altered in their innate immune status but also have distinct T-cell phenotypes that are often associated with increased antigen exposure.
MeSH term(s)	Adaptive Immunity ; Adolescent ; Allergens/immunology ; Amish ; Cells, Cultured ; Child ; Environmental Exposure/adverse effects ; Ethnic Groups ; Female ; Humans ; Hypersensitivity, Immediate/immunology ; Immunoglobulin E/blood ; Immunophenotyping ; Male ; Phenotype ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes/immunology ; Tumor Necrosis Factor alpha-Induced Protein 3/genetics ; Tumor Necrosis Factor alpha-Induced Protein 3/metabolism
Chemical Substances	Allergens ; Immunoglobulin E (37341-29-0) ; TNFAIP3 protein, human (EC 3.4.19.12) ; Tumor Necrosis Factor alpha-Induced Protein 3 (EC 3.4.19.12)
Language	English
Publishing date	2019-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2019.07.034
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Uh III Zs.92: Show issues

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Article ; Online: Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation.

Maisel, Katharina / Hrusch, Cara L / Medellin, Jorge E G / Potin, Lambert / Chapel, David B / Nurmi, Harri / Camacho, Daniel F / Gleyzer, Rachel / Alitalo, Kari / Sperling, Anne I / Swartz, Melody A

Mucosal immunology

2020 Volume 14, Issue 1, Page(s) 144–151

Abstract: In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the ... ...

Abstract	In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the allergic response to house dust mite (HDM). In the acute inflammatory phase, the lungs of mice treated with blocking antibodies against VEGFR-3 (mF4-31C1) displayed less inflammation overall, with dramatically reduced innate and T-cell numbers and reduced inflammatory chemokine levels. However, when inflammation was allowed to resolve and memory recall was induced 2 months later, mice treated with mF4-31C1 as well as VEGF-C/-D knockout models showed exacerbated type 2 memory response to HDM, with increased Th2 cells, eosinophils, type 2 chemokines, and pathological inflammation scores. This was associated with lower CCL21 and decreased T
MeSH term(s)	Allergens ; Animals ; Biomarkers ; Disease Susceptibility ; Immunologic Memory ; Immunophenotyping ; Lymphangiogenesis/genetics ; Mice ; Pyroglyphidae/immunology ; Respiratory Hypersensitivity/etiology ; Respiratory Hypersensitivity/metabolism ; Respiratory Hypersensitivity/pathology ; Signal Transduction ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Vascular Endothelial Growth Factor C/genetics ; Vascular Endothelial Growth Factor C/metabolism ; Vascular Endothelial Growth Factor Receptor-3/genetics ; Vascular Endothelial Growth Factor Receptor-3/metabolism
Chemical Substances	Allergens ; Biomarkers ; Vascular Endothelial Growth Factor C ; vascular endothelial growth factor C, mouse ; Vascular Endothelial Growth Factor Receptor-3 (EC 2.7.10.1)
Language	English
Publishing date	2020-06-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2411370-0
ISSN	1935-3456 ; 1933-0219
ISSN (online)	1935-3456
ISSN	1933-0219
DOI	10.1038/s41385-020-0308-4
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Zs.A 6796: Show issues

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Article ; Online: Protection against Staphylococcus aureus bacteremia-induced mortality depends on ILC2s and eosinophils.

Krishack, Paulette A / Louviere, Tyler J / Decker, Trevor S / Kuzel, Timothy G / Greenberg, Jared A / Camacho, Daniel F / Hrusch, Cara L / Sperling, Anne I / Verhoef, Philip A

JCI insight

2019 Volume 4, Issue 6

Abstract: The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2-mediated immune diseases are protected from developing sepsis. We evaluated CD4+ Th ...

Abstract	The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2-mediated immune diseases are protected from developing sepsis. We evaluated CD4+ Th cell polarization among patients with Staphylococcus aureus bacteremia and confirmed that survivors had a higher percentage of circulating Th2 cells but lower frequencies of Th17 cells and neutrophils early in the course of infection. To establish the mechanism of this protection, we used a mouse model of lethal S. aureus bacteremia and found that intratracheal pretreatment with the type 2-initiating cytokine IL-33 activated pulmonary type 2 innate lymphoid cells (ILC2s) and promoted eosinophilia. In addition, stimulation of type 2 immunity before lethal infection suppressed the pulmonary neutrophilic response to S. aureus. Mice lacking functional ILC2s did not respond to IL-33 and were not protected from lethal bacteremia, but treatment of these mice with the type 2 cytokines IL-5 and IL-13 rescued them from death. Depletion of eosinophils abrogated IL-33-mediated protection, indicating that eosinophilia is also necessary for the survival benefit. Thus, we have identified a potentially novel mechanism by which type 2 immunity can balance dysregulated septic inflammatory responses, thereby clarifying the protective benefit of type 2 immune diseases on sepsis mortality.
MeSH term(s)	Animals ; Antigens, CD1d/genetics ; Asthma/immunology ; Bacteremia/mortality ; Bacteremia/prevention & control ; Cytokines/metabolism ; Disease Models, Animal ; Eosinophils/immunology ; Eosinophils/metabolism ; Humans ; Hypersensitivity ; Immunity, Innate ; Interleukin-13 ; Interleukin-33/immunology ; Interleukin-5 ; Lung/metabolism ; Lung/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophils/immunology ; Promyelocytic Leukemia Zinc Finger Protein/genetics ; Pulmonary Edema/immunology ; Pulmonary Edema/pathology ; Staphylococcal Infections/immunology ; Staphylococcus aureus/immunology ; Th17 Cells/immunology ; Th2 Cells/immunology
Chemical Substances	Antigens, CD1d ; CD1d antigen, mouse ; Cytokines ; IL33 protein, human ; Il33 protein, mouse ; Interleukin-13 ; Interleukin-33 ; Interleukin-5 ; Promyelocytic Leukemia Zinc Finger Protein ; Zbtb16 protein, mouse
Language	English
Publishing date	2019-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.124168
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Article ; Online: T cell Co-Stimulatory molecules ICOS and CD28 stratify idiopathic pulmonary fibrosis survival.

Bonham, Catherine A / Hrusch, Cara L / Blaine, Kelly M / Manns, Stephenie T / Vij, Rekha / Oldham, Justin M / Churpek, Matthew M / Strek, Mary E / Noth, Imre / Sperling, Anne I

Respiratory medicine: X

2019 Volume 1

Abstract: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that kills as many Americans as breast cancer each year. This study investigated whether lung function decline and survival associates with adaptive immunity in patients with IPF, specifically ... ...

Abstract	Idiopathic pulmonary fibrosis (IPF) is a devastating disease that kills as many Americans as breast cancer each year. This study investigated whether lung function decline and survival associates with adaptive immunity in patients with IPF, specifically the expression of checkpoint molecules ICOS, CD28 and PD-1 on circulating CD4 T cells. Clinical data, blood samples and pulmonary function tests were collected prospectively and longitudinally from 59 patients with IPF over a study period of 5 years. Patients were followed until death, lung transplantation, or study end, and cell surface expression of CD45RO, CD28, ICOS, and PD-1 was measured on CD4 T cells via flow cytometry. Repeated measures of ICOS and CD28 on CD4 T cells revealed significant associations between declining ICOS and CD28 expression, and declining lung function parameters FVC and DLCO, independent of age, sex, race, smoking history, or immunosuppressant use. Strikingly, patients in the highest quintile of ICOS at study entry had markedly improved survival, while those with low CD28 fared poorly. No change in PD-1 expression was found. Analysis of ICOS and CD28 from the first blood draw identified three populations of IPF patients; those at high risk for early death, those with intermediate risk, and those at low risk. These results highlight the role of T cell mediated immunity in IPF survival, finding the assessment of two T cell stimulatory checkpoint molecules, CD28 and ICOS, was sufficient to discriminate three distinct survival trajectories over 5 years of patient follow up.
Language	English
Publishing date	2019-02-01
Publishing country	England
Document type	Journal Article
ISSN	2590-1435
ISSN (online)	2590-1435
DOI	10.1016/j.yrmex.2019.100002
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