Informatics-Based Discovery of Disease-Associated Immune Profiles.
Advances in flow and mass cytometry are enabling ultra-high resolution immune profiling in mice and humans on an unprecedented scale. However, the resulting high-content datasets challenge traditional views of cytometry data, which are both limited in scope and biased by pre-existing hypotheses. Computational solutions are now emerging (e.g., Citrus, AutoGate, SPADE) that automate cell gating or enable visualization of relative subset abundance within healthy versus diseased mice or humans. Yet these tools require significant computational fluency and fail to show quantitative relationships between discrete immune phenotypes and continuous disease variables. Here we describe a simple informatics platform that uses hierarchical clustering and nearest neighbor algorithms to associate manually gated immune phenotypes with clinical or pre-clinical disease endpoints of interest in a rapid and unbiased manner. Using this approach, we identify discrete immune profiles that correspond with either weight loss or histologic colitis in a T cell transfer model of inflammatory bowel disease (IBD), and show distinct nodes of immune dysregulation in the IBDs, Crohn's disease and ulcerative colitis. This streamlined informatics approach for cytometry data analysis leverages publicly available software, can be applied to manually or computationally gated cytometry data, is suitable for any clinical or pre-clinical setting, and embraces ultra-high content flow and mass cytometry as a discovery engine.
Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, United States of America.|Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, United States of America.
Amber
A
Delmas
Division of Digestive Disease, University of California Los Angeles, Los Angeles, California, United States of America.
Angelos
A
Oikonomopoulos
Division of Digestive Disease, University of California Los Angeles, Los Angeles, California, United States of America.
Precious N
PN
Lacey
Informatics Core, The Scripps Institute, Jupiter, Florida, United States of America.
Mohammad
M
Fallahi
Division of Digestive Disease, University of California Los Angeles, Los Angeles, California, United States of America.
Daniel W
DW
Hommes
Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, United States of America.|Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, United States of America.
Mark S
MS
Sundrud
Cytokine Growth Factor Rev. 2015 Jun;26(3):311-27
25498524
Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G135-46
19033538
Nature. 2012 Feb 01;482(7384):179-85
22297845
J Immunol. 2009 Jul 1;183(1):75-82
19535634
Gut. 2012 Dec;61(12):1693-700
22595313
J Comput Aided Mol Des. 2003 Oct;17(10):687-98
15068367
Nat Immunol. 2009 Jun;10(6):568-70
19448657
Immunol Res. 2014 May;58(2-3):218-23
24825775
N Engl J Med. 2013 Aug 22;369(8):699-710
23964932
Nature. 2012 Nov 1;491(7422):119-24
23128233
Clin Exp Immunol. 2005 Apr;140(1):22-31
15762871
Nat Commun. 2015 Jul 08;6:7577
26154811
Inflamm Bowel Dis. 2016 May;22(5):1157-67
26863267
J Leukoc Biol. 2016 Mar;99(3):483-93
26428679
J Exp Med. 2011 Aug 29;208(9):1875-87
21825017
PLoS One. 2014 Aug 29;9(8):e105602
25170899
Nat Immunol. 2011 Mar;12(3):255-63
21278737
J Immunol. 2014 Mar 1;192(5):2167-76
24489094
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5919-24
20231436
Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):E2770-7
24979804
Immunol Cell Biol. 2014 Jan;92(1):90-8
24189163
Stem Cell Reports. 2013 Aug 15;1(3):266-80
24319662
Nat Protoc. 2007;2(3):541-6
17406617
Immunology. 2011 Nov;134(3):235-45
21977994
Cell. 2015 Oct 8;163(2):381-93
26411290
J Immunol. 1984 Oct;133(4):1710-5
6206131
Curr Opin Gastroenterol. 2014 Nov;30(6):547-52
25203451
Science. 2015 Jul 10;349(6244):1259425
26160952
J Crohns Colitis. 2016 Mar;10 (3):338-45
26589954
Arthritis Res Ther. 2015 May 18;17:127
25981462
Bioinformatics. 2012 Sep 15;28(18):2400-1
22782546
Nat Rev Immunol. 2005 Jul;5(7):546-59
15965491
Gut. 2014 Oct;63(10 ):1578-86
24398881
Cancer Immunol Immunother. 2014 Jun;63(6):627-41
24682538
Immunity. 2016 May 17;44(5):1227-39
27178470
Nature. 2013 Apr 25;496(7446):461-8
23467089
Annu Rev Immunol. 2010;28:573-621
20192811
J Innate Immun. 2011;3(5):530-40
21335935
N Engl J Med. 2013 Aug 22;369(8):711-21
23964933
Mucosal Immunol. 2014 Nov;7(6):1354-65
24717354