Upregulation of IFN-Inducible and Damage-Response Pathways in Chronic Graft-versus-Host Disease.
Although chronic graft-versus-host disease (CGVHD) is the primary nonrelapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: 1) IFN-inducible genes, and 2) innate receptors for cellular damage. Corroborating these with multiplex RNA quantitation, we found that multiple IFN-inducible genes (affecting lymphocyte trafficking, differentiation, and Ag presentation) were concurrently upregulated in CGVHD monocytes compared with normal subjects and non-CGVHD control patients. IFN-inducible chemokines were elevated in both lichenoid and sclerotic CGHVD plasma and were linked to CXCR3+lymphocyte trafficking. Furthermore, the levels of the IFN-inducible genes CXCL10 and TNFSF13B (BAFF) were correlated at both the gene and the plasma levels, implicating IFN induction as a factor in elevated BAFF levels in CGVHD. In the second pathway, damage-/pathogen-associated molecular pattern receptor genes capable of inducing type I IFN were upregulated. Type I IFN-inducible MxA was expressed in proportion to CGVHD activity in skin, mucosa, and glands, and expression of TLR7 and DDX58 receptor genes correlated with upregulation of type I IFN-inducible genes in monocytes. Finally, in serial analyses after transplant, IFN-inducible and damage-response genes were upregulated in monocytes at CGVHD onset and declined upon therapy and resolution in both lichenoid and sclerotic CGVHD patients. This interlocking analysis of IFN-inducible genes, plasma analytes, and tissue immunohistochemistry strongly supports a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD.
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; hakimf@mail.nih.gov.
Frances T
0000-0003-2507-8229
FT
Hakim
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Sarfraz
0000-0002-0164-9739
S
Memon
Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
Ping
P
Jin
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Matin M
MM
Imanguli
Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
Huan
0000-0003-3100-6141
H
Wang
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Najibah
0000-0003-2718-6784
N
Rehman
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Xiao-Yi
XY
Yan
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Jeremy
J
Rose
Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892.
Jacqueline W
0000-0002-4472-9974
JW
Mays
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Susan
S
Dhamala
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Veena
V
Kapoor
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
William
W
Telford
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
John
0000-0001-5184-9184
J
Dickinson
Cancer Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Sean
0000-0002-8991-6458
S
Davis
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
David
D
Halverson
Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
Haley B
0000-0003-2760-3904
HB
Naik
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Kristin
0000-0002-1650-8269
K
Baird
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Daniel
D
Fowler
Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
David
0000-0001-5867-3265
D
Stroncek
Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
Edward W
EW
Cowen
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Steven Z
SZ
Pavletic
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Ronald E
RE
Gress
D000328:Adult; D017951:Antigen Presentation; D053264:B-Cell Activating Factor / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics; D054357:Chemokine CXCL10 / Q000378:metabolism; D002908:Chronic Disease; D000071457:DEAD Box Protein 58 / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D054367:Receptors, CXCR3 / Q000378:metabolism; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D014184:Transplantation, Homologous; D055815:Young Adult
D053264:B-Cell Activating Factor; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054367:Receptors, CXCR3; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; C495348:TLR7 protein, human; C505719:TNFSF13B protein, human; D051199:Toll-Like Receptor 7; D007372:Interferons; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58
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