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CXCR3 Blockade Inhibits T Cell Migration into the Skin and Prevents Development of Alopecia Areata
Dai, Zhenpeng; Xing, Luzhou; Cerise, Jane; Wang, Eddy Hsi Chun; Jabbari, Ali; de Jong, Annemieke; Petukhova, Lynn; Christiano, Angela M; Clynes, Raphael
Alopecia areata (AA) is an autoimmune disease of the hair follicle that results in hair loss of varying severity. Recently, we showed that IFN-γ-producing NKG2D(+)CD8(+) T cells actively infiltrate the hair follicle and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN-inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN-inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demonstrate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking Abs to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D(+)CD8(+) T cells in the skin and cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN-inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small-molecule inhibition, the latter being particularly intriguing as a topical therapeutic.
PMCID:5031416
PMID: 27412416
ISSN: 1550-6606
CID: 5710462
Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation
Do, Catherine; Lang, Charles F; Lin, John; Darbary, Huferesh; Krupska, Izabela; Gaba, Aulona; Petukhova, Lynn; Vonsattel, Jean-Paul; Gallagher, Mary P; Goland, Robin S; Clynes, Raphael A; Dwork, Andrew; Kral, John G; Monk, Catherine; Christiano, Angela M; Tycko, Benjamin
Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders. Targeted bis-seq confirmed hap-ASM in 12/13 loci tested, including CCDC155, CD69, FRMD1, IRF1, KBTBD11, and S100A( *)-ILF2, associated with immune phenotypes, MYT1L, PTPRN2, CMTM8 and CELF2, associated with neurological disorders, NGFR and HLA-DRB6, associated with both immunological and brain disorders, and ZFP57, a trans-acting regulator of genomic imprinting. Polymorphic CTCF and transcription factor (TF) binding sites were over-represented among hap-ASM DMRs and mQTLs, and analysis of the human data, supplemented by cross-species comparisons to macaques, indicated that CTCF and TF binding likelihood predicts the strength and direction of the allelic methylation asymmetry. These results show that hap-ASM is highly tissue specific; an important trans-acting regulator of genomic imprinting is regulated by this phenomenon; and variation in CTCF and TF binding sites is an underlying mechanism, and maps of hap-ASM and mQTLs reveal regulatory sequences underlying supra- and sub-threshold GWAS peaks in immunological and neurological disorders.
PMCID:4863666
PMID: 27153397
ISSN: 1537-6605
CID: 2504832
Functional Interpretation of Genome-Wide Association Study Evidence in Alopecia Areata [Letter]
Petukhova, Lynn; Christiano, Angela M
PMCID:4870380
PMID: 26763452
ISSN: 1523-1747
CID: 5710442
Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci
Betz, Regina C.; Petukhova, Lynn; Ripke, Stephan; Huang, Hailiang; Menelaou, Androniki; Redler, Silke; Becker, Tim; Heilmann, Stefanie; Yamany, Tarek; Duvic, Madeliene; Hordinsky, Maria; Norris, David; Price, Vera H.; Mackay-Wiggan, Julian; de Jong, Annemieke; DeStefano, Gina M.; Moebus, Susanne; Boehm, Markus; Blume-Peytavi, Ulrike; Wolff, Hans; Lutz, Gerhard; Kruse, Roland; Bian, Li; Amos, Christopher I.; Lee, Annette; Gregersen, Peter K.; Blaumeiser, Bettina; Altshuler, David; Clynes, Raphael; de Bakker, Paul I. W.; Noethen, Markus M.; Daly, Mark J.; Christiano, Angela M.
ISI:000348811100010
ISSN: 2041-1723
CID: 5713742
Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition
Xing, Luzhou; Dai, Zhenpeng; Jabbari, Ali; Cerise, Jane E; Higgins, Claire A; Gong, Weijuan; de Jong, Annemieke; Harel, Sivan; DeStefano, Gina M; Rothman, Lisa; Singh, Pallavi; Petukhova, Lynn; Mackay-Wiggan, Julian; Christiano, Angela M; Clynes, Raphael
Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies. Genome-wide association studies (GWAS) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8(+)NKG2D(+) T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ-producing CD8(+)NKG2D(+) effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rβ) prevented disease development, reducing the accumulation of CD8(+)NKG2D(+) T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.
PMID: 25129481
ISSN: 1546-170x
CID: 5710432
FGF5 is a crucial regulator of hair length in humans
Higgins, Claire A; Petukhova, Lynn; Harel, Sivan; Ho, Yuan Y; Drill, Esther; Shapiro, Lawrence; Wajid, Muhammad; Christiano, Angela M
Mechanisms that regulate the growth of eyelashes have remained obscure. We ascertained two families from Pakistan who presented with familial trichomegaly, or extreme eyelash growth. Using a combination of whole exome sequencing and homozygosity mapping, we identified distinct pathogenic mutations within fibroblast growth factor 5 (FGF5) that underlie the disorder. Subsequent sequencing of this gene in several additional trichomegaly families identified an additional mutation in FGF5. We further demonstrated that hair fibers from forearms of these patients were significantly longer than hairs from control individuals, with an increased proportion in the growth phase, anagen. Using hair follicle organ cultures, we show that FGF5 induces regression of the human hair follicle. We have identified FGF5 as a crucial regulator of hair growth in humans for the first time, to our knowledge, and uncovered a therapeutic target to selectively regulate eyelash growth.
PMCID:4115575
PMID: 24989505
ISSN: 1091-6490
CID: 5710422
Identification of distinct mutations in AAGAB in families with type 1 punctate palmoplantar keratoderma [Letter]
Furniss, Megan; Higgins, Claire A; Martinez-Mir, Amalia; Horev, Liran; Petukhova, Lynn; Stanimirović, Andrija; Miljković, Jovan; Zlotogorski, Abraham; Christiano, Angela M
PMCID:4870379
PMID: 24390136
ISSN: 1523-1747
CID: 5710412
The genetic architecture of alopecia areata
Petukhova, Lynn; Christiano, Angela M
A major impetus to initiating the Human Genome Project was the belief that information encoded in the human genome would "accelerate progress in understanding disease pathogenesis and in developing new approaches to diagnosis, treatment, and prevention in many areas of medicine". Alopecia areata (AA) is a notable example of how understanding the genetic basis of a disease can have an impact on the care of patients in a relatively short time. Our first genome-wide association study in AA identified an initial set of common variants that increase risk of AA, some of which are shared with other autoimmune diseases. Thus, there has already been rapid progress in the translation of this information into new therapeutic strategies for patients, as drugs are already on the market for some of these disorders that can now be tested in AA. Informed by the progress achieved with genetic studies for mechanistically aligned autoimmune diseases, we are poised to carry this work forward and interrogate the underlying disease mechanisms in AA. Importantly, future genetic studies aimed at identifying additional susceptibility genes will further establish the foundation for the application of precision medicine in the care of AA patients.
PMID: 24326542
ISSN: 1529-1774
CID: 5710402
Autosomal recessive gingival hyperplasia and dental anomalies caused by a 29-base pair duplication in the FAM20A gene [Letter]
Cabral, Rita M; Kurban, Mazen; Rothman, Lisa; Wajid, Muhammad; Shimomura, Yutaka; Petukhova, Lynn; Christiano, Angela M
PMID: 23697977
ISSN: 1435-232x
CID: 5710392
Position effect on FGF13 associated with X-linked congenital generalized hypertrichosis
DeStefano, Gina M; Fantauzzo, Katherine A; Petukhova, Lynn; Kurban, Mazen; Tadin-Strapps, Marija; Levy, Brynn; Warburton, Dorothy; Cirulli, Elizabeth T; Han, Yujun; Sun, Xiaoyun; Shen, Yufeng; Shirazi, Maryam; Jobanputra, Vaidehi; Cepeda-Valdes, Rodrigo; Cesar Salas-Alanis, Julio; Christiano, Angela M
X-linked congenital generalized hypertrichosis (Online Mendelian Inheritance in Man 307150) is an extremely rare condition of hair overgrowth on different body sites. We previously reported linkage in a large Mexican family with X-linked congenital generalized hypertrichosis cosegregating with deafness and with dental and palate anomalies to Xq24-27. Using SNP oligonucleotide microarray analysis and whole-genome sequencing, we identified a 389-kb interchromosomal insertion at an extragenic palindrome site at Xq27.1 that completely cosegregates with the disease. Among the genes surrounding the insertion, we found that Fibroblast Growth Factor 13 (FGF13) mRNA levels were significantly reduced in affected individuals, and immunofluorescence staining revealed a striking decrease in FGF13 localization throughout the outer root sheath of affected hair follicles. Taken together, our findings suggest a role for FGF13 in hair follicle growth and in the hair cycle.
PMCID:3651487
PMID: 23603273
ISSN: 1091-6490
CID: 5710382