Lauren Pachman1, Gabrielle Morgan2, Wilfredo Marin3, Sabah Kadri3, Kai Lee Yap3 and Amer Khojah4, 1Northwestern's Feinberg School of Medicine. Ann and Robert H. Lurie Children's Hospital of Chicago; Stanley Manne Children's Research Institute of Chicago, Lake Forest, IL, 2Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, IL, 3Ann & Robert H. Lurie Children's Hospital, Chicago, IL, 4Umm Al-Qura University, Makkah, Saudi Arabia
Background/Purpose: Juvenile Dermatomyositis (JDM) is a rare pediatric autoimmune disease characterized by proximal weakness and skin rash. Although the exact mechanism of JDM is not clear, the prevailing theory is a combination of environmental triggers and genetic susceptibility. Around 50 % of JDM subjects have a family history of autoimmune diseases such as systemic lupus erythematosus (SLE) and/or type 1 diabetes, suggesting a shared genetic predisposition. Monozygotic twins provide a unique opportunity to examine disease-specific genetic regulation.
Methods: 5 pairs of monozygotic twins were included in this IRB-approved (IRB #2008-13457) study at the Ann and Robert H. Lurie Children's Hospital of Chicago. Each twin set was discordant for juvenile dermatomyositis. Of note, in one twin pair, both children had developed concordant Mi-2 autoantibody, but only one twin fulfilled the criteria for JDM. We also included 5 age and gender-matched healthy control. Meso Scale Discovery® technique was used to measure the serum level of Interferon gamma-induced protein 10 (IP10) or CXCL10, Monocyte chemotactic protein-3 (MCP3), IL-17d, and angiopoietin 2 (Ang2), and endoglin. Three pairs of twins had their peripheral blood mononuclear cells (PBMCs) tested by RNASeq and one of the pair had whole-genome sequencing (WGS), along with their parents
Results: Three of the 5 sets of monozygotic twins were female. The age ranged from 3.29 years to 13.6 years, with the duration of untreated disease (DUD) ranging from 1.0 months to 11.5 months. As expected, the JDM twin had significantly lower nailfold capillary end row loops (ERL) than the healthy control but, to our surprise, 2 of the non-JDM twins had decreased ERL as well. The serum endoglin was significantly lower in both JDM-twins and non-JDM twins than in the healthy control. Other cytokines did not differ significantly which could be due to the small sample size. The RNASeq of 3 pairs of twins identified 4 genes that were differentially expressed between the JDM twins (case) compared with the non-JDM twins (control). These genes are Dermcidin (DCD), Keratin 14 (KRT14), Collagen Type I Alpha 1 Chain (COL1A1), and Collagen Type III Alpha 1 Chain (COL3A1). WGS did not identify any clinically significant variants that could be potentially related to their JDM phenotype
Conclusion: Monozygotic twins provide a unique opportunity to assess differential gene expression. The JDM twins had higher mRNA expression of DCD, KRT14, COL1A1, and COL3A1 than non-JDM twins. DCD and KRT14 are associated with other rare hereditary skin diseases such as Netherton Syndrome and epidermolysis bullosa simplex control. Both genes are almost exclusively expressed in skin tissue in healthy individuals. Therefore, the increased expression could be due to the presence of damaged skin cells in the circulation or represent a clue concerning an unknown disease process related to JDM. Soluble endoglin, an antiangiogenic molecule that binds to TGF-β, was lower in both the JDM twin and the healthy twin control which could suggest increased angiogenesis due to vascular damage, as manifest by loss of nailfold ER in both the JDM twin and their presumably healthy twin control.
Disclosures: L. Pachman, None; G. Morgan, None; W. Marin, None; S. Kadri, AbbVie/Abbott; K. Yap, None; A. Khojah, None.
