PMID- 25528552 OWN - NLM STAT- MEDLINE DCOM- 20151030 LR - 20181113 IS - 1750-1172 (Electronic) IS - 1750-1172 (Linking) VI - 9 DP - 2014 Dec 21 TI - Skin fibroblasts from individuals with Chediak-Higashi Syndrome (CHS) exhibit hyposensitive immunogenic response. PG - 212 LID - 10.1186/s13023-014-0212-7 [doi] LID - 212 AB - BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease characterized by immunodeficiency, oculocutaneous albinism, neurological dysfunction, and early death. Individuals with CHS present with increased susceptibility to infections of the skin, upper-respiratory tract, gastrointestinal tract, and oral tissues. Classical CHS is caused by mutations in the gene encoding lysosomal trafficking regulator (LYST). Although defects in cytotoxic T cell lytic secretory granule secretion and neutrophil phagocytosis are suggested to contribute to the immunodeficiency in CHS, the underlying molecular mechanisms are unknown. We hypothesized that skin fibroblasts from CHS subjects exhibit impaired immune response due to defective trafficking of inflammatory factors. METHODS AND RESULTS: Primary skin fibroblasts from CHS subjects or healthy controls were assessed for genes encoding inflammatory response factors using PCR array. At baseline, we found CD14, IL1R1 and TLR-1 were down-regulated significantly (>/=2 fold change) and the genes encoding TLR-3, IL-1beta and IL-6 were up-regulated in CHS cells compared to control cells. When challenged with E. coli lipopolysaccharide (LPS), CHS cells were less responsive than control cells, with only 8 genes significantly up-regulated (3-68 fold change) compared to baseline values, whereas 28 genes in control cells were significantly up-regulated at a much higher magnitude (3-4,629 fold change). In addition, 50% of the genes significantly up-regulated in LPS-treated control cells were significantly lower in LPS-treated CHS cells. IL-6, a fibroblast-derived proinflammatory cytokine essential for fighting infections was significantly lower in culture media of CHS cells with or without LPS. Furthermore, Western blot and immunofluorescent staining revealed that TLR-2 and TLR-4 were diminished on cell membranes of CHS cells and dissociated from Rab11a. CONCLUSIONS: For the first time, results from our study indicate defective trafficking of TLR-2 and TLR-4 contributes to the hyposensitive response of CHS skin fibroblasts to immunogenic challenge, providing a potential therapeutic target for clinical intervention in CHS. FAU - Wang, Le AU - Wang L AD - NIH/NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA. le.wang@nih.gov. FAU - Kantovitz, Kamila Rosamilia AU - Kantovitz KR AD - NIH/NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA. kamilark@yahoo.com.br. AD - University of Campinas - Piracicaba Dental School, Piracicaba, Sao Paulo, Brazil. kamilark@yahoo.com.br. FAU - Cullinane, Andrew Robert AU - Cullinane AR AD - NIH/NHGRI - National Human Genome Research Institute, Bethesda, MD, USA. andrew.cullinane@nih.gov. FAU - Nociti, Francisco Humberto Jr AU - Nociti FH Jr AD - NIH/NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA. fhnociti@gmail.com. AD - University of Campinas - Piracicaba Dental School, Piracicaba, Sao Paulo, Brazil. fhnociti@gmail.com. FAU - Foster, Brian Lee AU - Foster BL AD - NIH/NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA. brian.foster@nih.gov. FAU - Roney, Joseph Concepcion AU - Roney JC AD - NIH/NHGRI - National Human Genome Research Institute, Bethesda, MD, USA. joseph.roney@nih.gov. FAU - Tran, Anne Bich AU - Tran AB AD - NIH/NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA. anne.tran2@nih.gov. FAU - Introne, Wendy Jewell AU - Introne WJ AD - NIH/NHGRI - National Human Genome Research Institute, Bethesda, MD, USA. wintrone@mail.nih.gov. FAU - Somerman, Martha Joan AU - Somerman MJ AD - NIH/NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA. martha.somerman@nih.gov. LA - eng GR - Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20141221 PL - England TA - Orphanet J Rare Dis JT - Orphanet journal of rare diseases JID - 101266602 SB - IM MH - Cells, Cultured MH - Chediak-Higashi Syndrome/*diagnosis/genetics/*immunology MH - Female MH - Fibroblasts/*immunology/pathology MH - Gene Expression Profiling/methods MH - Humans MH - Immunogenetic Phenomena/genetics/*immunology MH - Immunologic Deficiency Syndromes/diagnosis/genetics/immunology MH - Male MH - Skin/*immunology/pathology PMC - PMC4296684 EDAT- 2014/12/22 06:00 MHDA- 2015/10/31 06:00 PMCR- 2014/12/21 CRDT- 2014/12/22 06:00 PHST- 2014/08/13 00:00 [received] PHST- 2014/12/10 00:00 [accepted] PHST- 2014/12/22 06:00 [entrez] PHST- 2014/12/22 06:00 [pubmed] PHST- 2015/10/31 06:00 [medline] PHST- 2014/12/21 00:00 [pmc-release] AID - s13023-014-0212-7 [pii] AID - 212 [pii] AID - 10.1186/s13023-014-0212-7 [doi] PST - epublish SO - Orphanet J Rare Dis. 2014 Dec 21;9:212. doi: 10.1186/s13023-014-0212-7.