OBJECTIVE: Immune-mediated destruction of hematopoietic stem and progenitor cells is pathophysiologic in most cases of aplastic anemia (AA). We have successfully determined the gene expression profile of the marrow CD34+ target cells in AA. T cells producing IFN-gamma and TNF-alpha have been implicated in hematopoietic destruction in AA. We sought to characterize T cells as immune mediators using the microarray approach. MATERIALS AND METHODS: We applied Affymetrix GeneChip techniques to determine the detailed profile of mRNA expression of CD4+ and CD8+ cells from the BM of newly diagnosed AA patients and healthy volunteers. For validation, we confirmed our microarray results using quantitative real-time PCR. RESULTS: Compared to healthy controls, there were 178 and 183 differentially expressed genes in patients' CD4+ cells and CD8+ T cells, respectively; activities of 22 selected genes were confirmed using real-time PCR. Dysregulated genes included those encoding cytokines/chemokines, and involved in transcription regulation, calcium and ion channel formation, and cell adhesion. Unexpected findings were overexpression of toll-like receptor genes in marrow CD4+ cells of patients and of genes for killer-cell immunoglobulin-like receptors (KIR) in AA marrow CD8+ cells. CONCLUSIONS: Our detailed results at the mRNA level provide insights into the mechanism of AA. Both innate and adaptive immune responses of CD4+ and CD8+ T cells appear to be active in immune-mediated marrow destruction. A variety of cytokines and chemokines active in pathophysiologic cells likely play important roles in the recruitment and activation of lymphocytes to cytotoxic effectors for marrow hematopoietic target cells in AA.
OBJECTIVE: Immune-mediated destruction of hematopoietic stem and progenitor cells is pathophysiologic in most cases of aplastic anemia (AA). We have successfully determined the gene expression profile of the marrow CD34+ target cells in AA. T cells producing IFN-gamma and TNF-alpha have been implicated in hematopoietic destruction in AA. We sought to characterize T cells as immune mediators using the microarray approach. MATERIALS AND METHODS: We applied Affymetrix GeneChip techniques to determine the detailed profile of mRNA expression of CD4+ and CD8+ cells from the BM of newly diagnosed AA patients and healthy volunteers. For validation, we confirmed our microarray results using quantitative real-time PCR. RESULTS: Compared to healthy controls, there were 178 and 183 differentially expressed genes in patients' CD4+ cells and CD8+ T cells, respectively; activities of 22 selected genes were confirmed using real-time PCR. Dysregulated genes included those encoding cytokines/chemokines, and involved in transcription regulation, calcium and ion channel formation, and cell adhesion. Unexpected findings were overexpression of toll-like receptor genes in marrow CD4+ cells of patients and of genes for killer-cell immunoglobulin-like receptors (KIR) in AA marrow CD8+ cells. CONCLUSIONS: Our detailed results at the mRNA level provide insights into the mechanism of AA. Both innate and adaptive immune responses of CD4+ and CD8+ T cells appear to be active in immune-mediated marrow destruction. A variety of cytokines and chemokines active in pathophysiologic cells likely play important roles in the recruitment and activation of lymphocytes to cytotoxic effectors for marrow hematopoietic target cells in AA.
Authors: David M Gravano; Mufadhal Al-Kuhlani; Dan Davini; P Dominick Sanders; Jennifer O Manilay; Katrina K Hoyer Journal: J Autoimmun Date: 2016-07-21 Impact factor: 7.094
Authors: Kohei Hosokawa; Sachiko Kajigaya; Xingmin Feng; Marie J Desierto; Maria Del Pilar Fernandez Ibanez; Olga Rios; Barbara Weinstein; Phillip Scheinberg; Danielle M Townsley; Neal S Young Journal: Haematologica Date: 2016-09-22 Impact factor: 9.941