ABSTRACT
A novel combination of tumors was found in a 68 year-old female with Multiple Endocrine Neoplasia type-1 (MEN 1) that included a cystic pancreatic endocrine neoplasm (CPEN), a pituitary adenoma, and multifocal cholesterol granulomas (MCGs) in the breast, pleura, and the extremities. The pancreatic tumor displayed a single central locule surrounded by a thin rim of neoplastic parenchyma. The tumor showed heterogeneity in the architecture that included glandular, trabecular and solid patterns. The tumor cells of the pancreas were immunohistochemically positive for both endocrine and pancreatic acinar markers including chromogranin A, synaptophysin, glucagon, lipase, and reg protein. Electron microscopy revealed that there were numerous smaller dense-cored neurosecretory granules, larger zymogen-like granules and microvilli on the apical side of the tumor cells. The pancreatic tumor was diagnosed as CPEN with acinar cell features. Analysis of the DNA extracted from the tissues revealed that there is a MEN1 germline mutation in exon 10 codon 527, and somatic mutation in exon 2 codon 32 in the pancreatic tumor, and one base pair deletion in exon 2 codon 79 in the pituitary adenoma. Here, we report the case and discuss possible pathogenesis of CPEN and MCGs in a patient with MEN 1.
Subject(s)
Adenoma/pathology , Breast Neoplasms/pathology , Cholesterol , Granuloma, Foreign-Body/pathology , Multiple Endocrine Neoplasia Type 1/pathology , Pancreas/pathology , Pancreatic Neoplasms/pathology , Pituitary Neoplasms/pathology , Adenoma/genetics , Aged , Breast Neoplasms/genetics , Female , Granuloma, Foreign-Body/genetics , Humans , Immunohistochemistry , Multiple Endocrine Neoplasia Type 1/genetics , Mutation , Pancreatic Neoplasms/genetics , Pituitary Neoplasms/genetics , Proto-Oncogene Proteins/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
PURPOSE: To identify the genetic basis of Schnyder crystalline corneal dystrophy (SCCD) through screening of positional candidate genes in affected patients. METHODS: Mutation screening of fifteen genes (CORT, CLSTN1, CTNNBIP1, DFFA, ENO1, GPR157, H6PD, KIF1B, LOC440559, LZIC, MGC4399, PEX14, PGD, PIK3CD, and SSB1) that lie within the candidate gene region for SCCD was performed in members of two families affected with SCCD. RESULTS: No presumed disease-causing mutations were identified in affected patients. Seventeen previously described single nucleotide polymorphisms (SNPs) were identified in eight of the candidate genes. Novel SNPs were identified in both affected and unaffected individuals in GPR157 (c.795C>T [Arg218Leu]; c.811C>T [Ala223Val]), MGC4399 (c.1024G>C [Leu277Leu]), and H6PD (c.754A>C [Asp151Ala]). CONCLUSIONS: No pathogenic mutations were identified in fifteen positional candidate genes in two families with SCCD. As the candidate gene region in each SCCD family previously examined with haplotype analysis has been mapped to the same chromosomal region, the absence of pathogenic mutations in these positional candidates in the families we examined reduces the number of remaining positional candidate genes by half, and the number of remaining candidate genes with a known gene function by two-thirds. We anticipate that screening of the remaining positional candidate genes will lead to the identification of the genetic basis of SCCD.
Subject(s)
Corneal Dystrophies, Hereditary/genetics , Eye Proteins/genetics , Adolescent , Adult , Child , Cholesterol/metabolism , Corneal Dystrophies, Hereditary/metabolism , Corneal Opacity/genetics , Corneal Opacity/metabolism , Corneal Stroma/metabolism , Corneal Stroma/pathology , DNA Mutational Analysis , Female , Genetic Markers , Granuloma, Foreign-Body/genetics , Granuloma, Foreign-Body/metabolism , Humans , Male , Middle Aged , Pedigree , Polymorphism, Single NucleotideABSTRACT
CCR8 was initially described as a Th2 cell-restricted receptor, but this has not been fully tested in vivo. The present study used ex vivo and in vivo approaches to examine the distribution and functional significance of CCR8 among CD4+ T cells. Populations of cytokine-secreting CD4+ T cells were generated in primed mice with Th1 or Th2 cell-mediated pulmonary granulomas, respectively elicited by i.v. challenge with either Mycobacteria bovis purified protein derivative- or Schistosoma mansoni egg Ag (SEA)-coated beads. Cytokine-producing CD4+ T cells were isolated from Ag-stimulated draining lymph node cultures by positive selection. Quantitative analysis of cytokine mRNA indicated enriched populations of IFN-gamma-, IL-4-, and IL-10-producing cells. Analysis of chemokine receptor mRNA indicated that IL-10+ cells selectively expressed CCR8 in the SEA bead-elicited type 2 response. The IL-10+CCR8+ populations were CD25+ and CD44+ but lacked enhanced Foxp3 expression. Adoptive transfer to naive recipients indicated that IL-10+ T cells alone could not transfer type 2 inflammation. Analysis of SEA bead-challenged CCR8-/- mice indicated significantly impaired IL-10 production as well as reductions in granuloma eosinophils. Adoptive transfer of CD4+CCR8+/+ T cells corrected cytokine and inflammation defects, but the granuloma eosinophil recruitment defect persisted when donor cells were depleted of IL-10+ cells. Accordingly, local IL-10 production correlated with CCR8 ligand (CCL1) expression and the appearance of CCR8+ cells in granulomatous lungs. Thus, IL-10-producing, CCR8+CD4+CD25+CD44+ T cells are generated during SEA challenge, which augment the Th2-mediated eosinophil-rich response to the parasite Ags.
Subject(s)
Antigens, Helminth/administration & dosage , CD4-Positive T-Lymphocytes/immunology , Cytokines/biosynthesis , Granuloma, Foreign-Body/immunology , Interleukin-10/biosynthesis , Receptors, Interleukin-2/biosynthesis , T-Lymphocytes, Regulatory/immunology , Th2 Cells/immunology , Adoptive Transfer , Animals , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/transplantation , Cells, Cultured , Chemokine CCL1 , Chemokines, CC/biosynthesis , Cytokines/deficiency , Cytokines/genetics , DNA-Binding Proteins/biosynthesis , Female , Forkhead Transcription Factors , Granuloma, Foreign-Body/genetics , Granuloma, Foreign-Body/pathology , Hyaluronan Receptors/biosynthesis , Hypersensitivity, Delayed/immunology , Hypersensitivity, Delayed/pathology , Interleukin-10/physiology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Lymph Nodes/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Knockout , Microspheres , Receptors, CCR8 , Schistosoma mansoni/immunology , T-Lymphocytes, Regulatory/metabolism , Th2 Cells/parasitology , Th2 Cells/pathologyABSTRACT
The granuloma formation is a host defense response against persistent irritants. Osteopontin is centrally involved in the formation of granulomas. Three osteopontin alleles, designated a, b, and c, have been found in mice. Here we used a murine model of zymosan (beta-glucan)-induced granuloma formation in the liver to determine possible functional differences between the osteopontin alleles in cell-mediated immunity. In contrast to mice with alleles a or c, mice with the allele b was defective in granuloma formation. As detected by mRNA expression, cytokines and chemokines known to be critically involved in granuloma formation were elicited in liver tissue, regardless of the osteopontin allele expressed. Alignment of the deduced amino acid sequences showed that unlike osteopontin c, b differs from a in 11 amino acids. All three osteopontin alleles had normal cell-binding properties. However, only the b allelic form was defective in the induction of cell migration as tested with dendritic cells. In conclusion, generation of a granulomatous response in mice depends critically on the presence of a functional osteopontin allele. Defective granuloma formation in mice with allele b is likely to be because of an impaired chemotactic function of the osteopontin b protein on immunocompetent cells.