Hypomorphic mutation in the RAG2 gene affects dendritic cell distribution and migration

Research output: Contribution to journalArticle

Abstract

OS is a severe combined immunodeficiency characterized by erythrodermia and protracted diarrhea as a result of infiltration of oligoclonal-activated T cells, caused by hypomorphic mutations in RAGs. The RAG2R229Q mouse model fully recapitulates the clinical OS phenotype. We evaluated whether T and B cell defects, together with the abnormal lymphoid structure, could affect DC homeostasis and function. High density of LCs was observed in skin biopsies of Omenn patients and in the derma of RAG2R229Q mice, correlating with the presence of erythrodermia. In vivo models of cutaneous skin painting and CHS demonstrated a decreased migration of RAG2R229Q DCs-in particular, LCs- into draining LNs. Interestingly, at steady state, RAG2R229Q mice showed a reduction in DC number in all hematopoietic organs except LNs. Analysis of the MHCII marker revealed a diminished expression also upon the LPS-driven inflammatory condition. Despite the decreased number of peripheral DCs, BM pre-cDCs were present in normal number compared with RAG2+/+ controls, whereas pDCs and monocytes were reduced significantly. Overall, these results point to a secondary defect in the DC compartment, which contributes to clinical manifestations and autoimmunity in OS.

Original languageEnglish
Pages (from-to)1221-1230
Number of pages10
JournalJournal of Leukocyte Biology
Volume94
Issue number6
DOIs
Publication statusPublished - Dec 2013

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Dendritic Cells
Cell Movement
Skin
Mutation
Genes
T-Lymphocytes
Severe Combined Immunodeficiency
Paintings
Autoimmunity
Monocytes
Diarrhea
Homeostasis
B-Lymphocytes
Phenotype
Biopsy

Keywords

  • Immune dysregulation
  • Omenn syndrome
  • Primary immunodeficiency

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

Cite this

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title = "Hypomorphic mutation in the RAG2 gene affects dendritic cell distribution and migration",
abstract = "OS is a severe combined immunodeficiency characterized by erythrodermia and protracted diarrhea as a result of infiltration of oligoclonal-activated T cells, caused by hypomorphic mutations in RAGs. The RAG2R229Q mouse model fully recapitulates the clinical OS phenotype. We evaluated whether T and B cell defects, together with the abnormal lymphoid structure, could affect DC homeostasis and function. High density of LCs was observed in skin biopsies of Omenn patients and in the derma of RAG2R229Q mice, correlating with the presence of erythrodermia. In vivo models of cutaneous skin painting and CHS demonstrated a decreased migration of RAG2R229Q DCs-in particular, LCs- into draining LNs. Interestingly, at steady state, RAG2R229Q mice showed a reduction in DC number in all hematopoietic organs except LNs. Analysis of the MHCII marker revealed a diminished expression also upon the LPS-driven inflammatory condition. Despite the decreased number of peripheral DCs, BM pre-cDCs were present in normal number compared with RAG2+/+ controls, whereas pDCs and monocytes were reduced significantly. Overall, these results point to a secondary defect in the DC compartment, which contributes to clinical manifestations and autoimmunity in OS.",
keywords = "Immune dysregulation, Omenn syndrome, Primary immunodeficiency",
author = "Virginia Maina and Veronica Marrella and Stefano Mantero and Barbara Cassani and Elena Fontana and Achille Anselmo and {Del Prete}, Annalisa and Silvano Sozzani and Paolo Vezzoni and Poliani, {Pietro Luigi} and Anna Villa",
year = "2013",
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T1 - Hypomorphic mutation in the RAG2 gene affects dendritic cell distribution and migration

AU - Maina, Virginia

AU - Marrella, Veronica

AU - Mantero, Stefano

AU - Cassani, Barbara

AU - Fontana, Elena

AU - Anselmo, Achille

AU - Del Prete, Annalisa

AU - Sozzani, Silvano

AU - Vezzoni, Paolo

AU - Poliani, Pietro Luigi

AU - Villa, Anna

PY - 2013/12

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N2 - OS is a severe combined immunodeficiency characterized by erythrodermia and protracted diarrhea as a result of infiltration of oligoclonal-activated T cells, caused by hypomorphic mutations in RAGs. The RAG2R229Q mouse model fully recapitulates the clinical OS phenotype. We evaluated whether T and B cell defects, together with the abnormal lymphoid structure, could affect DC homeostasis and function. High density of LCs was observed in skin biopsies of Omenn patients and in the derma of RAG2R229Q mice, correlating with the presence of erythrodermia. In vivo models of cutaneous skin painting and CHS demonstrated a decreased migration of RAG2R229Q DCs-in particular, LCs- into draining LNs. Interestingly, at steady state, RAG2R229Q mice showed a reduction in DC number in all hematopoietic organs except LNs. Analysis of the MHCII marker revealed a diminished expression also upon the LPS-driven inflammatory condition. Despite the decreased number of peripheral DCs, BM pre-cDCs were present in normal number compared with RAG2+/+ controls, whereas pDCs and monocytes were reduced significantly. Overall, these results point to a secondary defect in the DC compartment, which contributes to clinical manifestations and autoimmunity in OS.

AB - OS is a severe combined immunodeficiency characterized by erythrodermia and protracted diarrhea as a result of infiltration of oligoclonal-activated T cells, caused by hypomorphic mutations in RAGs. The RAG2R229Q mouse model fully recapitulates the clinical OS phenotype. We evaluated whether T and B cell defects, together with the abnormal lymphoid structure, could affect DC homeostasis and function. High density of LCs was observed in skin biopsies of Omenn patients and in the derma of RAG2R229Q mice, correlating with the presence of erythrodermia. In vivo models of cutaneous skin painting and CHS demonstrated a decreased migration of RAG2R229Q DCs-in particular, LCs- into draining LNs. Interestingly, at steady state, RAG2R229Q mice showed a reduction in DC number in all hematopoietic organs except LNs. Analysis of the MHCII marker revealed a diminished expression also upon the LPS-driven inflammatory condition. Despite the decreased number of peripheral DCs, BM pre-cDCs were present in normal number compared with RAG2+/+ controls, whereas pDCs and monocytes were reduced significantly. Overall, these results point to a secondary defect in the DC compartment, which contributes to clinical manifestations and autoimmunity in OS.

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KW - Omenn syndrome

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