Hypomorphic mutation in the RAG2 gene affects dendritic cell distribution and migration.
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 RAG2(R229Q) 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 RAG2(R229Q) mice, correlating with the presence of erythrodermia. In vivo models of cutaneous skin painting and CHS demonstrated a decreased migration of RAG2(R229Q) DCs-in particular, LCs-into draining LNs. Interestingly, at steady state, RAG2(R229Q) 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.
1.via Manzoni 56, 20089, Rozzano (Milan), Italy. anna.villa@humanitasresearch.it.
Virginia
V
Maina
Veronica
V
Marrella
Stefano
S
Mantero
Barbara
B
Cassani
Elena
E
Fontana
Achille
A
Anselmo
Annalisa
A
Del Prete
Silvano
S
Sozzani
Paolo
P
Vezzoni
Pietro Luigi
PL
Poliani
Anna
A
Villa
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D003873:Dermatitis, Exfoliative / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020405:Dermis / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007801:Langerhans Cells / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; C499308:Rag2 protein, mouse
Omenn syndrome; immune dysregulation; primary immunodeficiency