Targeted Deletion of fgl2 Leads to Impaired Regulatory T Cell Activity and Development of Autoimmune Glomerulonephritis
Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2-/- bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify th...
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| Veröffentlicht in: | The Journal of immunology (1950) 2008-01, Vol.180 (1), p.249-260 |
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| creator | Shalev, Itay Liu, Hao Koscik, Cheryl Bartczak, Agata Javadi, Mojib Wong, Kit Man Maknojia, Asif He, Wei Liu, Ming Feng Diao, Jun Winter, Erin Manuel, Justin McCarthy, Doug Cattral, Mark Gommerman, Jennifer Clark, David A Phillips, M. James Gorczynski, Reginald R Zhang, Li Downey, Greg Grant, David Cybulsky, Myron I Levy, Gary |
| description | Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2-/- bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2-/- mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2-/- mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcgammaRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease. |
| doi_str_mv | 10.4049/jimmunol.180.1.249 |
| format | Article |
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James ; Gorczynski, Reginald R ; Zhang, Li ; Downey, Greg ; Grant, David ; Cybulsky, Myron I ; Levy, Gary</creator><creatorcontrib>Shalev, Itay ; Liu, Hao ; Koscik, Cheryl ; Bartczak, Agata ; Javadi, Mojib ; Wong, Kit Man ; Maknojia, Asif ; He, Wei ; Liu, Ming Feng ; Diao, Jun ; Winter, Erin ; Manuel, Justin ; McCarthy, Doug ; Cattral, Mark ; Gommerman, Jennifer ; Clark, David A ; Phillips, M. James ; Gorczynski, Reginald R ; Zhang, Li ; Downey, Greg ; Grant, David ; Cybulsky, Myron I ; Levy, Gary</creatorcontrib><description>Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2-/- bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2-/- mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2-/- mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcgammaRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.180.1.249</identifier><identifier>PMID: 18097026</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Animals ; Antibodies - pharmacology ; Antigens, CD - metabolism ; Autoimmune Diseases - genetics ; Autoimmune Diseases - pathology ; B-Lymphocytes - immunology ; Body Weight - genetics ; Dendritic Cells - immunology ; Fibrinogen - antagonists & inhibitors ; Fibrinogen - genetics ; Fibrinogen - metabolism ; Gene Deletion ; Glomerulonephritis - genetics ; Glomerulonephritis - pathology ; Lymph Nodes - immunology ; Mice ; Mice, Mutant Strains ; Receptors, IgG - metabolism ; RNA, Messenger - analysis ; RNA, Messenger - metabolism ; Spleen - immunology ; T-Lymphocytes, Regulatory - immunology ; Thymus Gland - immunology</subject><ispartof>The Journal of immunology (1950), 2008-01, Vol.180 (1), p.249-260</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c407t-5a819b0c3eb5a69d69478db7cd10f8e42540ed178ebfd18f286a84db283108383</citedby><cites>FETCH-LOGICAL-c407t-5a819b0c3eb5a69d69478db7cd10f8e42540ed178ebfd18f286a84db283108383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18097026$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shalev, Itay</creatorcontrib><creatorcontrib>Liu, Hao</creatorcontrib><creatorcontrib>Koscik, Cheryl</creatorcontrib><creatorcontrib>Bartczak, Agata</creatorcontrib><creatorcontrib>Javadi, Mojib</creatorcontrib><creatorcontrib>Wong, Kit Man</creatorcontrib><creatorcontrib>Maknojia, Asif</creatorcontrib><creatorcontrib>He, Wei</creatorcontrib><creatorcontrib>Liu, Ming Feng</creatorcontrib><creatorcontrib>Diao, Jun</creatorcontrib><creatorcontrib>Winter, Erin</creatorcontrib><creatorcontrib>Manuel, Justin</creatorcontrib><creatorcontrib>McCarthy, Doug</creatorcontrib><creatorcontrib>Cattral, Mark</creatorcontrib><creatorcontrib>Gommerman, Jennifer</creatorcontrib><creatorcontrib>Clark, David A</creatorcontrib><creatorcontrib>Phillips, M. 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Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2-/- mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2-/- mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcgammaRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease.</description><subject>Animals</subject><subject>Antibodies - pharmacology</subject><subject>Antigens, CD - metabolism</subject><subject>Autoimmune Diseases - genetics</subject><subject>Autoimmune Diseases - pathology</subject><subject>B-Lymphocytes - immunology</subject><subject>Body Weight - genetics</subject><subject>Dendritic Cells - immunology</subject><subject>Fibrinogen - antagonists & inhibitors</subject><subject>Fibrinogen - genetics</subject><subject>Fibrinogen - metabolism</subject><subject>Gene Deletion</subject><subject>Glomerulonephritis - genetics</subject><subject>Glomerulonephritis - pathology</subject><subject>Lymph Nodes - immunology</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Receptors, IgG - metabolism</subject><subject>RNA, Messenger - analysis</subject><subject>RNA, Messenger - metabolism</subject><subject>Spleen - immunology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Thymus Gland - immunology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcGO0zAQhi0EYrsLL8AB-cQtZew6jnOsyrKsVAkJlbPlJJPWKycutrNR3x6X7apHTnP5_m9G8xPyicFSgKi_PtlhmEbvlkzBki25qN-QBStLKKQE-ZYsADgvWCWrG3Ib4xMASODiPbnJgboCLhdk3pmwx4Qd_YYOk_Uj9T3t947TLZou0uTp43A0NmTkF-4nZ5IPJ7qjG3SOrttkn206UTOeDc_o_HHAMZ0l6yn5fxcifXB-wDA5P-LxEGyy8QN51xsX8eNl3pHf3-93mx_F9ufD42a9LVoBVSpKo1jdQLvCpjSy7mQtKtU1Vdsx6BUKXgrAjlUKm75jqudKGiW6hqsVA7VSqzvy5cV7DP7PhDHpwcY2n25G9FPUFbCSQ83-C3IQpcxsBvkL2AYfY8BeH4MdTDhpBvrci37tRec3a6ZzLzn0-WKfmgG7a-RSxHX9we4Pc_62joNxLuNMz_N8Nf0FdFSZ1g</recordid><startdate>20080101</startdate><enddate>20080101</enddate><creator>Shalev, Itay</creator><creator>Liu, Hao</creator><creator>Koscik, Cheryl</creator><creator>Bartczak, Agata</creator><creator>Javadi, Mojib</creator><creator>Wong, Kit Man</creator><creator>Maknojia, Asif</creator><creator>He, Wei</creator><creator>Liu, Ming Feng</creator><creator>Diao, Jun</creator><creator>Winter, Erin</creator><creator>Manuel, Justin</creator><creator>McCarthy, Doug</creator><creator>Cattral, Mark</creator><creator>Gommerman, Jennifer</creator><creator>Clark, David A</creator><creator>Phillips, M. 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James</au><au>Gorczynski, Reginald R</au><au>Zhang, Li</au><au>Downey, Greg</au><au>Grant, David</au><au>Cybulsky, Myron I</au><au>Levy, Gary</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted Deletion of fgl2 Leads to Impaired Regulatory T Cell Activity and Development of Autoimmune Glomerulonephritis</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2008-01-01</date><risdate>2008</risdate><volume>180</volume><issue>1</issue><spage>249</spage><epage>260</epage><pages>249-260</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2-/- bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2-/- mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2-/- mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcgammaRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>18097026</pmid><doi>10.4049/jimmunol.180.1.249</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antibodies - pharmacology Antigens, CD - metabolism Autoimmune Diseases - genetics Autoimmune Diseases - pathology B-Lymphocytes - immunology Body Weight - genetics Dendritic Cells - immunology Fibrinogen - antagonists & inhibitors Fibrinogen - genetics Fibrinogen - metabolism Gene Deletion Glomerulonephritis - genetics Glomerulonephritis - pathology Lymph Nodes - immunology Mice Mice, Mutant Strains Receptors, IgG - metabolism RNA, Messenger - analysis RNA, Messenger - metabolism Spleen - immunology T-Lymphocytes, Regulatory - immunology Thymus Gland - immunology |
| title | Targeted Deletion of fgl2 Leads to Impaired Regulatory T Cell Activity and Development of Autoimmune Glomerulonephritis |
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