title: Splenic extrafollicular reactions and BM plasma cells sustain IgM response associated with hypercholesterolemia.
abstract: Hypercholesterolemia associated with atherosclerotic disease is known to be associated with increased total and oxidized (ox) low-density lipoprotein (LDL)-specific IgM antibodies in circulation. However, the B-cell responses accounting for this increase remain to be elucidated. Here, we observed an association between total IgM and oxLDL-specific IgM autoantibodies with cholesterol in the plasma of hypercholesterolemic apolipoprotein E deficient (apoE(-/-)) mice. Our findings also indicated that oxLDL-specific IgM autoantibodies production was restricted to the spleen, but not the lymph nodes. Further examination of the spleen revealed that the extrafollicular responses, but not germinal center reactions, were the dominant antibody-producing pathway. A quiescent population of IgM(+) plasma cells including oxLDL-specific IgM antibody secreting cells in BM also sustained the elevated IgM antibodies response in circulation. We determined that IgM(+) plasma cells in the BM were, at least in part, splenic derived by depleting CD11c(+) DCs and plasmablasts to disrupt the humoral responses. In addition, lowering hypercholesterolemia reduced IgM response by interfering with extrafollicular and BM responses. By elucidating the mechanism underlying the elevated IgM response observed in hypercholesterolemia, this study provides insight into novel immunotherapeutic avenues.
authors: Department of Microbiology, Immunology Programme, National University of Singapore, Singapore.|Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore.
authors: Lawrence Han Boon
authors: LH
authors: Khoo
authors: Department of Microbiology, Immunology Programme, National University of Singapore, Singapore.
authors: Chung Hwee
authors: CH
authors: Thiam
authors: Department of Microbiology, Immunology Programme, National University of Singapore, Singapore.
authors: Serena Ying
authors: SY
authors: Soh
authors: Department of Microbiology, Immunology Programme, National University of Singapore, Singapore.
authors: Véronique
authors: V
authors: Angeli
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000150:complications / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood; D001384:Azetidines / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D000069438:Ezetimibe; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000276:immunology*; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000097:blood; D008077:Lipoproteins, LDL / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D001323:Autoantibodies; D001384:Azetidines; D007075:Immunoglobulin M; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D000069438:Ezetimibe
keywords: Antibodies; Extrafollicular responses; Hypercholesterolemia; Plasma cells; Spleen