Artery Tertiary Lymphoid Organs Control Multilayered Territorialized Atherosclerosis B-Cell Responses in Aged ApoE-/- Mice.
Explore aorta B-cell immunity in aged apolipoprotein E-deficient (ApoE(-/-)) mice.



Transcript maps, fluorescence-activated cell sorting, immunofluorescence analyses, cell transfers, and Ig-ELISPOT (enzyme-linked immunospot) assays showed multilayered atherosclerosis B-cell responses in artery tertiary lymphoid organs (ATLOs). Aging-associated aorta B-cell-related transcriptomes were identified, and transcript atlases revealed highly territorialized B-cell responses in ATLOs versus atherosclerotic lesions: ATLOs showed upregulation of bona fide B-cell genes, including Cd19, Ms4a1 (Cd20), Cd79a/b, and Ighm although intima plaques preferentially expressed molecules involved in non-B effector responses toward B-cell-derived mediators, that is, Fcgr3 (Cd16), Fcer1g (Cd23), and the C1q family. ATLOs promoted B-cell recruitment. ATLO B-2 B cells included naive, transitional, follicular, germinal center, switched IgG1(+), IgA(+), and IgE(+) memory cells, plasmablasts, and long-lived plasma cells. ATLOs recruited large numbers of B-1 cells whose subtypes were skewed toward interleukin-10(+) B-1b cells versus interleukin-10(-) B-1a cells. ATLO B-1 cells and plasma cells constitutively produced IgM and IgG and a fraction of plasma cells expressed interleukin-10. Moreover, ApoE(-/-) mice showed increased germinal center B cells in renal lymph nodes, IgM-producing plasma cells in the bone marrow, and higher IgM and anti-MDA-LDL (malondialdehyde-modified low-density lipoprotein) IgG serum titers.



ATLOs orchestrate dichotomic, territorialized, and multilayered B-cell responses in the diseased aorta; germinal center reactions indicate generation of autoimmune B cells within the diseased arterial wall during aging.
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Prasad
P
Srikakulapu
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Desheng
D
Hu
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Changjun
C
Yin
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Sarajo K
SK
Mohanta
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Sai Vineela
SV
Bontha
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Li
L
Peng
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Michael
M
Beer
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Christian
C
Weber
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Coleen A
CA
McNamara
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Gianluca
G
Grassia
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Pasquale
P
Maffia
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.).
Rudolf A
RA
Manz
From the Cardiovascular Research Center, Department of Medicine (P.S., C.A.M.), Department of Surgery (S.V.B.), University of Virginia, Charlottesville; Institute for Immunology (D.H.) and Institute for Cardiovascular Prevention (C.Y., S.K.M., C.W., A.J.R.H.), Ludwig-Maximilians-University, Munich, Germany; Institute of Molecular Immunology, Helmholtz-Zentrum München, Oberschleißheim, Germany (D.H.); Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany (M.B.); Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.G., P.M.); BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M.); Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (R.A.M.); and Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen University, Xiamen, China (L.P.). andreas.habenicht@med.uni-muenchen.de.
Andreas J R
AJ
Habenicht
D000375:Aging / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D007136:Immunoglobulins / Q000097:blood; D007156:Immunologic Memory; D008077:Lipoproteins, LDL / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000031:analogs & derivatives / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D000072717:Tertiary Lymphoid Structures / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome
D001057:Apolipoproteins E; D001323:Autoantibodies; D016207:Cytokines; D007136:Immunoglobulins; D008077:Lipoproteins, LDL; C502964:malondialdehyde-low density lipoprotein, mouse; D008315:Malondialdehyde
B-lymphocytes; aging; atherosclerosis; germinal center; inflammation