Artery tertiary lymphoid organs control multilayered territorialized atherosclerosis B-cell responses in Aged ApoE-/- mice

Prasad Srikakulapu, Desheng Hu, Changjun Yin, Sarajo K. Mohanta, Sai Vineela Bontha, Li Peng, Michael Beer, Christian Weber, Coleen A. McNamara, Gianluca Grassia, Pasquale Maffia, Rudolf A. Manz, Andreas J.R. Habenicht

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Abstract

Objective - Explore aorta B-cell immunity in aged apolipoprotein E-deficient (ApoE-/-) mice. Approach and Results - 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. Conclusions - 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.

Original languageEnglish (US)
Pages (from-to)1174-1185
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Volume36
Issue number6
DOIs
StatePublished - Jun 1 2016

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Apolipoproteins E
Atherosclerosis
B-Lymphocytes
Arteries
Plasma Cells
Germinal Center
Interleukin-10
Aorta
Enzyme-Linked Immunospot Assay
Immunoglobulin G
Immunoglobulin M
Atlases
Malondialdehyde
LDL Lipoproteins
Transcriptome
Immunoglobulin A
Immunoglobulin E
Fluorescent Antibody Technique
Immunity
Flow Cytometry

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Artery tertiary lymphoid organs control multilayered territorialized atherosclerosis B-cell responses in Aged ApoE-/- mice. / Srikakulapu, Prasad; Hu, Desheng; Yin, Changjun; Mohanta, Sarajo K.; Bontha, Sai Vineela; Peng, Li; Beer, Michael; Weber, Christian; McNamara, Coleen A.; Grassia, Gianluca; Maffia, Pasquale; Manz, Rudolf A.; Habenicht, Andreas J.R.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 36, No. 6, 01.06.2016, p. 1174-1185.

Research output: Contribution to journalArticle

Srikakulapu, P, Hu, D, Yin, C, Mohanta, SK, Bontha, SV, Peng, L, Beer, M, Weber, C, McNamara, CA, Grassia, G, Maffia, P, Manz, RA & Habenicht, AJR 2016, 'Artery tertiary lymphoid organs control multilayered territorialized atherosclerosis B-cell responses in Aged ApoE-/- mice', Arteriosclerosis, thrombosis, and vascular biology, vol. 36, no. 6, pp. 1174-1185. https://doi.org/10.1161/ATVBAHA.115.306983
Srikakulapu, Prasad ; Hu, Desheng ; Yin, Changjun ; Mohanta, Sarajo K. ; Bontha, Sai Vineela ; Peng, Li ; Beer, Michael ; Weber, Christian ; McNamara, Coleen A. ; Grassia, Gianluca ; Maffia, Pasquale ; Manz, Rudolf A. ; Habenicht, Andreas J.R. / Artery tertiary lymphoid organs control multilayered territorialized atherosclerosis B-cell responses in Aged ApoE-/- mice. In: Arteriosclerosis, thrombosis, and vascular biology. 2016 ; Vol. 36, No. 6. pp. 1174-1185.
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abstract = "Objective - Explore aorta B-cell immunity in aged apolipoprotein E-deficient (ApoE-/-) mice. Approach and Results - 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. Conclusions - 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.",
author = "Prasad Srikakulapu and Desheng Hu and Changjun Yin and Mohanta, {Sarajo K.} and Bontha, {Sai Vineela} and Li Peng and Michael Beer and Christian Weber and McNamara, {Coleen A.} and Gianluca Grassia and Pasquale Maffia and Manz, {Rudolf A.} and Habenicht, {Andreas J.R.}",
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AU - Srikakulapu, Prasad

AU - Hu, Desheng

AU - Yin, Changjun

AU - Mohanta, Sarajo K.

AU - Bontha, Sai Vineela

AU - Peng, Li

AU - Beer, Michael

AU - Weber, Christian

AU - McNamara, Coleen A.

AU - Grassia, Gianluca

AU - Maffia, Pasquale

AU - Manz, Rudolf A.

AU - Habenicht, Andreas J.R.

PY - 2016/6/1

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N2 - Objective - Explore aorta B-cell immunity in aged apolipoprotein E-deficient (ApoE-/-) mice. Approach and Results - 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. Conclusions - 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.

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