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Published in: Immunity & Ageing 1/2021

Open Access 01-12-2021 | Human Immunodeficiency Virus | Research

Metabolic phenotype of B cells from young and elderly HIV individuals

Authors: Daniela Frasca, Suresh Pallikkuth, Savita Pahwa

Published in: Immunity & Ageing | Issue 1/2021

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Abstract

Background

HIV infection induces inflammaging and chronic immune activation (IA), which are negatively associated with protective humoral immunity. Similar to HIV, aging is also associated with increased inflammaging and IA. The metabolic requirements of B cell responses in HIV infected (HIV+) individuals are not known, although metabolic abnormalities have been reported in these individuals. How these metabolic abnormalities are exacerbated by aging is also not known.

Methods

B cells were isolated by magnetic sorting from the blood of young and elderly HIV + individuals, as well as from the blood of age-matched healthy controls. We evaluated the composition of the B cell pool by flow cytometry, the expression of RNA for pro-inflammatory and metabolic markers by qPCR and their metabolic status using a Seahorse XFp extracellular flux analyzer.

Results

In this study we have evaluated for the first time the metabolic phenotype of B cells from young and elderly HIV + individuals as compared to those obtained from age-matched healthy controls. Results show that the B cell pool of HIV + individuals is enriched in pro-inflammatory B cell subsets, expresses higher levels of RNA for pro-inflammatory markers and is hyper-metabolic, as compared to healthy controls, and more in elderly versus young HIV + individuals, suggesting that this higher metabolic phenotype of B cells is needed to support B cell IA. We have identified the subset of Double Negative (DN) B cells as the subset mainly responsible for this hyper-inflammatory and hyper-metabolic profile.

Conclusions

Our results identify a relationship between intrinsic B cell inflammation and metabolism in HIV + individuals and suggest that metabolic pathways in B cells from HIV + individuals may be targeted to reduce inflammaging and IA and improve B cell function and antibody responses.
Literature
1.
go back to reference Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54.CrossRef Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54.CrossRef
2.
go back to reference Deeks SG, Verdin E, McCune JM. Immunosenescence and HIV. Curr Opin Immunol. 2012;24(4):501–6.CrossRef Deeks SG, Verdin E, McCune JM. Immunosenescence and HIV. Curr Opin Immunol. 2012;24(4):501–6.CrossRef
3.
go back to reference Zicari S, Sessa L, Cotugno N, Ruggiero A, Morrocchi E, Concato C, Rocca S, Zangari P, Manno EC, Palma P. Immune activation, inflammation, and non-AIDS co-morbidities in HIV-infected patients under long-term ART. Viruses. 2019;11(3):200. https://doi.org/10.3390/v11030200. Zicari S, Sessa L, Cotugno N, Ruggiero A, Morrocchi E, Concato C, Rocca S, Zangari P, Manno EC, Palma P. Immune activation, inflammation, and non-AIDS co-morbidities in HIV-infected patients under long-term ART. Viruses. 2019;11(3):200. https://​doi.​org/​10.​3390/​v11030200.
4.
go back to reference Frasca D, Diaz A, Romero M, Blomberg BB. Human peripheral late/exhausted memory B cells express a senescent-associated secretory phenotype and preferentially utilize metabolic signaling pathways. Exp Gerontol. 2017;87(Pt A):113–20.CrossRef Frasca D, Diaz A, Romero M, Blomberg BB. Human peripheral late/exhausted memory B cells express a senescent-associated secretory phenotype and preferentially utilize metabolic signaling pathways. Exp Gerontol. 2017;87(Pt A):113–20.CrossRef
5.
go back to reference Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. High TNF-alpha levels in resting B cells negatively correlate with their response. Exp Gerontol. 2014;54:116–22.CrossRef Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. High TNF-alpha levels in resting B cells negatively correlate with their response. Exp Gerontol. 2014;54:116–22.CrossRef
6.
go back to reference Ahmed D, Roy D, Cassol E. Examining relationships between metabolism and persistent inflammation in HIV patients on antiretroviral therapy. Mediators Inflamm. 2018;2018:6238978. Ahmed D, Roy D, Cassol E. Examining relationships between metabolism and persistent inflammation in HIV patients on antiretroviral therapy. Mediators Inflamm. 2018;2018:6238978.
7.
go back to reference Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–90.CrossRef Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–90.CrossRef
8.
go back to reference Vitale G, Salvioli S, Franceschi C. Oxidative stress and the ageing endocrine system. Nat Rev Endocrinol. 2013;9(4):228–40.CrossRef Vitale G, Salvioli S, Franceschi C. Oxidative stress and the ageing endocrine system. Nat Rev Endocrinol. 2013;9(4):228–40.CrossRef
9.
go back to reference Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and ‘Garb-aging’. Trends Endocrinol Metab. 2017;28(3):199–212.CrossRef Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and ‘Garb-aging’. Trends Endocrinol Metab. 2017;28(3):199–212.CrossRef
10.
go back to reference Frasca D, Diaz A, Romero M, D’Eramo F, Blomberg BB. Aging effects on T-bet expression in human B cell subsets. Cell Immunol. 2017;321:68–73.CrossRef Frasca D, Diaz A, Romero M, D’Eramo F, Blomberg BB. Aging effects on T-bet expression in human B cell subsets. Cell Immunol. 2017;321:68–73.CrossRef
11.
go back to reference Rinaldi S, Pallikkuth S, George VK, de Armas LR, Pahwa R, Sanchez CM, Pallin MF, Pan L, Cotugno N, Dickinson G, et al. Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age. Aging. 2017;9(4):1307–25.CrossRef Rinaldi S, Pallikkuth S, George VK, de Armas LR, Pahwa R, Sanchez CM, Pallin MF, Pan L, Cotugno N, Dickinson G, et al. Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age. Aging. 2017;9(4):1307–25.CrossRef
12.
go back to reference Colonna-Romano G, Bulati M, Aquino A, Pellicano M, Vitello S, Lio D, Candore G, Caruso C. A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people. Mech Ageing Dev. 2009;130(10):681–90.CrossRef Colonna-Romano G, Bulati M, Aquino A, Pellicano M, Vitello S, Lio D, Candore G, Caruso C. A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people. Mech Ageing Dev. 2009;130(10):681–90.CrossRef
13.
go back to reference Nevalainen T, Autio A, Kummola L, Salomaa T, Junttila I, Jylha M, Hurme M. CD27- IgD- B cell memory subset associates with inflammation and frailty in elderly individuals but only in males. Immun Ageing. 2019;16:19.CrossRef Nevalainen T, Autio A, Kummola L, Salomaa T, Junttila I, Jylha M, Hurme M. CD27- IgD- B cell memory subset associates with inflammation and frailty in elderly individuals but only in males. Immun Ageing. 2019;16:19.CrossRef
14.
go back to reference Frasca D, Ferracci F, Diaz A, Romero M, Lechner S, Blomberg BB. Obesity decreases B cell responses in young and elderly individuals. Obesity (Silver Spring). 2016;24(3):615–25.CrossRef Frasca D, Ferracci F, Diaz A, Romero M, Lechner S, Blomberg BB. Obesity decreases B cell responses in young and elderly individuals. Obesity (Silver Spring). 2016;24(3):615–25.CrossRef
15.
go back to reference Adlowitz DG, Barnard J, Biear JN, Cistrone C, Owen T, Wang W, Palanichamy A, Ezealah E, Campbell D, Wei C, et al. Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of B cell depletion therapy, and biomarkers of response. PLoS One. 2015;10(6):e0128269. Adlowitz DG, Barnard J, Biear JN, Cistrone C, Owen T, Wang W, Palanichamy A, Ezealah E, Campbell D, Wei C, et al. Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of B cell depletion therapy, and biomarkers of response. PLoS One. 2015;10(6):e0128269.
16.
go back to reference Claes N, Fraussen J, Vanheusden M, Hellings N, Stinissen P, Van Wijmeersch B, Hupperts R, Somers V. Age-associated B cells with proinflammatory characteristics are expanded in a proportion of multiple sclerosis patients. J Immunol. 2016;197(12):4576–83. Claes N, Fraussen J, Vanheusden M, Hellings N, Stinissen P, Van Wijmeersch B, Hupperts R, Somers V. Age-associated B cells with proinflammatory characteristics are expanded in a proportion of multiple sclerosis patients. J Immunol. 2016;197(12):4576–83.
17.
go back to reference Golinski ML, Demeules M, Derambure C, Riou G, Maho-Vaillant M, Boyer O, Joly P, Calbo S. CD11c(+) B cells are mainly memory cells, precursors of antibody secreting cells in healthy donors. Front Immunol. 2020;11:32. Golinski ML, Demeules M, Derambure C, Riou G, Maho-Vaillant M, Boyer O, Joly P, Calbo S. CD11c(+) B cells are mainly memory cells, precursors of antibody secreting cells in healthy donors. Front Immunol. 2020;11:32.
18.
go back to reference Martorana A, Balistreri CR, Bulati M, Buffa S, Azzarello DM, Camarda C, Monastero R, Caruso C, Colonna-Romano G. Double negative (CD19 + IgG + IgD-CD27-) B lymphocytes: a new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer’s disease patients. Immunol Lett. 2014;162(1 Pt B):303–9.CrossRef Martorana A, Balistreri CR, Bulati M, Buffa S, Azzarello DM, Camarda C, Monastero R, Caruso C, Colonna-Romano G. Double negative (CD19 + IgG + IgD-CD27-) B lymphocytes: a new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer’s disease patients. Immunol Lett. 2014;162(1 Pt B):303–9.CrossRef
19.
go back to reference Saadoun D, Terrier B, Bannock J, Vazquez T, Massad C, Kang I, Joly F, Rosenzwajg M, Sene D, Benech P, et al. Expansion of autoreactive unresponsive CD21-/low B cells in Sjogren’s syndrome-associated lymphoproliferation. Arthritis Rheum. 2013;65(4):1085–96.CrossRef Saadoun D, Terrier B, Bannock J, Vazquez T, Massad C, Kang I, Joly F, Rosenzwajg M, Sene D, Benech P, et al. Expansion of autoreactive unresponsive CD21-/low B cells in Sjogren’s syndrome-associated lymphoproliferation. Arthritis Rheum. 2013;65(4):1085–96.CrossRef
20.
go back to reference Wehr C, Eibel H, Masilamani M, Illges H, Schlesier M, Peter HH, Warnatz K. A new CD21low B cell population in the peripheral blood of patients with SLE. Clin Immunol. 2004;113(2):161–71.CrossRef Wehr C, Eibel H, Masilamani M, Illges H, Schlesier M, Peter HH, Warnatz K. A new CD21low B cell population in the peripheral blood of patients with SLE. Clin Immunol. 2004;113(2):161–71.CrossRef
21.
go back to reference Moir S, Ho J, Malaspina A, Wang W, DiPoto AC, O’Shea MA, Roby G, Kottilil S, Arthos J, Proschan MA, et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J Exp Med. 2008;205(8):1797–805.CrossRef Moir S, Ho J, Malaspina A, Wang W, DiPoto AC, O’Shea MA, Roby G, Kottilil S, Arthos J, Proschan MA, et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J Exp Med. 2008;205(8):1797–805.CrossRef
22.
go back to reference Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS, Haddad NS, Ley AM, Kyu S, Howell JC, Ozturk T, et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol. 2020;21(12):1506–16.CrossRef Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS, Haddad NS, Ley AM, Kyu S, Howell JC, Ozturk T, et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol. 2020;21(12):1506–16.CrossRef
23.
go back to reference Frasca D, Diaz A, Romero M, Thaller S, Blomberg BB. Metabolic requirements of human pro-inflammatory B cells in aging and obesity. PLoS One. 2019;14(7):e0219545.CrossRef Frasca D, Diaz A, Romero M, Thaller S, Blomberg BB. Metabolic requirements of human pro-inflammatory B cells in aging and obesity. PLoS One. 2019;14(7):e0219545.CrossRef
24.
go back to reference Frasca D, Diaz A, Romero M, Ferracci F, Blomberg BB. MicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals. J Immunol. 2015;195(5):2134–40. Frasca D, Diaz A, Romero M, Ferracci F, Blomberg BB. MicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals. J Immunol. 2015;195(5):2134–40.
25.
go back to reference Frasca D, Diaz A, Romero M, Blomberg BB. Leptin induces immunosenescence in human B cells. Cell Immunol. 2020;348:103994.CrossRef Frasca D, Diaz A, Romero M, Blomberg BB. Leptin induces immunosenescence in human B cells. Cell Immunol. 2020;348:103994.CrossRef
26.
go back to reference Jenks SA, Cashman KS, Zumaquero E, Marigorta UM, Patel AV, Wang X, Tomar D, Woodruff MC, Simon Z, Bugrovsky R, et al. Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity. 2018;49(4):725–39 e726. Jenks SA, Cashman KS, Zumaquero E, Marigorta UM, Patel AV, Wang X, Tomar D, Woodruff MC, Simon Z, Bugrovsky R, et al. Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity. 2018;49(4):725–39 e726.
27.
go back to reference de Armas LR, Pallikkuth S, Pan L, Rinaldi S, Cotugno N, Andrews S, Pahwa R, McDermott AB, Palma P, Pahwa S. Single cell profiling reveals PTEN overexpression in influenza-specific B cells in aging HIV-infected individuals on anti-retroviral therapy. Sci Rep. 2019;9(1):2482. de Armas LR, Pallikkuth S, Pan L, Rinaldi S, Cotugno N, Andrews S, Pahwa R, McDermott AB, Palma P, Pahwa S. Single cell profiling reveals PTEN overexpression in influenza-specific B cells in aging HIV-infected individuals on anti-retroviral therapy. Sci Rep. 2019;9(1):2482.
28.
go back to reference Frasca D, Romero M, Garcia D, Diaz A, Blomberg BB. Hyper-metabolic B cells in the spleens of old mice make antibodies with autoimmune specificities. Immun Ageing. 2021;18(1):9.CrossRef Frasca D, Romero M, Garcia D, Diaz A, Blomberg BB. Hyper-metabolic B cells in the spleens of old mice make antibodies with autoimmune specificities. Immun Ageing. 2021;18(1):9.CrossRef
Metadata
Title
Metabolic phenotype of B cells from young and elderly HIV individuals
Authors
Daniela Frasca
Suresh Pallikkuth
Savita Pahwa
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Immunity & Ageing / Issue 1/2021
Electronic ISSN: 1742-4933
DOI
https://doi.org/10.1186/s12979-021-00245-w

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