T Cell Dissimilarities in B Cell Activating Factor-Deficient Versus B Cell Activating Factor Receptor 3-Deficient Systemic Lupus Erythematosus-Prone NZM 2328 Mice As Contributors to Their Divergent Clinical Outcomes

Overview

Journal ACR Open Rheumatol

Date 2024 Aug 14

PMID 39143363

Authors

William Stohl

Ying Wu

Malka Stohl

Affiliations

Soon will be listed here.

Abstract

Objective: We assessed the contributions of B cell and T cell subsets to the disparate clinical outcomes in NZM.Baff and NZM.Br3 mice.

Methods: We assessed in NZM wild-type, NZM.Baff, and NZM.Br3 mice numbers and percentages of B cells and subsets, T cells and subsets, and in vivo proliferation and survival of forkhead box P3 (Foxp3) cells by fluorescence-activated cell sorting. Relationships between percentages of Foxp3 cells and numbers of CD19 and CD4 cells were assessed by linear regressions.

Results: In each age and sex cohort, percentages and numbers of CD19 cells were similar in NZM.Baff and NZM.Br3 mice. Percentages of CD3 and CD4 cells were greater in NZM.Br3 than in NZM.Baff mice, with the CD4 to CD3 cell ratios being greater in NZM.Br3 than in NZM.Baff mice and percentages of Foxp3 cells in NZM.Br3 mice being lower than in NZM.Baff mice. Percentages of Foxp3 cells correlated positively with CD19 cells in NZM.Baff mice but negatively in NZM.Br3 mice. In vivo proliferation and survival of Foxp3 cells were lower in NZM.Baff mice than in NZM.Br3 mice.

Conclusion: Differences between NZM.Baff and NZM.Br3 mice in Foxp3 cells and their relationships with CD19 cells may have more to do with their divergent clinical outcomes than do differences in numbers of B cells. These unexpected findings suggest that B cell activating factor (BAFF)-B cell maturation antigen (BCMA) or BAFF-Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) interactions may help drive development of clinical systemic lupus erythematosus (SLE) even under conditions of considerable B cell depletion. Insufficient blocking of BAFF-BCMA and BAFF-TACI interactions may lie at the heart of incomplete clinical response to BAFF-targeting agents in human SLE.

References

Stohl W, Yu N . Promotion of T Regulatory Cells in Mice by B Cells and BAFF. J Immunol. 2020; 204(9):2416-2428. DOI: 10.4049/jimmunol.1900057. View

Schneider P, Mackay F, Steiner V, Hofmann K, Bodmer J, Holler N . BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999; 189(11):1747-56. PMC: 2193079. DOI: 10.1084/jem.189.11.1747. View

Yu G, Boone T, Delaney J, Hawkins N, Kelley M, Ramakrishnan M . APRIL and TALL-I and receptors BCMA and TACI: system for regulating humoral immunity. Nat Immunol. 2001; 1(3):252-6. DOI: 10.1038/79802. View

Touma Z, Sayani A, Pineau C, Fortin I, Matsos M, Ecker G . Belimumab use, clinical outcomes and glucocorticoid reduction in patients with systemic lupus erythematosus receiving belimumab in clinical practice settings: results from the OBSErve Canada Study. Rheumatol Int. 2017; 37(6):865-873. PMC: 5434147. DOI: 10.1007/s00296-017-3682-9. View

Dhillon S . Telitacicept: First Approval. Drugs. 2021; 81(14):1671-1675. DOI: 10.1007/s40265-021-01591-1. View

Yan M, Wang H, Chan B, Roose-Girma M, Erickson S, Baker T . Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol. 2001; 2(7):638-43. DOI: 10.1038/89790. View

Rovin B, Furie R, Latinis K, Looney R, Fervenza F, Sanchez-Guerrero J . Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012; 64(4):1215-26. DOI: 10.1002/art.34359. View

Merrill J, Neuwelt C, Wallace D, Shanahan J, Latinis K, Oates J . Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2009; 62(1):222-33. PMC: 4548300. DOI: 10.1002/art.27233. View

Carter L, Isenberg D, Ehrenstein M . Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum. 2013; 65(10):2672-9. DOI: 10.1002/art.38074. View

10.

Isenberg D, Gordon C, Licu D, Copt S, Rossi C, Wofsy D . Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis. 2014; 74(11):2006-15. PMC: 4680140. DOI: 10.1136/annrheumdis-2013-205067. View

11.

Wu Y, Bressette D, CARRELL J, Kaufman T, Feng P, Taylor K . Tumor necrosis factor (TNF) receptor superfamily member TACI is a high affinity receptor for TNF family members APRIL and BLyS. J Biol Chem. 2000; 275(45):35478-85. DOI: 10.1074/jbc.M005224200. View

12.

Stohl W, Hiepe F, Latinis K, Thomas M, Scheinberg M, Clarke A . Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. 2012; 64(7):2328-37. PMC: 3350827. DOI: 10.1002/art.34400. View

13.

von Bulow G, Bram R . NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily. Science. 1997; 278(5335):138-41. DOI: 10.1126/science.278.5335.138. View

14.

Gross J, Dillon S, Mudri S, Johnston J, Littau A, Roque R . TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS. Immunity. 2001; 15(2):289-302. DOI: 10.1016/s1074-7613(01)00183-2. View

15.

Wofsy D, Seaman W . Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med. 1985; 161(2):378-91. PMC: 2187572. DOI: 10.1084/jem.161.2.378. View

16.

Khattri R, Cox T, Yasayko S, Ramsdell F . An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003; 4(4):337-42. DOI: 10.1038/ni909. View

17.

Tivol E, Borriello F, Schweitzer A, Lynch W, Bluestone J, Sharpe A . Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995; 3(5):541-7. DOI: 10.1016/1074-7613(95)90125-6. View

18.

Hori S, Nomura T, Sakaguchi S . Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299(5609):1057-61. DOI: 10.1126/science.1079490. View

19.

Isenberg D, Petri M, Kalunian K, Tanaka Y, Urowitz M, Hoffman R . Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2015; 75(2):323-31. DOI: 10.1136/annrheumdis-2015-207653. View

20.

Harless S, Lentz V, Sah A, Hsu B, Clise-Dwyer K, Hilbert D . Competition for BLyS-mediated signaling through Bcmd/BR3 regulates peripheral B lymphocyte numbers. Curr Biol. 2001; 11(24):1986-9. DOI: 10.1016/s0960-9822(01)00598-x. View