Anti-myeloperoxidase IgM B Cells in Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Feb 12

PMID 39939347

Authors

C M Wortel

R van de Wetering

E M Stork

T Kissel

S Reijm

D van der Woude

K A van Schie

L A Trouw

Yko Teng

A Rutgers

P Heeringa

R E Voll

M Rizzi

N Venhoff

Rem Toes

H U Scherer

Affiliations

Soon will be listed here.

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a prototypic autoimmune disease, with a subset of AAV patients manifesting anti-myeloperoxidase (MPO) IgG. Patients with AAV respond positively to B cell-targeting and complement-targeting therapies, but disease flares are not uncommon. Here, by comparing samples from healthy individuals and MPO AVV patients, we show that B cell autoreactivity against MPO in the circulation of patients is dominated by CD27IgM B cells whereas MPO-specific IgG cells are infrequent. Additionally, while naive anti-MPO-IgM B cells are present in both patients and controls and produce anti-MPO IgM upon stimulation, anti-MPO-IgM memory B cells and serum anti-MPO IgM are features of patients. Our results thus hint that defective elimination of B cell reactivity to MPO in the human repertoire, the presence of activated IgM anti-MPO B cells in disease, and a dominant role for anti-MPO IgM in complement activation, may all contribute to MPO AAV etiology and thereby serve as potential target for therapy.

References

Vaccaro C, Zhou J, Ober R, Ward E . Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol. 2005; 23(10):1283-8. DOI: 10.1038/nbt1143. View

PIROFSKY B, Rosner E . DTT test: a new method to differentiate IgM and IgG erythrocyte antibodies. Vox Sang. 1974; 27(5):480-8. DOI: 10.1111/j.1423-0410.1974.tb02446.x. View

Hsieh S, Yu H, Cheng S, Li K, Lu M, Wu C . Anti-myeloperoxidase antibodies enhance phagocytosis, IL-8 production, and glucose uptake of polymorphonuclear neutrophils rather than anti-proteinase 3 antibodies leading to activation-induced cell death of the neutrophils. Clin Rheumatol. 2006; 26(2):216-24. DOI: 10.1007/s10067-006-0285-3. View

Falk R, Terrell R, Charles L, Jennette J . Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990; 87(11):4115-9. PMC: 54058. DOI: 10.1073/pnas.87.11.4115. View

Kissel T, Ge C, Hafkenscheid L, Kwekkeboom J, Slot L, Cavallari M . Surface Ig variable domain glycosylation affects autoantigen binding and acts as threshold for human autoreactive B cell activation. Sci Adv. 2022; 8(6):eabm1759. PMC: 8827743. DOI: 10.1126/sciadv.abm1759. View

Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y . Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002; 110(7):955-63. PMC: 151154. DOI: 10.1172/JCI15918. View

Kerkman P, Rombouts Y, van der Voort E, Trouw L, Huizinga T, Toes R . Circulating plasmablasts/plasmacells as a source of anticitrullinated protein antibodies in patients with rheumatoid arthritis. Ann Rheum Dis. 2013; 72(7):1259-63. DOI: 10.1136/annrheumdis-2012-202893. View

Silva F, Specks U, Sethi S, Valentina Irazabal M, Fervenza F . Successful pregnancy and delivery of a healthy newborn despite transplacental transfer of antimyeloperoxidase antibodies from a mother with microscopic polyangiitis. Am J Kidney Dis. 2009; 54(3):542-5. DOI: 10.1053/j.ajkd.2009.02.016. View

Bosch X, Guilabert A, Font J . Antineutrophil cytoplasmic antibodies. Lancet. 2006; 368(9533):404-18. DOI: 10.1016/S0140-6736(06)69114-9. View

10.

Granel J, Korkmaz B, Nouar D, Weiss S, Jenne D, Lemoine R . Pathogenicity of Proteinase 3-Anti-Neutrophil Cytoplasmic Antibody in Granulomatosis With Polyangiitis: Implications as Biomarker and Future Therapies. Front Immunol. 2021; 12:571933. PMC: 7930335. DOI: 10.3389/fimmu.2021.571933. View

11.

Berti A, Hillion S, Hummel A, Son Y, Chriti N, Peikert T . Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis. JCI Insight. 2021; 6(22). PMC: 8663783. DOI: 10.1172/jci.insight.150999. View

12.

Wieslander J . How are antineutrophil cytoplasmic autoantibodies detected?. Am J Kidney Dis. 1991; 18(2):154-8. DOI: 10.1016/s0272-6386(12)80872-9. View

13.

Trouw L, Haisma E, Levarht E, van der Woude D, Ioan-Facsinay A, Daha M . Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways. Arthritis Rheum. 2009; 60(7):1923-31. DOI: 10.1002/art.24622. View

14.

Hurtado P, Jeffs L, Nitschke J, Patel M, Sarvestani G, Cassidy J . CpG oligodeoxynucleotide stimulates production of anti-neutrophil cytoplasmic antibodies in ANCA associated vasculitis. BMC Immunol. 2008; 9:34. PMC: 2483256. DOI: 10.1186/1471-2172-9-34. View

15.

Esquivel-Valerio J, Flores-Suarez L, Rodriguez-Amado J, Garza-Elizondo M, Rendon A, Salinas-Carmona M . Antineutrophil cytoplasm autoantibodies in patients with tuberculosis are directed against bactericidal/permeability increasing protein and are detected after treatment initiation. Clin Exp Rheumatol. 2010; 28(1 Suppl 57):35-9. View

16.

Kelly S, Jackson K, Peters T, Suan D, Goodnow C . Isolation and characterisation of PR3-specific B cells and their immunoglobulin sequences. J Autoimmun. 2023; 142:103129. DOI: 10.1016/j.jaut.2023.103129. View

17.

Bansal P, Tobin M . Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement. Ann Allergy Asthma Immunol. 2004; 93(4):398-401. DOI: 10.1016/S1081-1206(10)61400-7. View

18.

Jayne D, Merkel P, Schall T, Bekker P . Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021; 384(7):599-609. DOI: 10.1056/NEJMoa2023386. View

19.

Little M, Nightingale P, Verburgh C, Hauser T, Groot K, Savage C . Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis. 2009; 69(6):1036-43. DOI: 10.1136/ard.2009.109389. View

20.

Jeffs L, A Peh C, Nelson A, Tan P, Davey E, Chappell K . IgM ANCA in healthy individuals and in patients with ANCA-associated vasculitis. Immunol Res. 2019; 67(4-5):325-336. DOI: 10.1007/s12026-019-09091-x. View