Functions of Double-Negative B Cells in Autoimmune Diseases, Infections, and Cancers

Sep 24, 2026

Most mature B cells can be divided into four IgD/CD27-defined subtypes: naıve, unswitched memory, switched memory, and double-negative (DN) B cells. Despite their low frequency in normal peripheral blood, DN B cells contribute to disease-specific immune outcomes, including autoimmunity in autoimmune disorders, antiviral and antipathogenic effects in COVID-19, and antipathogenic activity in malaria. DN B cells are also reported in nasopharyngeal carcinoma and non-small-cell lung cancer, where they may suppress immunity, implying functional heterogeneity and motivating mechanistic and therapeutic studies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

B-cell subsets and IgD/CD27 classification

DN B cell features and proposed mechanisms

Review Functions of double-negative B cells in autoimmune diseases, infections, and cancers Michael King Yung Chung1 , Lanqi Gong1, 2 , Dora Lai-Wan Kwong1, 2 , Victor Ho-Fun Lee1, 2 , Ann Wing-Mui Lee1, 2 , Xin-Yuan Guan1, 2 , Ngar-Woon Kam1,3,* & Wei Dai1, 2,** Abstract Most mature B cells can be divided into four subtypes based on the expression of the surface markers IgD and CD27: IgD+CD27 􀀁 na€ıve B cells, IgD+CD27+ unswitched memory B cells, IgD 􀀁 CD27+ switched memory B cells, and IgD 􀀁 CD27 􀀁 double-negative (DN) B cells. Despite their small population size in normal peripheral blood, DN B cells play integral roles in various diseases. For example, they generate autoimmunity in autoimmune conditions, while these cells may generate both autoimmune and antipathogenic responses in COVID-19, or act in a purely antipathogenic capacity in malaria. Recently, DN B cells have been identified in nasopharyngeal carcinoma and non-small-cell lung cancers, where they may play an immunosuppressive role. The distinct functions that DN B cells play in different diseases suggest that they are a heterogeneous B-cell population. Therefore, further study of the mechanisms underlying the involvement of DN B cells in these diseases is essential for understanding their pathogenesis and the development of therapeutic strategies. Further research is thus warranted to characterize the DN B-cell population in detail. Keywords autoimmune disease; cancer immunosuppression; COVID-19; double-negative B cells; tumor microenvironment Subject Category Immunology DOI 10.15252/emmm.202217341 | Received 21 December 2022 | Revised 11 April 2023 | Accepted 13 April 2023 | Published online 5 June 2023 EMBO Mol Med (2023) 15: e17341 See the Glossary for abbreviations used in this article. Introduction B cells are a key component of the adaptive immune response. They can differentiate into plasma cells to secrete pathogenneutralizing antibodies and proinflammatory cytokines (Pioli, 2019) or develop into memory B cells to provide long-lasting protection (Batista & Harwood, 2009) . Alternatively, they can present antigens to activate other immune cells (Hong et al, 2018) . The myriad of functions of B cells cements their status as an integral part of the human immune system. Human “mature B cells,” which have passed the B-cell selection progress in the bone marrow and spleen (Rolink et al, 2001), can be categorized into different subsets based on their expression of the surface markers IgD and CD27 (Liet al, 2021) . IgD is an antibody expressed on the surface of antigennave B cells (Li et al, 2021), while CD27 expression on B cells indicates the expression of immunoglobin genes that underwent somatic hypermutation (SHM) in the germinal center (GC) within the B-cell follicles of lymphoid organs, a process B cells endure to produce high-affinity antigen-specific antibodies (Klein et al, 1998) . The four major mature B-cell subsets in human blood include IgD+CD27 􀀁 antigen-nave B cells, IgD+CD27+ unswitched memory B cells that produce IgM antibodies in a T-cell-independent manner (Capolunghi et al, 2013) and migrate to B-cell follicles, where they differentiate into GC B cells to further their development (Seifert et al, 2015), and IgD 􀀁 CD27+ switched memory cells that mature into IgD 􀀁 CD27+ antibody-secreting cells (ASCs) upon activation to produce high-affinity antibodies. They express class-switched antibodies such as IgG, which have higher affinity than unswitched IgM antibodies (M€akel€a et al, 1970) . IgD 􀀁 CD27 􀀁 B cells are termed double-negative (DN) B cells and will be the focus of this review (Li et al, 2021) . Consistent with what their lack of CD27 expression may suggest, DN B cells underwent less SHM than their CD27-expressing counterparts. Fecteau et al (2006) compared IgG-producing DN B cells and switched memory B cells from healthy individuals and detected significantly lower mutation levels on the IgG transcripts from

FAQs

How are double-negative B cells defined among mature B-cell subtypes?

Double-negative (DN) B cells lack both IgD and CD27 surface marker expression, distinguishing them from naıve, unswitched memory, and switched memory subsets.

What roles can DN B cells play in different diseases?

DN B cells are linked to autoimmunity in autoimmune conditions, may generate both autoimmune and antipathogenic responses in COVID-19, act antipathogenically in malaria, and may exert immunosuppressive roles in certain cancers.

Why is further study of DN B cells considered essential?

Their low abundance in normal blood yet diverse disease-linked functions suggest DN B cells are heterogeneous; detailed mechanistic studies are needed to clarify pathogenesis and support therapeutic strategy development.

Sep 24, 2026

Uploaded by Nguyễn Văn Học