KEY POINTS * Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of pancreatic β cells * An accumulating body of evidence suggests that T1DM is

associated with loss of tolerance by autoreactive B cells * Although islet antigen-reactive B cells give rise to autoantibody secreting cells, their most important contribution to pathology

in T1DM seems to be presentation of self-antigens to T cells * Loss of tolerance of islet-reactive B cells is associated with certain genetic polymorphisms * B cells contribute to diabetic

kidney disease (DKD) through the production of antibodies that lead to the formation and deposition of immune complexes in the kidney * In a clinical trial, B cell-depletion therapy showed

exogenous insulin and imposes an enormous burden on patients and health-care resources. T1DM is also associated with an increased risk of comorbidities, such as cardiovascular disease,

retinopathy, and diabetic kidney disease (DKD), further contributing to the burden of this disease. Although T cells are largely considered to be responsible for β-cell destruction in T1DM,

increasing evidence points towards a role for B cells in disease pathogenesis. B cell-depletion, for example, delays disease progression in patients with newly diagnosed T1DM. Loss of

tolerance of islet antigen-reactive B cells occurs early in disease and numbers of pancreatic CD20+ B cells correlate with β-cell loss. Although the importance of B cells in T1DM is

increasingly apparent, exactly how these cells contribute to disease and its comorbidities, such as DKD, is not well understood. Here we discuss the role of B cells in the pathogenesis of

T1DM and how these cells are activated during disease development. Finally, we speculate on how B cells might contribute to the development of DKD. Access through your institution Buy or

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DIABETES Article 02 February 2024 A PERSPECTIVE ON TREATING TYPE 1 DIABETES MELLITUS BEFORE INSULIN IS NEEDED Article 13 March 2023 ADULT-ONSET AUTOIMMUNE DIABETES Article 22 September 2022

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in nonobese diabetic mice. _J. Immunol._ 181, 8133–8144 (2008). CAS  PubMed  PubMed Central  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Immunology and Microbiology, University of Colorado School of Medicine, 12800 E 19th Avenue, RC1 North, P18–8100, Aurora, 80045–2537, Colorado, USA Mia J. Smith & John C. Cambier *

Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, 80523–1682, Colorado, USA Mia J. Smith * Barbara Davis Center for

Childhood Diabetes, University of Colorado School of Medicine, 1775 Aurora Court, Aurora, 80045–2537, Colorado, USA Kimber M. Simmons Authors * Mia J. Smith View author publications You can

also search for this author inPubMed Google Scholar * Kimber M. Simmons View author publications You can also search for this author inPubMed Google Scholar * John C. Cambier View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors researched the data for the article, discussed the content, wrote the article and reviewed

and/or edited the manuscript before submission. CORRESPONDING AUTHOR Correspondence to John C. Cambier. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial

interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR TABLE 1 GLOSSARY * Germinal centre reaction The anatomical site in which B cells and

T cells respond collaboratively to immunogen, leading to B cell proliferation, somatic Ig gene mutation, affinity maturation and immunoglobulin class switch recombination. * Anergy A mode

of B cell tolerance characterized by unresponsiveness to antigenic stimulation, including the inability to become activated, proliferate and secrete antibody. * Diabetogenic T cells T cells

that can cause diabetes, such as insulin-reactive T cells. * Cross-presenting The process by which antigen presenting cells process and present extracellular antigens to CD8+ T cells. *

High-affinity anti-insulin antibodies Antibodies with an affinity for insulin >10−9 mol/l. * Plasma cells Terminally differentiated B cells that secrete antibody. * Recombining sequence

rearrangements DNA rearrangements that delete one or both Ig κ genes, leading to expression of Ig λ light chains. * λ-Immunoglobulin light chain-positive B cells B cells that express λ light

chains as a component of their B cell antigen receptor; high levels of these cells is indicative of increased receptor editing. * Insulitis Inflammation of the pancreas due to infiltration

of lymphocytes. * Haplotypes A set of genes inherited from a single parent. * Antibody-dependent cell-mediated cytotoxicity The process by which an effector cell of the immune system, such

as a natural killer cell, targets a cell for lysis based on the presence of antibodies that are bound to surface antigens on the target cell. * Mixed meal tolerance test An assay to

determine the amount of insulin an individual produces; the individual consumes a drink containing a mixture of protein, fat, and carbohydrates that stimulates the release of insulin from

pancreatic β cells; blood is drawn several times over a period of hours and assayed for C-peptide, which reflects endogenous insulin production. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Smith, M., Simmons, K. & Cambier, J. B cells in type 1 diabetes mellitus and diabetic kidney disease. _Nat Rev Nephrol_ 13, 712–720

(2017). https://doi.org/10.1038/nrneph.2017.138 Download citation * Published: 17 October 2017 * Issue Date: November 2017 * DOI: https://doi.org/10.1038/nrneph.2017.138 SHARE THIS ARTICLE

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