2026-09-09 ジョンズ・ホプキンス大学（JHU）
＜関連情報＞
- https://hub.jhu.edu/2026/09/09/federal-funds-support-type-1-diabetes-treatment/
- https://academic.oup.com/jimmunol/article-abstract/215/4/vkag056/8658748
- https://www.cell.com/cell/fulltext/S0092-8674(19)30505-7
自然発生的なIgM自己抗体を利用して糖尿病誘発性T細胞を標的とする：1型糖尿病に対する精密医療アプローチ Leveraging a naturally occurring IgM autoantibody to target diabetogenic T cells: a precision medicine approach to type 1 diabetes
Rafid Al-Hallaf,Zainab Agha,Patrizio Caturegli,Avi Rosenberg,Risa Wolf,Kevin C Chan,Yi Song,Sangyun Lee,Ruhong Zhou,Chunfa Jie,Thomas Donner,Abdel Rahim A Hamad
The Journal of Immunology Published:17 April 2026
DOI:https://doi.org/10.1093/jimmun/vkag056
Abstract
Current immunotherapies for autoimmune diseases lack sufficient specificity and often compromise protective immunity, underscoring the need for precision-based approaches. Here, we identify x-mAb, a germline-encoded IgM autoantibody derived from dual-expresser lymphocytes of patients with type 1 diabetes (T1D), as a potent agent for precision immunotherapy. In the nonobese diabetic mouse model, x-mAb prevents disease onset, induces durable remission, and preserves functional pancreatic islets without disrupting systemic immune homeostasis. Mechanistically, x-mAb selectively targets islet-reactive CD4 and CD8 tissue-resident memory (Trm) T cells in pancreas and pancreatic lymph nodes, as shown by MHC tetramer staining and in vivo tracking. x-mAb engagement downregulates CD69, a key Trm retention molecule, resulting in a marked reduction of pathogenic pancreatic T cells. Critically, x-mAb recognizes analogous CD69+ Trm-like peripheral T cells in T1D patients and downregulates CD69 ex vivo, indicating a conserved and therapeutically targetable mechanism across species. Structural modeling revealed that x-mAb engages TCRαβ through multiple contact sites, with the most stable interactions targeting a conserved CDR3α SGGGGS motif shared by diabetogenic human and mouse clonotypes. Based on these findings, we propose natural IgM autoantibodies as a previously unrecognized reservoir for precision biologics that selectively target autoreactive T cells while preserving immune competence.
1型糖尿病患者由来の特異的な二重受容体発現リンパ球に存在するパブリックBCRは、強力なT細胞自己抗原をコードする A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen
Rizwan Ahmed ∙ Zahra Omidian ∙ Adebola Giwa ∙ … ∙ Chunfa Jie ∙ Thomas Donner ∙ Abdel Rahim A. Hamad
Cell Published: May 30, 2019
DOI:https://doi.org/10.1016/j.cell.2019.05.007
Highlights
- Dual expressers (DEs) are new lymphocytes that coexpress functional BCR and TCR
- A single BCR clonotype (x-clonotype) predominates DEs in T1D subjects
- x-clonotype encodes a potent autoantigen with an optimal register for HLA-DQ8
- x-mAb secreted by DEs is a potent stimulator of insulin-specific CD4 T cells
Summary
T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.
