Abstract
Myeloid cells are the major players of innate immunity and inflammation. The function of myeloid cells is critically regulated by the adaptor protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). Here we sought to identify the internal trigger of chronic inflammation and aberrant B cell activation in these mice. We first detected gut dysbiosis and transmigration of commensal bacteria to the liver in aging M-Traf3-/- mice using 16s rRNA gene sequencing of fecal bacterial DNA and bacterial culture of liver homogenates, respectively. To determine if gut dysbiosis and bacterial transmigration induce chronic inflammation and aberrant B cell activation, we treated mice with broad-spectrum antibiotics. We found that depletion of commensal bacteria with antibiotics effectively prevented chronic inflammation and BCL development in aging M-Traf3-/- mice. We next demonstrated that systemic IgG responses against commensal bacteria were induced in the mice as shown by fecal bacteria FACS analysis. Interestingly, our sequencing data of the IgH gene VDJ region revealed that many malignant B cell clones of M-Traf3-/- mice had undergone class switch recombination and contained somatic hypermutations, indicating their origination from germinal center (GC) or post-GC B cells. We also noticed that the CDR3 sequences of malignant B cell clones derived from M-Traf3-/- mice exhibit high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, aging M-Traf3-/- mice with BCL contained high titers of antibodies against commensal bacteria, but not autoantigens, in the serum. Taken together, our findings suggest that commensal bacteria dysbiosis and transmigration can promote chronic inflammation and BCL development in individuals with compromised innate immunity. Accordingly, inhibition of commensal bacteria may serve as an effective therapeutic strategy for the prevention and treatment of chronic inflammation and B-cell lymphomas in these patients.
Citation Format: Jaeyong Jung, Sining Zhu, Almin I Lalani, Judith Shakarchi, Guojun Gary Wu, Wei-Xing Zong, Liping Zhao, Ping Xie. Commensal bacteria are required for chronic inflammation and B lymphoma development in myeloid cell-specific TRAF3-deficient mice [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-018.
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