Abstract
Myeloid cells are central players in innate immunity and inflammation. Their function is regulated by the adapter protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). In this study, we aimed to identify the internal trigger of this disease phenotype in these mice. We first detected gut microbiota dysbiosis and transmigration of commensal bacteria (CB) to the liver in aging M-Traf3-/- mice. Interestingly, depletion of CB using antibiotics effectively prevented BCL development in these mice. Systemic IgG responses against CB were induced and the IgH CDR3 sequences of malignant B-cell clones of M-Traf3-/- mice showed high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, M-Traf3-/- mice with BCL exhibited high serum titers of antibodies against CB. Together, our findings offer insights into the mechanisms underlying increased risks of B-cell lymphomagenesis observed in patients with compromised innate immunity.
Significance:
We present evidence that microbiota dysbiosis in animals with compromised innate immunity increases risk of intestinal bacteria transmigration to internal organs, which subsequently induces malignant transformation of CB-reactive B-cell clones. Accordingly, antibiotic treatment or blocking CB transmigration may serve as a strategy for preventing BCL in patients with innate immunodeficiency.