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Background and Aims In IgA nephropathy (IgAN), mesangial IgA deposition activates the complement systems and amplifies the local inflammation, resulting in renal injuries. Although previous studies based on repeat biopsies suggested that the change of MEST-C scores of Oxford classification might be related to the prognosis, there have been few reports about immunofluorescence (IF) changes in repeat biopsies. In this study, we aimed to elucidate the relationship between the changes in the degree of glomerular IgA and C3 depositions and clinical prognosis of IgAN based on repeat biopsy observation. Method Fifty-five patients with IgAN who underwent repeat biopsies at our hospital between 2000 and 2019 were analyzed retrospectively. IF staining in each case was graded with a semiquantitative scale from 0 to 3 (0, negative; 1, weak; 2, moderate; 3, strong staining). MEST-C scores of the Oxford classification were also evaluated. When each score of IF staining or MEST-C in second biopsy was less compared with that in the first biopsy, it was regarded as “improved”. The primary outcome was the time to achieve complete remission (CR), which is defined as disappearance of both urinary protein (UP) ( Results Twenty-seven patients (48%) were male. At the first biopsy, median age and eGFR were 38.5 years (Interquartile ratio (IQR) 17-49) and 92 mL/min/1.73 m2 (IQR 63-108). Median urinary protein creatinine ratio was 0.6 g/gCr (IQR 0.3-1.7) and 45 patients (80%) had microhematuria. Thirty-three patients (59%) were treated by renin angiotensin system inhibitors and forty-three patients (78%) were treated by immunosuppressive therapy. Median period between the two biopsies was 36 months (IQR 25-55). Median IF scores of glomerular IgA and C3 were 2 (IQR 2-3) and 2 (IQR 1-2) in the first biopsies and 2 (IQR 1-2) and 1 (IQR 1-2) in the second biopsies, respectively. During the median 55 months (IQR 17-99) follow up period, disappearance of UP and microhematuria were observed in 47 (84%) and 36 (64%). Thirty-three (59%) patients reached CR. Improvement of the degree of C3 deposition between two biopsies was significantly associated with CR (Hazard ratio (HR) 0.37; 95% confidential interval (CI) 0.17-0.80, p=0.012), while that of IgA deposition had no association (HR 057; CI 0.27-1.19, p=0.125). Improvement of the degree of C3 deposition was also significantly associated with disappearance of microhematuria (HR 0.45; 95%CI 0.24-0.86, p=0.016), but not with disappearance of UP (HR 0.60; 95%CI 0.34-1.2, p=0.15). Multivariate linear regression revealed that the rate of eGFR decline was not related to IF scores. Any of the Oxford classification scores were not associated with these outcomes. Conclusion Attenuation of glomerular C3 deposition is associated with CR. This suggest that C3 deposition, rather than IgA deposition, may be related with the clinical prognosis of IgAN.

Hematopoietic stem cell and multipotent progenitor (MPP) commitment can be tuned in response to an infection so that their differentiation is biased toward myeloid cells. Here, we find that Bach2, which inhibits myeloid differentiation in common lymphoid progenitors, represses a cohort of myeloid genes and activates those linked to lymphoid function. Bach2 repressed both Cebpb and its target Csf1r, encoding C/EBPβ and macrophage colony-stimulating factor receptor (M-CSFr), respectively, whereas C/EBPβ repressed Bach2 and activated Csf1r. Bach2 and C/EBPβ further bound to overlapping regulatory regions at their myeloid target genes, suggesting the presence of a gene regulatory network (GRN) with mutual repression between these factors and a feedforward loop leading to myeloid gene regulation. Lipopolysaccharide reduced the expression of Bach2, resulting in enhanced myeloid differentiation. The Bach2-C/EBPβ GRN pathway thus tunes MPP commitment to myeloid and lymphoid lineages both under normal conditions and after infection.

BTB and CNC homology 2 (Bach2) is a transcriptional repressor that is required for the formation of the germinal center (GC) and reactions, including class switch recombination and somatic hypermutation of Ig genes in B cells, within the GC. Although BCR-induced proliferation is essential for GC reactions, the function of Bach2 in regulating B cell proliferation has not been elucidated. In this study, we demonstrate that Bach2 is required to sustain high levels of B cell proliferation in response to BCR signaling. Following BCR engagement in vitro, B cells from Bach2-deficient (Bach2−/−) mice showed lower incorporation of BrdU and reduced cell cycle progression compared with wild-type cells. Bach2−/− B cells also underwent increased apoptosis, as evidenced by an elevated frequency of sub-G1 cells and early apoptotic cells. Transcriptome analysis of BCR-engaged B cells from Bach2−/− mice revealed reduced expression of the antiapoptotic gene Bcl2l1 encoding Bcl-xL and elevated expression of cyclin-dependent kinase inhibitor (CKI) family genes, including Cdkn1a, Cdkn2a, and Cdkn2b. Reconstitution of Bcl-xL expression partially rescued the proliferation defect of Bach2−/− B cells. Chromatin immunoprecipitation experiments showed that Bach2 bound to the CKI family genes, indicating that these genes are direct repression targets of Bach2. These findings identify Bach2 as a requisite factor for sustaining high levels of BCR-induced proliferation, survival, and cell cycle progression, and it promotes expression of Bcl-xL and repression of CKI genes. BCR-induced proliferation defects may contribute to the impaired GC formation observed in Bach2−/− mice.