Essential and Instructive Roles of GATA Factors in Eosinophil Development

GATA transcription factors are major regulators of hematopoietic and immune system. Among GATA factors, GATA-1, GATA-2, and GATA-3 play crucial roles in the development of erythroid cells, hematopoietic stem, and progenitor cells, and T helper type 2 (Th2) cells, respectively. A high level of GATA-1 and GATA-2 expression has been observed in eosinophils, but their roles in eosinophil development remain uncertain both in vitro and in vivo. Here we show that enforced expression of GATA-1 in human primary myeloid progenitor cells completely switches myeloid cell fate into eosinophils. Expression of GATA-1 exclusively promotes development and terminal maturation of eosinophils. Functional domain analyses revealed that the COOH-terminal finger is essential for this capacity while the other domains are dispensable. Importantly, GATA-1–deficient mice failed to develop eosinophil progenitors in the fetal liver. On the other hand, GATA-2 also showed instructive capacity comparable to GATA-1 in vitro and efficiently compensated for GATA-1 deficiency in terms of eosinophil development in vivo, indicating that proper accumulation of GATA factors is critical for eosinophil development. Taken together, our findings establish essential and instructive roles of GATA factors in eosinophil development. GATA-1 and GATA-2 could be novel molecular targets for therapeutic approaches to allergic inflammation

Mucosal Immune System Dysregulation in the Pathogenesis of IgA Nephropathy

The mucosal immune system, via a dynamic immune network, serves as the first line of defense against exogenous antigens. Mucosal immune system dysregulation is closely associated with the pathogenesis of immunoglobulin A nephropathy (IgAN), as illustrated by IgAN having the clinical feature of gross hematuria, often concurrent with mucosal infections. Notably, previous studies have demonstrated the efficacy of tonsillectomy and found that a targeted-release formulation of budesonide reduced proteinuria in patients with IgAN. However, it remains unclear how exogenous antigens interact with the mucosal immune system to induce or exacerbate IgAN. Thus, in this review, we focus on the dysregulation of mucosal immune response in the pathogenesis of IgAN

Galactose-Deficient IgA1 as a Candidate Urinary Marker of IgA Nephropathy

In patients with IgA nephropathy (IgAN), circulatory IgA1 and IgA1 in the mesangial deposits contain galactose-deficient IgA1 (Gd-IgA1). Some of the Gd-IgA1 from the glomerular deposits is excreted in the urine and thus urinary Gd-IgA1 may represent a disease-specific marker. We recruited 338 Japanese biopsy-proven IgAN patients and 120 patients with other renal diseases (disease controls). Urine samples collected at the time of renal biopsy were used to measure Gd-IgA1 levels using a specific monoclonal antibody (KM55 mAb). Urinary Gd-IgA1 levels were significantly higher in patients with IgAN than in disease controls. Moreover, urinary Gd-IgA1 was significantly correlated with the severity of the histopathological parameters in IgAN patients. Next, we validated the use of urinary Gd-IgA1 levels in the other Asian cohorts. In the Korean cohort, urinary Gd-IgA1 levels were also higher in patients with IgAN than in disease controls. Even in Japanese patients with IgAN and trace proteinuria (less than 0.3 g/gCr), urinary Gd-IgA1 was detected. Thus, urinary Gd-IgA1 may be an early disease-specific biomarker useful for determining the disease activity of IgAN