Campylobacter bacteremia in hemodialysis patients by eating raw meat - the importance of sanitary education.

In 2011, simultaneous, widespread outbreaks of food poisoning by contaminated enterohemorrhagic Escherichia coli in beef, which killed four and hospitalized more than 30 people, occurred in Japan. While the press was widely reporting this disaster, two maintenance hemodialysis patients were suffering from Campylobacter bacteremia by eating undercooked meat. One patient was infected with C. upsaliensis and the other with C. fetus. Although these patients could be successfully treated, they led us to consider the characteristics of C. upsaliensis and C. fetus as opportunistic pathogens, as well as changes in dietary behaviors and food markets. Moreover, they emphasized the need for hemodialysis patients to be not only educated in that they should restrict potassium, phosphate and water intake, but also that they should take care of food sanitation.

Development of a model of early-onset IgA nephropathy.

ddY mice spontaneously develop IgA nephropathy (IgAN) with a variable age of disease onset. Establishing a model with early-onset IgAN could aid the investigation of mechanisms that underlie the pathogenesis of this disease. On the basis of histologic grading in serial biopsies, we previously classified ddY mice into early-onset, late-onset, and quiescent groups. Here, we selectively mated mice with the early-onset phenotype for >20 generations and established "grouped ddY" mice that develop IgAN within 8 weeks of age. Similar to human IgAN, the prognosis was worse for male mice than females. These mice homogeneously retained genotypes of four marker loci previously associated with the early-onset phenotype, confirming a close association of these loci with early-onset IgAN in ddY mice. Grouped ddY mice comprised two sublines, however, which had distinct genotypes at a susceptibility locus for high serum IgA levels, which maps within the Ig heavy-chain gene complex. The subline bearing the Igh-2(a) IgA allotype had a more rapid course of fatal disease and lower oligosaccharide content, suggesting that aberrant IgA glycosylation may promote the progression of murine IgAN. Taken together, these data indicate that grouped ddY mice may be a useful model for the identification of susceptibility genes and the underlying molecular mechanisms involved in the pathogenesis of human IgAN.

Reevaluation of the mucosa-bone marrow axis in IgA nephropathy with animal models.

Impaired immune regulation along the 'mucosa-bone marrow axis' has been postulated to play an important role in the pathogenesis of IgA nephropathy (IgAN). Animal models have allowed us to study such changes in detail. Recently, we established several useful animal models, including IgAN-prone mice. Using these animal models, our group is approaching the underlying mechanisms by which bone marrow and mucosal cell interrelate and finally induce this disease. Accumulating evidence from these approaches suggests that there is dysregulation of innate and cellular immunity in IgAN resulting in changes in the mucosal immune system. These changes appear to be closely linked to disruption of mucosal tolerance, resulting in abnormal priming and dissemination of cells to sites such as the bone marrow where they are responsible for synthesis of nephritogenic IgA. Our clinical studies further support these ideas and indicate that the tonsils may be a major mucosal priming site in human IgAN. In addition, our findings also suggest clinical application of nephritogenic IgA (IgA1) as a biological marker and possible future treatment strategies that focus on manipulating the priming and dissemination of these memory cells in order to prevent the appearance of nephritogenic IgA (IgA1) in the systemic compartment.

Different pathological roles of toll-like receptor 9 on mucosal B cells and dendritic cells in murine IgA nephropathy.

Although pathogenesis of IgA nephropathy (IgAN) is still obscure, pathological contribution of mucosal immunity including production of nephritogenic IgA and IgA immune complex (IC) has been discussed. We have reported that mucosal toll-like receptor (TLR)-9 is involved in the pathogenesis of human and murine IgAN. However, cell-type expressing TLR9 in mucosa remains unclear. To address this, we nasally challenged cell-specific CpG DNA ((i): dendritic cell: (DC), (ii): B cell, (iii): both), known as ligand for TLR9, to IgAN prone mice and analyzed disease phenotype of each group. After 8 times of the weekly administration, every group showed deterioration of glomerular damage. However, CpG-A-group showed clear extension of mesangial proliferative lesions with increase of serum IgA-IgG2a IC and its glomerular depositions, while CpG-B-group showed extent of glomerular sclerotic lesions with increase of serum and glomerular IgA and M2 macrophage infiltration. Present results indicate that mucosal TLR9 on B cells and DC may differently contribute to the progression of this disease via induction of nephritogenic IgA or IgA-IgG IC, respectively. This picture is suggestive for the pathological difference between child and adult IgAN.

Pathological role of tonsillar B cells in IgA nephropathy.

Although impaired immune regulation along the mucosa-bone marrow axis has been postulated to play an important role, the pathogenesis of IgA nephropathy (IgAN) is unknown; thus, no disease-specific therapy for this disease exists. The therapeutic efficacy of tonsillectomy or tonsillectomy in combination with steroid pulse therapy for IgAN has been discussed. Although randomized control trials for these therapies are ongoing in Japan, the scientific rationale for these therapies remains obscure. It is now widely accepted that abnormally glycosylated IgA1 and its related immune complex (IC) are probably key molecules for the pathogenesis, and are thus considered possible noninvasive biomarkers for this disease. Emerging evidence indicates that B cells in mucosal infections, particularly in tonsillitis, may produce the nephritogenic IgA. In this paper, we briefly summarize characteristics of the nephritogenic IgA/IgA IC, responsible B cells, and underlying mechanisms. This clinical and experimental information may provide important clues for a therapeutic rationale.