Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.

IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'

Identification of candidate genes involved in endogenous protection mechanisms against acute pancreatitis in mice.

We surveyed changes of the gene expression profile in caerulein-exposed pancreas using Affymetrix GeneChip system (39,000 genes). Up-regulation of genes coding for claudin 4, claudin 7, F11 receptor, cadherin 1, integrin beta 4, syndecan 1, heat shock proteins b1/90aa1, Serpinb6a, Serpinb6b, Serpinb9, Bax, Bak1, calpain 2, calpain 5, microtubule-associated protein 1 light chain 3 alpha, S100 calcium-binding proteins A4/A10 were found in mouse pancreas exposed to caerulein for 12h. In contrast, the anti-apoptotic gene Bcl2 was down-regulated. The functions of these genes concern tight junction formation, cell-cell/cell-matrix adhesions, stress response, protease inhibition, apoptosis, autophagy, and regulation of cytoskeletal dynamics. Caerulein-exposed pancreatic acinar cells were immunohistochemically stained for claudin 4, cadherin 1, integrin beta 4, heat shock protein b1, and Serpinb6a. In conclusion, we have newly identified a set of genes that are likely to be involved in endogenous self-protection mechanisms against acute pancreatitis.

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease.

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135 mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed.

A novel model of insulin-dependent diabetes with renal and retinal lesions by transgenic expression of CaMKIIalpha (Thr286Asp) in pancreatic beta-cells.

BACKGROUND: The activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in pancreatic beta-cells has been thought to play a central role in Ca2+-mediated insulin secretion. However, the physiological and pathological significance of CaMKII activation in pancreatic beta-cells has never been investigated in vivo. METHODS: We generated transgenic (TG) mice overexpressing the constitutively active-type CaMKIIalpha (Thr286Asp) in beta-cells. The mice were extensively examined histologically and biochemically. Time-course changes of blood glucose, haemoglobin A1C and insulin were also determined. RESULTS: Western blot and immunohistochemical analyses showed overexpression of CaMKIIalpha proteins in pancreatic beta-cells of TG mice. All TG mice developed severe hypoinsulinaemic diabetes by P28. In vivo BrdU labelling analysis revealed that cell proliferation in TG islets is severely impaired. Immunohistochemical examination revealed accumulations of NF-kappaB in nuclei of TG beta-cells at P21, which are associated with DNA laddering, a hallmark of apoptosis. At P28, pancreatic and serum insulin levels were both significantly (p < 0.05) lower in TG mice (0.037 +/- 0.005 ng/microg and 0.50 +/- 0.01 ng/mL) than in wild-type mice (0.997 +/- 0.093 ng/microg and 2.50 +/- 0.22 ng/mL). TG mice at P140 showed enlargement of kidney, mesangial expansion and glomerulosclerosis, which are associated with urinary albumin excretion. TG mice at P140-P168 developed severe retinal lesions such as disrupted ganglion cells and showed a flat pattern in electroretinography. CONCLUSIONS: The TG mice established herein will be valuable as a novel model of severe insulin-dependent diabetes accompanied by an early progression of diabetic micro-vascular complications.