Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we find that high fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem-cells (ISCs) of the mammalian intestine. Mechanistically, HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-d) signature in intestinal stem and (non-ISC) progenitor cells, and pharmacologic activation of PPAR-d recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-d dependent manner. Interestingly, HFD- and agonist-activated PPAR-d signaling endow organoid-initiating capacity to progenitors, and enforced PPAR-d signaling permits these progenitors to form in vivo tumors upon loss of the tumor suppressor Apc. These findings highlight how diet-modulated PPAR-d activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumors.

Hypertrophic pachymeningitis (HP) is an inflammatory condition in which the dura mater of the cranium or spine becomes thickened, leading to symptoms that result from mass effect, nerve compression, or vascular compromise. The differential diagnosis of HP includes immune-mediated conditions such as rheumatoid arthritis and vasculitis, malignancies, and infections. Many times, no diagnosis is reached; in such cases, the disease has been described as idiopathic HP. IgG4-related disease (IgG4-RD) is a recently described inflammatory condition known to cause tumefactive lesions at myriad anatomical locations. Both IgG4-RD and idiopathic HP share similar demographics, histopathology, and natural history. We hypothesized that IgG4-RD is a common cause of idiopathic HP.To investigate this hypothesis, we identified all pathology specimens diagnosed as noninfectious HP during 25 years at our institution. Fourteen cases had stained slides and paraffin blocks to permit review of the original hematoxylin and eosin stained slides as well as immunostaining of cell blocks. Recently published consensus guidelines describing characteristic histopathology and the necessary quantity of IgG4+ plasma cell infiltrate were used to diagnose IgG4-RD.Four cases (66.6%) that had been regarded previously as representing idiopathic HP were diagnosed as IgG4-RD; of all the reviewed cases, IgG4-RD represented 29% of cases. Of the remaining cases, 3 cases were associated with granulomatosis with polyangiitis (GPA), 2 with lymphoma, and 1 each with rheumatoid arthritis, giant cell arteritis, and sarcoidosis. Two of the cases could not be diagnosed more precisely and were classified as undifferentiated HP. Clinical history, serologic tests, cerebrospinal fluid studies, and radiology alone could not identify the cause of HP. Rather, biopsy with histopathology and immunostaining was necessary to reach an accurate diagnosis. Significant IgG4+ plasma cell infiltrates were observed in rheumatoid arthritis, granulomatosis with polyangiitis, and lymphoma, underscoring the importance of histopathology in making the diagnosis of IgG4-RD.This case series demonstrates that IgG4-RD may be the most common etiology of noninfectious HP and highlights the necessity of biopsy for accurate diagnosis.

Idiopathic retroperitoneal fibrosis (RPF) is a periaortic sclerotic disease that encases adjacent retroperitoneal structures, particularly the ureters. A subset of idiopathic RPF cases can be associated with IgG4-related disease, but the frequency of this association is not clear. We selected 23 cases of idiopathic RPF and identified IgG4-related RPF cases based on the presence of IgG4+ plasma cells in the tissue, using an IgG4/IgG ratio cutoff of >40%. We then compared the IgG4-related RPF patients and the non-IgG4-related RPF patients in terms of both the presence of histopathologic features typical of IgG4-related disease and the simultaneous occurrence (or history) of other organ manifestations typical of IgG4-related disease. The IgG4-related RPF and non-IgG4-related RPF groups were also analyzed in terms of clinical, laboratory, and radiologic features and treatment review.We identified 13 cases of IgG4-related RPF (57% of the total cohort). The distinguishing features of IgG4-related RPF were histopathologic and extra-organ manifestations of IgG4-related disease. The IgG4-related RPF patients were statistically more likely than non-IgG4-related RPF patients to have retroperitoneal biopsies showing lymphoplasmacytic infiltrate (p = 0.006), storiform fibrosis (p = 0.006), or tissue eosinophilia (p = 0.0002). Demographics of the 2 groups, including a middle-aged, male predominance (mean age, 58 yr; 73% male), were similar.IgG4-related disease accounts for a substantial percentage of patients with “idiopathic” RPF. Histopathologic features such as storiform fibrosis, obliterative phlebitis, and tissue eosinophilia are critical to identifying this disease association. Extraretroperitoneal manifestations of IgG4-related disease are also often present among patients with IgG4-related RPF. Elevated IgG4/total IgG ratios in tissue biopsies are more useful than the number of IgG4+ plasma cells per high-power field in cases of RPF that are highly fibrotic.