Luis Socha

Macrophage migration inhibitory factor exhibits a pronounced circadian rhythm relevant to its role as a glucocorticoid counter-regulator

In humans, maximal expression of T helper 1 cytokines coincide with the nocturnal nadir of plasma cortisol, whereas T helper 2 cytokine responses are dominant during day‐time. The pro‐inflammatory cytokine, macrophage migration inhibitory factor counter‐regulates glucocorticoid‐mediated immune suppression. To determine the relationship between cortisol and macrophage migration inhibitory factor, healthy volunteers had blood drawn hourly for 24 h for measurement of plasma cortisol and basal‐ and stimulated‐macrophage migration inhibitory factor. Similar to cortisol, macrophage migration inhibitory factor peaked during the late morning whereas interferon‐γ, tumour necrosis factor‐α, interleukin‐1 and interleukin‐12 demonstrated a nocturnal peak. After oral cortisone, plasma macrophage migration inhibitory factor rose 2–4‐fold, whereas the other cytokines decreased. There was no correlation between cortisol during the insulin tolerance test and plasma macrophage migration inhibitory factor. The late morning peak of macrophage migration inhibitory factor, by antagonizing cortisol‐mediated pro‐inflammatory cytokine suppression may prolong the duration of early morning inflammation. These observations explain the beneficial role of macrophage migration inhibitory factor neutralization in models of inflammatory arthritis.

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.

The Role of Endoplasmic Reticulum Stress in Nonimmune Diabetes: NOD.k iHEL, a Novel Model of β Cell Death

Abstract: The final common pathway in diabetes development is β cell apoptosis. We herein describe a novel diabetes model based on transgenic NOD.k iHEL mice, wherein male mice develop diabetes due to nonimmune‐mediated β cell death. Histology and electron microscopy confirm endoplasmic reticulum (ER) abnormalities that are consistent with endoplasmic stress caused by the HEL transgene. The NOD.k iHEL model may be particularly useful for studying mechanisms of β cell death secondary to ER stress and also for testing potential therapies designed to protect β cells from stress‐induced apoptosis. The observation that only male NOD.k iHEL mice develop diabetes and exhibit ER abnormalities is intriguing and suggests these mice may be useful in deciphering the link between hyperandrogenism, insulin resistance, and diabetes.

Mechanisms of Accelerated Immune-Mediated Diabetes Resulting from Islet β Cell Expression of a Fas Ligand Transgene

Nonobese diabetic (NOD) mice transgenic for Fas ligand (FasL) on islet β cells (HIPFasL mice) exhibit an accelerated diabetes distinct from the normal autoimmune diabetes of NOD mice. This study was undertaken to define the mechanism underlying accelerated diabetes development in HIPFasL mice. It was found that diabetes in HIPFasL mice is dependent on the NOD genetic background, as HIPFasL does not cause diabetes when crossed into other mice strains and is lymphocyte dependent, as it does not develop in HIPFasLSCID mice. Diabetes development in NODSCID recipients of diabetic HIPFasL splenocytes is slower than when using splenocytes from diabetic NOD mice. β cells from HIPFasL mice are more susceptible to cytokine-induced apoptosis than wild-type NOD β cells, and this can be blocked with anti-FasL Ab. HIPFasL islets are more rapidly destroyed than wild-type islets when transplanted into nondiabetic NOD mice. This confirms that FasL+ islets do not obtain immune privilege, and instead NOD β cells constitutively expressing FasL are more susceptible to apoptosis induced by Fas-FasL interaction. These findings are consistent with the accelerated diabetes of young HIPFasL mice being a different disease process from the autoimmune diabetes of wild-type NOD mice. The data support a mechanism by which cytokines produced by the insulitis lesion mediate up-regulation of β cell Fas expression, resulting in suicide or fratricide of HIPFasL β cells that overexpress FasL.

Use of Artificial Neural Networks in Improving Renal Transplantation Outcomes

Recent advances in renal transplantation, including the matching of major histocompatibility complex or new immunosuppressants, have improved 1-year survival of cadaver kidney grafts to more than 85%. Further optimization of kidney transplant outcomes is necessary to enhance both the graft survival time and the quality of life. Techniques derived from the artificial intelligence enable better prediction of graft outcomes by using donor and recipient data. The authors used an artificial neural network (ANN) to model kidney graft rejection and trained it with data on 1542 kidney transplants. The ANN correctly predicted 85% of successful and 72% of failed transplants. Also, ANN correctly predicted the type of rejection (hyperacute, acute, subacute, and chronic) for approximately 60% of the failed transplants. These results indicate that the ANN-based approach is useful for prediction of both the general outcomes of kidney transplants and the prediction of the type of rejection.

Autoimmune diabetes in the NOD mouse: an essential role of Fas-FasL signaling in β cell apoptosis

Abstract: Despite evidence that both Fas and FasL can be expressed in pancreatic islets, there has been considerable controversy regarding the potential role of Fas signaling in autoimmune β cell death. Using the HIPFasL model, we have been able to demonstrate that, in the presence of an inflammatory infiltrate, FasL‐expressing β cells are exquisitely sensitive to Fas‐mediated apoptosis and that this can be blocked by preventing FasL‐Fas interaction. This points to a highly important role of Fas‐FasL interaction in autoimmune β cell death.

Elevated Lymphocyte Expression of CLIP Is Associated with Type 1 Diabetes and May Be a Useful Marker of Autoimmune Susceptibility

Abstract: Type 1 diabetes (T1D) susceptibility in humans and in the non‐obese diabetic mouse is linked to MHC class II molecules characterized by an amino acid substitution at position 57 of the beta‐chain (nonAspB57). The mechanism whereby nonAspB57 MHC molecules contribute to diabetes susceptibility is not currently known. As CLIP is displaced from MHC class II molecules upon peptide binding, if nonAspB57 haplotypes are associated with high CLIP expression, this may reflect a defect in peptide loading. Non‐obese diabetic mice have higher mononuclear cell CLIP expression than non‐diabetes prone strains, raising the question of whether humans with T1D also exhibit increased CLIP levels. We therefore sought to test whether subjects with T1D have higher levels of leukocyte CLIP expression. Cell surface expression of CLIP was measured on lymphocytes and monocytes using a FITC‐conjugated antibody against human CLIP (Pharmingen). Leukocyte CLIP expression was significantly higher in the blood of T1D patients compared to non‐diabetic controls. Increased CLIP expression was not a secondary effect of hyperglycemia as CLIP expression was not increased in subjects with type 2 diabetes. This confirms that elevated CLIP expression is a feature of T1D and may be a useful marker for T1D susceptibility.