Autoreactive CD4(+) T cells are involved in the pathogenesis of many autoimmune diseases, but the antigens that stimulate their responses have been difficult to identify and in most cases are not well defined. In the nonobese diabetic (NOD) mouse model of type 1 diabetes, we have identified the peptide WE14 from chromogranin A (ChgA) as the antigen for highly diabetogenic CD4(+) T cell clones. Peptide truncation and extension analysis shows that WE14 bound to the NOD mouse major histocompatibility complex class II molecule I-A(g7) in an atypical manner, occupying only the carboxy-terminal half of the I-A(g7) peptide-binding groove. This finding extends the list of T cell antigens in type 1 diabetes and supports the idea that autoreactive T cells respond to unusually presented self peptides.

/pdf/chromogranin-a-is-an-autoantigen-in-type-1-diabetes-3vt6x55ter.pdf

Chromogranin A is an autoantigen in type 1 diabetes

The chromogranins (chromogranin A and chromogranin B), secretogranins (secretogranin II and secretogranin III), and additional related proteins (7B2, NESP55, proSAAS, and VGF) that together comprise the granin family subserve essential roles in the regulated secretory pathway that is responsible for controlled delivery of peptides, hormones, neurotransmitters, and growth factors. Here we review the structure and function of granins and granin-derived peptides and expansive new genetic evidence, including recent single-nucleotide polymorphism mapping, genomic sequence comparisons, and analysis of transgenic and knockout mice, which together support an important and evolutionarily conserved role for these proteins in large dense-core vesicle biogenesis and regulated secretion. Recent data further indicate that their processed peptides function prominently in metabolic and glucose homeostasis, emotional behavior, pain pathways, and blood pressure modulation, suggesting future utility of granins and granin-derived peptides as novel disease biomarkers.

/pdf/the-extended-granin-family-structure-function-and-biomedical-1r4uxqayi3.pdf

The Extended Granin Family: Structure, Function, and Biomedical Implications

—The detection of left ventricular (LV) hypertrophy on echocardiography is a powerful risk indicator in essential hypertension. However, the prognostic impact of LV mass values within the “normal” range and the shape of the relation between LV mass and prognosis remain unclear. Thus, 1925 white subjects with uncomplicated essential hypertension underwent off-therapy 24-hour blood pressure monitoring and M-mode echocardiography. During 4.0±2 years of follow-up, there were 181 major cardiovascular events (2.4/100 patient-years) and 49 deaths from all causes. In the 5 gender-specific quintiles of LV mass distribution (partition values: 92, 105, 120, and 138 g/m2 in men and 79, 91, 102, and 116 g/m2 in women), cardiovascular event rates were 0.8, 1.7, 2.2, 2.9, and 4.3 per 100 patient-years. After adjustment for several risk factors, including 24-hour ambulatory blood pressure, the relative risk (RR) of developing a cardiovascular event increased progressively from the first quintile (RR 1) to the sec...

Continuous Relation Between Left Ventricular Mass and Cardiovascular Risk in Essential Hypertension

Chromogranin A (CgA) belongs to the granin family of uniquely acidic secretory proteins co-stored and co-secreted with other hormones and peptides in elements of the diffuse neuroendocrine system. The granins arise from different genes and are characterized by numerous sites for post-translational cleavage into shorter peptides with postulated regulatory properties. This review is directed towards endocrine aspects of CgA and its biologically active peptides. There is ample evidence from in vitro studies of distinct effects and targets for three CgA-derived peptides, vasostatin-I, pancreastatin and catestatin. Endocrine regulations are indicated from in vivo studies, consistent with the postulated prohormone function of CgA for peptides with regulatory properties. Most of the effects fit into patterns of direct or indirect, inhibitory modulations of major functions, implicating CgA peptides in regulation of calcium and glucose metabolism, cardiovascular functions, gastrointestinal motility and nociception, tissue repair, inflammatory responses and as host defense peptides in the first phase of microbial invasions.

The endocrine role for chromogranin A: a prohormone for peptides with regulatory properties.

CAPS-1 and CAPS-2 are essential synaptic vesicle priming proteins.

The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release–inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga–/– and humanized mice through transgenic insertion of a human CHGA haplotype in order to probe CHGA and catestatin in vivo. Chga–/– mice displayed extreme phenotypic changes, including: (a) decreased chromaffin granule size and number; (b) elevated BP; (c) loss of diurnal BP variation; (d) increased left ventricular mass and cavity dimensions; (e) decreased adrenal catecholamine, neuropeptide Y (Npy), and ATP contents; (f) increased catecholamine/ATP ratio in the chromaffin granule; and (g) increased plasma catecholamine and Npy levels. Rescue of elevated BP to normalcy was achieved by either exogenous catestatin replacement or humanization of Chga–/– mice. Loss of the physiological “brake” catestatin in Chga–/– mice coupled with dysregulation of transmitter storage and release may act in concert to alter autonomic control of the circulation in vivo, eventuating in hypertension.

/pdf/hypertension-from-targeted-ablation-of-chromogranin-a-can-be-5raa3a4277.pdf

Saugata Ray

Papers

Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog