Ghrelin for cachexia

Ghrelin, a natural ligand for the growth hormone (GH)-secretagogue receptor, is primarily produced in the stomach. Administration of ghrelin stimulates food intake and GH secretion in both animals and humans. Ghrelin is the only circulating hormone known to stimulate appetite in humans. As GH is an anabolic hormone, protein stores are spared at the expense of fat during conditions of caloric restriction. Ghrelin also inhibits the production of anorectic proinflammatory cytokines. Thus, ghrelin exhibits anti-cachectic actions via both GH-dependent and -independent mechanisms. Several studies are evaluating the efficacy of ghrelin in the treatment of cachexia caused by a variety of diseases, including congestive heart failure, chronic obstructive pulmonary disease, cancer, and end-stage renal disease. These studies will hopefully lead to the development of novel clinical applications for ghrelin in the future. These studies have also facilitated a better understanding of the molecular basis of the anti-catabolic effects of ghrelin. This review summarizes the recent advances in this area of research

Ghrelin and Functional Dyspepsia

The majority of patients with dyspepsia have no identifiable cause of their disease, leading to a diagnosis of functional dyspepsia (FD). While a number of different factors affect gut activity, components of the nervous and endocrine systems are essential for normal gut function. Communication between the brain and gut occurs via direct neural connections or endocrine signaling events. Ghrelin, a peptide produced by the stomach, affects gastric motility/emptying and secretion, suggesting it may play a pathophysiological role in FD. It is also possible that the functional abnormalities in FD may affect ghrelin production in the stomach. Plasma ghrelin levels are reported to be altered in FD, correlating with FD symptom score. Furthermore, some patients with FD suffer from anorexia with body-weight loss. As ghrelin increases gastric emptying and promotes feeding, ghrelin therapy may be a new approach to the treatment of FD

Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves’ Disease

Graves’ disease (GD) is an organ-specific autoimmune disease, and thyrotropin (TSH) receptor (TSHR) is a major autoantigen in this condition. Since the extracellular domain of human TSHR (TSHR-ECD) is shed into the circulation, TSHR-ECD is a preferentially immunogenic portion of TSHR. Both genetic factors and environmental factors contribute to development of GD. Inheritance of human leukocyte antigen (HLA) genes, especially HLA-DR3, is associated with GD. TSHR-ECD protein is endocytosed into antigen-presenting cells (APCs), and processed to TSHR-ECD peptides. These peptide epitopes bind to HLA-class II molecules, and subsequently the complex of HLA-class II and TSHR-ECD epitope is presented to CD4+ T cells. The activated CD4+ T cells secrete cytokines/chemokines that stimulate B-cells to produce TSAb, and in turn hyperthyroidism occurs. Numerous studies have been done to identify T- and B-cell epitopes in TSHR-ECD, including (1) in silico, (2) in vitro, (3) in vivo, and (4) clinical experiments. Murine models of GD and HLA-transgenic mice have played a pivotal role in elucidating the immunological mechanisms. To date, linear or conformational epitopes of TSHR-ECD, as well as the molecular structure of the epitope-binding groove in HLA-DR, were reported to be related to the pathogenesis in GD. Dysfunction of central tolerance in the thymus, or in peripheral tolerance, such as regulatory T cells, could allow development of GD. Novel treatments using TSHR antagonists or mutated TSHR peptides have been reported to be effective. We review and update the role of immunogenic TSHR epitopes and HLA in GD, and offer perspectives on TSHR epitope specific treatments

Epitope Recognition in HLA-DR3 Transgenic Mice Immunized to TSH-R Protein or Peptides

Development of Graves\u27 disease is related to HLA-DR3. The extracellular domain (ECD) of human TSH receptor (hTSH-R) is a crucial antigen in Graves\u27 disease. hTSH-R peptide 37 (amino acids 78–94) is an important immunogenic peptide in DR3 transgenic mice immunized to hTSH-R. This study examined the epitope recognition in DR3 transgenic mice immunized to hTSH-R protein and evaluated the ability of a mutant hTSH-R peptide to attenuate the immunogenicity of hTSH-R peptide 37. DR3 transgenic mice were immunized to recombinant hTSH-R-ECD protein or peptides. A mutant hTSH-R 37 peptide (ISRIYVSIDATLSQLES: 37m), in which DR3 binding motif position 5 was mutated V\u3eA, and position 8 Q\u3eS, was synthesized. 37m should bind to HLA-DR3 but not bind T cell receptors. DR3 transgenic mice were immunized to hTSH-R 37 and 37m. Mice immunized to hTSH-R-ECD protein developed strong anti-hTSH-R antibody, and antisera reacted strongly with hTSH-R peptides 1–5 (20–94), 21 (258–277), 41 (283–297), 36 (376–389), and 31 (399–418). Strikingly, antisera raised to hTSH-R peptide 37 bound to hTSH-R peptides 1–7 (20–112), 10 (132–50), 33 (137–150), 41, 23 (286–305), 24 (301–320), 36, and 31 as well as to hTSH-R-ECD protein. Both antibody titers to hTSH-R 37 and reaction of splenocytes to hTSH-R 37 were significantly reduced in mice immunized to hTSH-R 37 plus 37m, compared with mice immunized to hTSH-R 37 alone. The ability of immunization to a single peptide to induce antibodies that bind hTSH-R-ECD protein, and multiple unrelated peptides, is a unique observation. Immunogenic reaction to hTSH-R peptide 37 was partially suppressed by 37m, and this may contribute to immunotherapy of autoimmune thyroid disease

Successful Treatment of Protein-Losing Gastroenteropathy with Steroid Pulse and Immunosuppressive Therapies in a Patient with Sjögren Syndrome

We report the case of a 59-year-old female who developed facial edema together with hypoproteinemia. On the basis of 99mTc-human serum albumin scintigraphy and a1-antitrypsin clearance, she was diagnosed with protein-losing gastroenteropathy. Furthermore, she was diagnosed with Sjögren syndrome on the basis of eye and oral dryness, positive result with anti-SSA antibody, and salivary gland biopsy. Her symptoms improved with the use of immunosuppressive agents following steroid pulse therapy. Therefore, steroid pulse therapy and immunosuppressive agents should be considered as possible effective treatment strategies for protein-losing gastroenteropathy associated with autoimmune diseases

Sight-threatening Graves’ orbitopathy: Twenty years’ experience of a multidisciplinary thyroid-eye outpatient clinic

CONTEXT: Sight-threatening Graves' orbitopathy affects 3% to 5% of patients with Graves' orbitopathy. OBJECTIVES: To describe the management of patients with sight-threatening Graves' orbitopathy seen in a multidisciplinary thyroid-eye outpatient clinic dedicated to Graves' orbitopathy (GO). PATIENTS AND METHODS: We enrolled all patients with sight-threatening GO (dysthyroid optic neuropathy and corneal ulcer as defined in the EUGOGO statement) seen and treated in our GO multidisciplinary thyroid-eye outpatient clinic over the last two decades. RESULTS: A total of 31 patients (median age 51 years old) including 24 women (77%) and 58% active smokers. This population represented 47 cases (case = eye) of sight-threatening GO. Dysthyroid optic neuropathy (DON) occurred in 40 eyes, corneal ulcer in 15 eyes and both in 8. At presentation, the clinical features of DON were reduced visual acuity (85%), visual field defects (80%), optic disc swelling (42%) and reduced colour vision (100%). At one year, surgical orbital decompression (OD) was performed in 82.5% of DON cases. Only seven eyes with DON were treated with pulses of intra-venous glucocorticoids. For 10 patients, several therapeutic strategies (OD n = 4, punctal plug n = 1, amniotic membrane graft n = 2, tarsorrhaphy n = 2, botulinum toxin injection = 3 and eyelid surgery n = 2) were used to treat corneal ulcer. For each ophthalmological parameter, more than 85% of DON cases had recovery or improvement after treatment. For visual acuity in corneal ulcer, it was 71.4%. CONCLUSION: We report 47 cases of sight-threatening GO. Orbital decompression was performed in the majority of DON cases and several therapeutic strategies were necessary to treat corneal ulcer. The results are satisfactory in sight-threatening Graves' orbitopathy due to multidisciplinary management

The regions within the N-terminus critical for human glucagon like peptide-1 receptor (hGLP-1R) cell Surface expression

The hGLP-1R is a target for the treatment of type 2 diabetes and belongs to the class B family of GPCRs. Like other class B GPCRs, the GLP-1R contains an N-terminal signal peptide (SP) and undergoes N-linked glycosylation, which are important for its trafficking and maturation. This study analysed the role of the SP, the hydrophobic region after the SP (HRASP), glycosylation and the conserved residues within the N-terminus in GLP-1R trafficking. HGLP-1R targeted to the cell surface showed no SP, and the SP deleted mutant, but not the mutants defective in SP cleavage, showed cell surface expression, demonstrating the importance of SP cleavage for hGLP-1R cell surface expression. The N-terminal deletions of hGLP-1R revealed that the HRASP, not the SP, is essential for cell surface expression of GLP-1R. Further, inhibition of hGLP-1R glycosylation prevented cell surface expression of the receptor. Mutation of Trp39, Tyr69 and Tyr88, which are required for agonist binding, in the GLP-1R abolished cell surface expression of the receptor independent of the SP cleavage or N-linked glycosylation. In conclusion, the N-terminus of hGLP-1R regulates receptor trafficking and maturation. Therefore this study provides insight into the role of hGLP-1R N-terminus on the receptor cell surface expression