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Background: Paraneoplastic pemphigus (PNP) is a devastating autoimmune blistering disease, involving mucocutaneous and internal organs, and associated with underlying neoplasms. PNP is characterized by the production of autoantibodies targeting proteins of the plakin and cadherin families involved in maintenance of cell architecture and tissue cohesion. Nevertheless, the identity of an antigen of Mr 170,000 (p170), thought to be critical in PNP pathogenesis, has remained unknown., Methodology/principal Findings: Using an immunoprecipitation and mass spectrometry based approach, we identified p170 as alpha-2-macroglobuline-like-1, a broad range protease inhibitor expressed in stratified epithelia and other tissues damaged in the PNP disease course. We demonstrate that 10 PNP sera recognize alpha-2-macroglobuline-like-1 (A2ML1), while none of the control sera obtained from patients with bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus and normal subjects does., Conclusions/significance: Our study unravels a broad range protease inhibitor as a new class of target antigens in a paraneoplastic autoimmune multiorgan syndrome and opens a new challenging investigation avenue for a better understanding of PNP pathogenesis.

Overexpression of receptors for regulatory peptides in various human diseases is reportedly of clinical interest. Among these peptides, bombesin and gastrin-releasing peptide (GRP) have been shown to play a physiological and pathophysiological role in pancreatic tissues. Our aim has been to localize bombesin receptors in the human diseased pancreas to identify potential clinical applications of bombesin analogs in this tissue. The presence of bombesin receptor subtypes has been evaluated in specimens of human pancreatic tissues with chronic pancreatitis (n = 23) and ductal pancreatic carcinoma (n = 29) with in vitro receptor autoradiography on tissue sections incubated with 125I-[Tyr4]-bombesin or the universal ligand 125I-[D-Tyr6, beta-Ala11, Phe13, Nle14]-bombesin(6-14) as radioligands and displaced by subtype-selective bombesin receptor agonists and antagonists. GRP receptors were identified in the pancreatic exocrine parenchyma in 17 of 20 cases with chronic pancreatitis. No measurable bombesin receptors were found in the tumor tissue of ductal pancreatic carcinomas, however, GRP receptors were detected in a subset of peritumoral small veins in 19 of 29 samples. Moreover, residual pancreatic islets in these tissues were shown to express the BB3 receptor subtype. These data demonstrate the presence of bombesin receptors in three distinct tissue compartments of the pancreas, namely GRP receptors in the exocrine parenchyma in chronic pancreatitis and in peritumoral vessels around ductal pancreatic carcinomas, and BB3 receptors in residual pancreatic islets. Such a selective expression of bombesin receptor subtypes in pancreatic tissues may not only be of pathophysiological significance but may represent the basis for potential diagnostic and therapeutic clinical applications of bombesin analogs, including GRP receptor scintigraphy to differentiate chronic pancreatitis from ductal pancreatic carcinoma.

The evaluation of peptide receptors in man is needed not only to discover the physiological target tissues of a given peptide but also to identify diseases with a sufficient receptor overexpression for diagnostic or therapeutic interventions. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors have been evaluated in human tumors and in their tissues of origin using in vitro receptor autoradiography with 125I-VIP or 125I-acetyl-PACAP-27 in tissue sections. The VIP/PACAP receptor subtypes VPAC1, VPAC2, and PAC1 were evaluated in these tissues by determining the rank order of potencies of VIP and PACAP as well as VPAC1- and VPAC2-selective analogues. The VIP/PACAP receptors expressed in the great majority of the most frequently occurring human tumors, including breast (100% receptor incidence), prostate (100%), pancreas (65%), lung (58%), colon (96%), stomach (54%), liver (49%), and urinary bladder (100%) carcinomas as well as lymphomas (58%) and meningiomas (100%), are predominantly of the VPAC1 type. Their cells or tissues of origin, i.e., hepatocytes, breast lobules and ducts, urothelium, prostate glands, pancreatic ducts, lung acini, gastrointestinal mucosa, and lymphocytes, also predominantly express VPAC1. Leiomyomas predominantly express VPAC2 receptors, whereas paragangliomas, pheochromocytomas, and endometrial carcinomas preferentially express PAC1 receptors. Conversely, VPAC2 receptors are found mainly in smooth muscle (i.e., stomach), in vessels, and in stroma (e.g., of the prostate), whereas PAC1 receptors are present in the adrenal medulla and in some uterine glands. Whereas the very wide distribution of VIP/PACAP receptors in the normal human body is indicative of a key role of these peptides in human physiology, the high VIP/PACAP receptor expression in tumors may represent the molecular basis for clinical applications of VIP/PACAP such as in vivo scintigraphy and radiotherapy of tumors as well as VIP/PACAP analogue treatment for tumor growth inhibition.

Background & Aims: Gastrin and cholecystokinin (CCK) are gut-brain peptides, with multiple functions in the gastrointestinal tract mediated through CCK-B-gastrin and CCK-A receptors. The receptor localization is, however, not well established in humans. The aim of this study was to investigate the distribution and pharmacological characteristics of CCK-A and CCK-B receptors in the human upper gastrointestinal tract and compare them with those in the rat and dog., Methods: CCK receptors were localized by in vitro receptor autoradiography with 125I-[Leu15]gastrin-I and 125I-[D-Tyr-Gly, Nle(28,31)]-CCK 26-33 in stomach and gallbladder., Results: High concentrations of CCK-B-gastrin receptors were detected in the midglandular region of the human fundic mucosa. CCK-A receptors were found in the basal region of the antral and fundic mucosa. CCK-A receptors were also located in the muscularis propria of antrum, fundus, and gallbladder, whereas CCK-B-gastrin receptors were only detected in gastric fundic circular muscle. Two nonpeptide CCK receptor antagonists distinguish both receptor subtypes. Comparisons among humans, dogs, and rats suggest that localization and density of CCK receptor subtypes in the upper gastrointestinal tract are species-dependent., Conclusions: Localization of CCK receptor subtypes in human upper gastrointestinal tract provides a biochemical and morphological basis for the separate regulatory roles of gastrin and CCK.