Neuroimmunomodulation in human autoimmune liver disease.

Bidirectional interaction between immune and nervous systems is considered an important biological process in health and disease. However, little is known about the mechanisms involved in their interaction in the human liver. This study examines the distribution of intrahepatic NPY, SP immunoreactive (IR) nerve fibers and their antomical relationship with immunocells containing tumor necrosis factor-α (TNF-α) and nuclear factor κB (NF-κB) in patients with autoimmune hepatitis. Liver specimens were obtained from control liver and autoimmune hepatitis patients. The immunoreactivity was determined by immunohisto- and immunocytochemistry and confocal laser microscopy. In hepatitis, the number of NPY-IR and SP-IR nerve fibers increased significantly. These IR nerve fibers were in very close contact with the lymphocytes. In healthy controls, no NPY-IR, SP-IR or NF-κB IR lymphocytes and only a few TNF-α positive cells, were observed. In hepatitis, some of the lymphocytes showed immunoreactivity for SP and NPY in the portal area. Fluorescent double-labeled immunostaining revealed that in these cells NPY did not colocalize with TNF-α or NF-κB. However, some of the SP fluorescence-positive immune cells exhibited immunostaining for p65 of NF-κB, where their labeling was detected in the nuclei. Under the electronmicroscope, these cells could be identified (lymphocytes, plasmacells and mast cells). The gap between the IR nerve fibers and immunocells was 1 µm or even less. Overexpression of SP in lymphocytes may amplify local inflammation, while NPY may contribute to liver homeostasis in hepatitis. Neural immunomodulation (SP antagonists and NPY) might be a novel therapeutic concept in the management of liver inflammation.

Colocalization of substance P with tumor necrosis factor-α in the lymphocytes and mast cells in gastritis in experimental rats.

OBJECTIVE: Substance P (SP) elicits numerous potent neuroimmunomodulatory effects, increasing the release of tumor necrosis factor alpha (TNF-α). The study aimed to investigate immunoneural communication in experimentally-induced gastritis in rats. METHODS: SP-containing nerve fibers and lymphocytes and mast cells were counted in the mucosa of the stomachs of rats using double immunohistochemical and confocal laser microscopic methods, proving colocalization of SP and TNF-α in the lymphocytes and mast cells. RESULTS: In controls, only the nerve fibers showed SP immunoreactivity (IR). However, in gastritis the number of SP-IR fibers and TNF-α IR lymphocytes and mast cells increased significantly (P < 0.001); SP-IR fibers were seen in close contact with lymphocytes and mast cells. Numerous lymphocytes (13.1%) and mast cells (10.8%) showed IR for both SP and TNF-α (colocalization) within the same cells. CONCLUSION: SP release from nerve fibers, lymphocytes and mast cells together with TNF-α can enhance the development of gastric inflammation and participate in tissue damage in gastritis.

Distribution and possible origin of neuropeptide-containing nerve elements in the mammalian liver.

The intrahepatic distribution of nerve fibres is highly species dependent, therefore we searched for a species where the innervation pattern is similar to that of the human liver. Livers of rats, cats, guinea pigs and humans were used. The different nerve elements were identified by ABC immunohistochemistry and analysed semiquantitatively. Large numbers of neuropeptide Y (NPY) and dopamine-beta-hydroxylase immunoreactive (IR) nerve fibres were observed in the human and guinea pig liver, and they were in close contact with portal triads, central veins and ran parallel with liver sinuses. A few substance P, somatostatin and vasoactive intestinal polypeptide IR nerve fibres were also detected intralobularly, while galanin nerve fibres were only observed around portal triads. In the rat liver only a few NPY-positive nerve fibres were found, exclusively in portal tracts. Some nerve cell bodies (IR for NPY and somatostatin) were also found in the liver of guinea pigs, young cats and humans, therefore some of the nerve terminals might originate from these intrinsic ganglia. It can be concluded that the innervation pattern of the guinea pig liver shows the highest similarity to that of the human liver.

[Changes of the different neuropeptide containing nerve elements in the inflamed human gall bladder]. / A küllözo neuropeptidtartalmú idegelemek számának változása humán gyulladt epehólyagban.

BACKGROUND, AIMS: The changes of different neuropeptide containing nerve elements might play a role in the pathogenesis of cholecystitis and the formation of gallstones, therefore the authors have investigated the density of the neuropeptide containing nerve fibres and immunocompetent cells in human gallbladder (control and cholecystitis). METHODS: The different neuropeptide containing nerve elements and immunocytes were detected by avidin-biotin-peroxidase (ABC) immunohistochemistry. RESULTS: In the control gallbladder the density of the different neuropeptide containing nerve fibres showed different pattern in all layers. In the inflamed gallbladder the number of the vasoactive intestinal polypeptide (VIP) positive nerve fibres increased significantly, very dense immunoreactive (IR) nerve fibres were located mainly in the tunica mucosa just below the epithelial lining. The number of the VIP IR nerve cell bodies was also increased. However, the number of the substance P (SP) IR nerve fibres was decreased significantly in the cholecystitis. The number of the neuropeptide Y (NPY) nerve fibres showed no changes, while their distribution was altered compared to the control. In the inflamed area the number of immunocompetent cells was strongly increased (being granulocytes, lymphocytes, plasma cells and mast cells) and some of them were also immunoreactive for SP, calcitonin gene-related peptide (CGRP) and VIP. Close contacts were detected between IR nerve fibres and the immunocytes in several cases. CONCLUSIONS: During inflammation the changes of the neuropeptide containing nerve fibres might alter the function (causing dilation) of the gall bladder, the activated immunocytes can also synthesize neuropeptides (SP, CGRP, VIP), so the released materials (cytokines, chemokines, histamine, as well as neuropeptides) might act in an autocrine and/or paracrine way influencing the function of the organ and of the immune system.

Correlation and immunolocalization of substance P nerve fibers and activated immune cells in human chronic gastritis.

UNLABELLED: Neuropeptides are able to modulate cytokine production by macrophages in response to various stimulators and have a major role in inflammation of different organs. Mammalian poly (ADP-ribose) polymerase (PARP) and nuclear factor kappa B (NF-kappaB) both have been suggested to play a crucial role in inflammatory disorders. Unregulated increase of tumor necrosis factor-alpha (TNF-alpha) may also be pathogenic in inflammatory diseases. The aim of this study was to investigate the correlation between the number of Substance P (SP) containing nerve fibers and activated immune cells using immunohisto-, immunocytochemical (EM) and confocal laser microscopic methods. To investigate expression and activation of immune cells gastric biopsy samples from patients with chronic gastritis were used. The number of SP containing nerve fibers and activated immune cells increased significantly in gastritis. Using monoclonal p65 antibody, activated NF-kappaB was found in inflamed mucosa but was absent in uninflamed mucosa. Immunobinding for the activated form of p65 of NF-kappaB was found in 22% of macrophages and 45% of lymphocytes. The number of immune cells showing IR for NF-kappaB, PARP and TNF-alpha correlated with the increasing number of SP containing fibres. Confocal laser microscopy was used to confirm the colocalization of SP in TNF-alpha and NFkappaB positive lymphocytes and mast cells in inflamed mucosa. Immunoelectronmicroscopic investigation confirmed that these cells belong to lymphocytes, mast cells and macrophages. CONCLUSIONS: The increase of SP in nerve fibers and in activated immune cells further activate the production of other proinflammatory mediators (e.g. TNF-alpha) and therefore generate the chronic inflammation.