Current therapies for autoimmune diseases are not cures but merely palliatives, aimed at reducing symptoms. For the most part, these treatments provide nonspecific suppression of the immune system and thus do not distinguish between a pathogenic autoimmune response and a protective immune response. Recently emerging evidence not only has indicated the involvement of members of the TNF receptor/ligand superfamilies but also has revealed exciting innovative strategies for the treatment of autoimmune diseases and other chronic inflammatory diseases without depressing the immune response in general. In this review, we will discuss the regulatory mechanisms of TNF receptor/ligand family members, such as HVEM/ LIGHT, 4-1BB/4-1BBL, and GITR/GITRL that regulate T and B cell functions and participate in the process of inflammatory diseases. We will also discuss how intervening in the costimulatory pathways mediated by these molecules might have some potential as a therapeutic approach to immune disorders.
Animals ; Apoptosis ; Autoimmune Diseases/immunology/metabolism/pathology ; B-Lymphocytes/immunology/physiology ; Dendritic Cells/physiology ; Human ; Inflammation/*immunology ; Lymphocyte Activation/immunology ; Models, Biological ; Receptors, Tumor Necrosis Factor/*physiology ; T-Lymphocytes/immunology/physiology ; Tumor Necrosis Factor/immunology/*physiology

Lymphocytic hypophysitis is a rare inflammatory disorder which is caused by autoimmune destruction of the pituitary gland. Almost all reported cases have been in women and the disease is often associated with pregnancy. We describe here the first male case of lymphocytic hypophysitis in Korea. The patient presented with headache, impotence, decreased libido, and deteriorated vision. Endocrinologic studies showed panhypopituitarism, and pituitary MRI imaging revealed a homogeneously enhanced pituitary mass with a thickened stalk. Treatment with prednisolone and thyroid hormone for five months was ineffective. Transsphenoidal resection of the pituitary mass was performed successfully with normalization of the visual field defect. Histologic examination revealed diffuse lymphocytic infiltration with dense collagenous fibrosis, consistent with lymphocytic hypophysitis. Lymphocytic hypophysitis should be considered in differential diagnosis even in men with hypopituitarism and an enlarged pituitary gland.
Adult ; Autoimmune Diseases/diagnosis* ; Autoimmune Diseases/pathology ; Autoimmune Diseases/surgery ; Eosinophilia ; Female ; Human ; Korea ; Lymphocytes/cytology ; Lymphocytes/immunology* ; Lymphocytes/metabolism ; Magnetic Resonance Imaging ; Male ; Pituitary Diseases/diagnosis* ; Pituitary Diseases/pathology ; Pituitary Diseases/surgery ; Pituitary Gland/pathology* ; Pituitary Gland/surgery ; Pituitary Hormones/metabolism ; Pregnancy

OBJECTIVETo observe the morphological and molecular biological peculiarities of the experimental autoimmune prostatitis (EAP) rat model made by SC purified prostate protein twice with immune adjuvant.

METHODSMale rats were intradermally immunized with a saline extract of male rat prostate glands (RPG) in Freund's complete adjuvant (FCA) and Pertussis-Diphtheria-Tetanus vaccine 0.5 ml i.p. at the 0 and 30th day, and the concentrations of the extract were respectively 5 mg/ml, 10 mg/ml and 15 mg/ml. At the 45th day, the rats were sacrificed and the morphological and molecular biological changes of the prostate specimens were observed to determine the effective concentration of RPG for a successful model.

RESULTSThe expression of inflammation genes such as TNF-alpha, IL-1beta, IL-2 and iNOS obviously increased in the high-dosage model group; LM, EM and in situ hybridization revealed appearant chronic inflammation response, but this was not the case in the other two dosage groups.

CONCLUSION15 mg/ml RPG mixed with FCA (1:1) 1.0 ml SC with Pertussis-Diphtheria-Tetanus vaccine 0.5 ml i.p. was an effective dosage for the successful model in our experiment.

Animals ; Autoimmune Diseases ; immunology ; metabolism ; pathology ; Diphtheria-Tetanus-Pertussis Vaccine ; administration & dosage ; Disease Models, Animal ; Freund's Adjuvant ; administration & dosage ; Injections, Intraperitoneal ; Male ; Prostate ; metabolism ; pathology ; Prostatitis ; immunology ; metabolism ; pathology ; Proteins ; administration & dosage ; Rats ; Rats, Wistar

OBJECTIVETo investigate the relations between anti-myelin basic protein antibody (anti-MBP) variation and myelinoclasis in the brain stem following brain trauma.

METHODSIn rat models of brain trauma, MBP content and anti-MBP titer in the blood were measured using enzyme-linked immunosorbent assay (ELISA) at different time points after brain trauma, and the degree of myelinoclasis in the brain stem slices was assessed with osmic acid staining.

RESULTSEarly after brain trauma, MBP content in the blood increased followed by significant reduction 10 days later. Four days after the trauma, anti-MBP titer was markedly increased, accompanied by obvious exacerbation of myelinoclasis in the brain stem, both reaching the highest levels on day 10, at the point of which anti-MBP titer increased by 4 folds and the number of myelinoclasis by 10 folds compared with the control group. Anti-MBP titer and brain stem myelinolysis both lowered 30 days later. Correlation analysis showed an intimate positive correlation between anti-MBP titer and the degree of myelinoclasis.

CONCLUSIONAfter brain trauma, MBP is released as a specific antigen into the blood to stimulate the immune system for anti-MBP production, and the antibody is intimately related to the brain stem myelinoclasis.

Animals ; Antibodies ; metabolism ; Brain Injuries ; complications ; Brain Stem ; immunology ; pathology ; Demyelinating Autoimmune Diseases, CNS ; etiology ; immunology ; Female ; Male ; Myelin Basic Protein ; Nerve Tissue Proteins ; blood ; immunology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Transcription Factors ; blood ; immunology

OBJECTIVETo investigate clinicopathological features of fibrous mass-forming chronic pancreatitis (FMCP), to compare clinicopathological and immunohistochemical characteristics between autoimmune pancreatitis (AIP) and fibrous mass-forming non-autoimmune pancreatitis (nAIP) and to provide evidence for pathological diagnosis, differential diagnosis and clinical treatment strategy.

METHODSClinicopathological features were analyzed in 81 cases of FMCP. Infiltrating IgG4(+) plasmacytes were counted by immunohistochemical staining.

RESULTSAmong 81 cases of FMCP, 20 cases were diagnosed as AIP and 61 cases were interpreted as nAIP. AIP was more common in males over 50 years, whereas nAIP was seen in much younger patients (P = 0.001). The amount of inflammatory cells in the stroma of AIPs was remarkable higher than that in nAIPs (P = 0.002). The incidence of neuritis in AIPs (100%, 20/20) was also higher compared with that of nAIPs (75.4%, 46/61; P = 0.017). Storiformed-fibrosis was more common in AIPs (95.0%, 19/20) than in nAIPs (1.6%, 1/61;P = 0.000). Pancreatic intraepithelial neoplasia (PanIN) was observed in 50.0%(10/20) of AIPs and 32.8%(20/61) of nAIPs, with a greater severity observed in AIPs (P = 0.031). Tubular complex (TC) was more commonly observed in AIPs (65.0%, 13/20) than nAIPs (26.2%, 16/61;P = 0.002). Among 81 cases of FMCP, 61 cases had less than 11 IgG4(+) plasmacytes /HPF, 7 cases had 10-30/HPF and 13 cases had over 30/HPF.

CONCLUSIONSFMCPs include both AIP and nAIP. AIP has distinct pathological features and the presence of IgG4(+) plasmacyte is an important diagnostic parameter. FMCP appears to be an important precancerous lesion of pancreatic ductal adenocarcinoma. Surgery may be considered for patients with FMCP due to its mass-forming nature. In contrast, patients with AIP are treated medically due to its steroid-responsiveness. Therefore, accurate and timely diagnosis of AIP is of clinical relevance to avoid unnecessary surgical complications and to prevent progression of the disease.

Adult ; Aged ; Autoimmune Diseases ; immunology ; pathology ; surgery ; Carcinoma, Pancreatic Ductal ; immunology ; pathology ; surgery ; Diagnosis, Differential ; Female ; Fibrosis ; Humans ; Immunoglobulin G ; metabolism ; Male ; Middle Aged ; Pancreas ; pathology ; Pancreatic Neoplasms ; immunology ; pathology ; surgery ; Pancreatitis, Chronic ; immunology ; pathology ; surgery ; Plasma Cells ; immunology ; Precancerous Conditions ; immunology ; pathology ; surgery ; Young Adult

OBJECTIVETo determine whether increased expressions of gelatinases occur with aging in vivo in kidney tissue of autoimmune MRL/lpr mice by in situ zymography.

METHODSMRL/lpr mice at the age of 8 weeks, 16 weeks and 24 weeks were investigated. Kidney protein extracts were compared for activities of MMP-2/9 by gelatin zymography. Immunohistochemistry and SDS-PAGE gelatin zymography were used to determine the expressions and activities of gelatinase A (MMP-2) and gelatinase B (MMP-9). To determine the net gelatinase activities in murine lupus kidney, in situ zymography was used with autoradiographic emulsion as substrate.

RESULTSBoth gelatinase A and B were seldom detected in the kidney tissue in 8 week old mice, Increased expressions of both latent and activated form enzymes of MMP-2/9 were identified in kidney extraction by SDS-PAGE gelatin zymography and immunohistochemical staining showed both MMP-2 and MMP-9 were obviously up-regulated within glomerulus as well as tubular-interstitium in mice at the age of 16 and 24 weeks. In situ zymography showed markedly increased gelatinase activities in kidney tissue consistent with the results of immunohistochemical staining, it is mainly derived from MMPs and inhibited by EDTA but not by PMSF or aprotinin.

CONCLUSIONSThese in vivo results suggested that MMP-2/-9 expressions were significantly up-regulated with aging in murine lupus nephritis, which may play an important role in promoting the remodeling formation of ECM and thus contribute to the progression of renal damage in this model.

Aging ; physiology ; Animals ; Autoimmune Diseases ; enzymology ; immunology ; pathology ; Disease Models, Animal ; Electrophoresis, Polyacrylamide Gel ; Female ; Lupus Nephritis ; enzymology ; immunology ; pathology ; Male ; Matrix Metalloproteinase 2 ; metabolism ; Matrix Metalloproteinase 9 ; metabolism ; Mice ; Mice, Inbred MRL lpr ; Up-Regulation

OBJECTIVETo investigate the protein and mRNA expression patterns of apoptosis-related genes, together with evidence of apoptosis, in relation to experimental autoimmune inner ear disease (AIED).

METHODSMale C57BL/6 mice at 4 weeks age (n = 80) were randomly assigned to one of the five group (n = 16). The inbred mice were given a single subcutaneous injection of diluted solution of pertussis and an emulsion containing equal parts of complete Freund adjuvant (CFA) and inner ear antigens (IEAg) extracted form guinea pig. The animals were sacrificed for inner ear examination at a defined time after the immunization (7, 14, 21 or 28 days). An autoimmune inner ear diseases model was established. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (d-UTP) nick end-laying (TUNEL) method. Using immunohistochemical techniques and reverse transcriptase polymerase chain reaction to clarify the profile of Fas, FasL, and bcl-2.

RESULTSUnder normal conditions, no TUNEL-positive cell was observed in the cochlea except for a few positive cells in the supporting cells of Corti's organ and macula sacculi. Inner ear antigens administration induced TUNEL-positive reactions in a wide variety of cells such as inner hair cells, supporting cells, stria vascularis and spiral ligament fibrocytes. No positive staining was evident in outer hair cells, spiral ganglion cells and Scarpa's ganglion cells during the whole period. Fas proteins were expressed in a wide range of cells in inner ear. The levels of Fas mRNA were no significant differences between normal and AIED mice. FasL and bcl-2 proteins could be detected in spiral ganglion cells and Scarpa's ganglion cells both in normal and AIED mice. FasL positive cells increased in number in inner ear of AIED mice. bcl-2 positive cells were not detectable in inner hair cells, stria vascularis and spiral ligament both in normal and AIED mice. The mRNA of three kinds of apoptosis-related genes was detectable in the normal and AIED mice. FasL mRNA was expressed at low levels in normal, being maximal at 14 d post inoculation and decreased gradually to steady levels by 2 weeks. The levels of bcl-2 mRNA increased significantly during the period of AIED.

CONCLUSIONApoptosis mediated by Fas/FasL signal system may play a role in the initiation and maintenance of AIED. bcl-2 has a crucial role in the regulation of the process of apoptosis in the inner ear of AIED mice.

Animals ; Apoptosis ; Autoimmune Diseases ; genetics ; immunology ; metabolism ; pathology ; Fas Ligand Protein ; genetics ; metabolism ; Guinea Pigs ; In Situ Nick-End Labeling ; Labyrinth Diseases ; genetics ; immunology ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins ; genetics ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Spiral Ganglion ; metabolism ; fas Receptor ; genetics ; metabolism