基于血凝块纤维网管控的凝血—免疫复合体免疫微环境重塑

创伤初期的免疫微环境是影响组织再生修复结局的重要阶段,而此阶段与创伤区的血液浸润、血凝块形成及其机化等凝血过程相重叠,二者的生物学过程涉及众多相同的免疫细胞集群及细胞因子。近年来发现,血凝块纤维网可通过多种方式作用于免疫细胞,并参与塑造免疫微环境。因此,揭示血凝块纤维网的免疫调控靶点,阐明其调控规律具有重要意义。针对这一“凝血-免疫复合体”,我们首先明确血凝块及其纤维网在组织再生中的作用,进一步揭示纤维网参与塑造免疫微环境的生物学基础,最后介绍基于纤维网管控调控“凝血-免疫复合体”免疫微环境的新进展,本综述旨在为新一代免疫智能型再生材料研发提供思路。

以高颅压为首发表现的自体免疫溶血性贫血1例

患者女,16岁,1990年9月22日因头痛6个月余,加重伴呕吐5天入院。头痛以双侧颓部及枕部为甚,呈胀痛,呕吐多为喷射性。发病前无发热、全身不适等感染表现。除脑膜刺激征可疑外。

Relationship between Vascular Elasticity and Spontaneous Rupture of Hepatocellular Carcinoma

Objective Spontaneous rupture of hepatocellular carcinoma (HCC) is common in Asia and Africa with unclear mechanism. In our previous study, we found that the deposition of immune complex on vascular wall and vascular injury were related to the HCC rupture. In this study, the structure of elastin around the small artery was deeply investigated to confirm our previous study. Methods Immunohistochemical technique and transmission electron microscopy were used to study 23 specimens from ruptured HCC and 30 cases of nonruptured HCC. Results The layer of elastin around the vascular wall was significant thicker in patients with ruptured HCC than that in nonruptured HCC. The proliferation of elastin, abnormal distribution of neutrophil elastase and degradation of collagen fibril were predominantly present in the specimens from ruptured HCC. The phenomenon of electron—dense deposit in the elastic lamina that represented the deposition of immune complex, and the signs of infiltrated neutrophils from bloodstream into the vascular wall that caused the vascular injury, also can be found in ruptured HCC. Since the damaged vessels could become stiff and weak, which would more prone to be splitting and results in hemorrhage and the rupture of HCC, we postulated that the preexisting of immune complex deposition and vascular injury may be relate to the ruptured HCC. Conclusion The vascular injury caused by immune complex deposition might relate to ruptured HCC. Key words hepatocellular carcinoma - rupture - elastin - elastase

Autoimmune thrombocytopenia in response to splenectomy in cirrhotic patients with accompanying hepatitis C

AIM： To estimate the contribution of autoimmune thrombocytopenia to hepatitis C virus-related liver cirrhosis （type C cirrhosis）, we evaluated the influence of splenectomy upon platelet-associated immunoglobulin G （PAIgG） levels and platelet numbers. METHODS： PAIgG titers and immune markers were determined in 24 type C cirrhotic patients with an intact spleen, 17 type C cirrhotic patients submitted to splenectomy, and 21 non-C cirrhosis with an intact spleen. RESULTS： Thrombocytopenia （PLT〈15×10^4/μL） in type C cirrhosis was diagnosed in all patients with an intact spleen, 8 patients submitted to splenectomy, and in 19 non-C cirrhosis with intact spleen. Elevated titers of PAIgG at more than 25.0 ng/107cells were detected in all cirrhotic patients except for one splenectomized patient. PAIgG titers （ng/10^7cells） were significantly higher in the type C cirrhosis with an intact spleen （247.9 ± 197.0） compared with the splenectomized patients （125.6±87.8） or non-C cirrhosis （152.4± 127.4）. PAIgG titers were negatively correlated with platelet counts in type C cirrhotic patients with an intact spleen. In comparison with the type C cirrhosis with an intact spleen, the splenectomized patients had a reduced CD4/CD8 ratio and serum neopterin levels. The spleen index （cm^2） was negatively correlated with platelet counts in the non-C cirrhosis, but not in the type C cirrhosis. CONCLUSION： Our data indicate that the autoimmune mechanism plays an important role in thrombocytosis complicated by HCV-positive cirrhosis. In addition, splenectomy may impair T cells function through, at least in part, a reduction of CD4/CD8 ratio, consequently suppressing PAIgG production.

Effect of perioperative autologous versus allogeneic blood transfusion on the immune system in gastric cancer patients

Background： Allogeneic blood transfusion-induced immunomodulation （TRIM） and its adverse effect on the prognosis of patients treated surgically for cancer remain complex and controversial. However, the potential risk associated with allogeneic blood transfusion has heightened interest in the use of autologous blood transfusion. In the present study, the serum concentrations of neopterin, interferon-gamma （IFN-γ）, T lymphocyte subsets （CD3^＋, CD4^＋, CD8^＋, CD4^＋/CD8^＋） and a possible association between these variables were investigated. The purpose was to further evaluate the effect of autologous versus allogeneic blood transfusion on immunological status in patients undergoing surgery for gastric cancer. Methods： Sixty ASA Ⅰ～Ⅱ（American Society of Anesthesiologists） patients undergoing elective radical resection for stomach cancer were randomly allocated to receive either allogeneic blood transfusion （n=30） or autologous blood transfusion （n=30）. Serum concentrations of the neopterin, IFN-γ and T lymphocyte subsets in the recipients were measured before induction of anesthesia, after operation, and on the 5th postoperative day. Results： Both two groups, serum neopterin, IFN-γ, percentages of T-cell subsets （CD3^＋, CD4^＋）, and CD4^＋/CD8^＋ ratio had significantly decreased after operation, but decreased more significantly in group H （receiving allogeneic blood transfusion） than those in group A （receiving autologous whole blood transfusion） （P〈0.05）. On the 5th postoperative day,serum neopterin, IFN-γ, CD3^＋, CD4^＋ T-cells, and CD4^＋/CD8^＋ ratio returned to the baseline values in group A. In contrast, the above remain decreasing in group H, where there were no significant relations between serum neopterin and IFN-γ. Conclusion：Perioperative surgical trauma and stress have an immunosuppressive impact on gastric cancer patients. Allogeneic blood transfusion exacerbates the impaired immune response. Autologous blood transfusion might be significantly beneficial for immune-compromised patients in the perioperative period, clearly showing its superiority over allogeneic blood transfusion.

Inflammatory pseudotumor of the liver and peripheral eosinophilia in autoimmune pancreatitis

AIM: Inflammatory pseudotumor (IPT) of the liver is a rare benign lesion, the etiology of which remains obscure.It is not associated with any particular diseases apart from phlebitis and Crohn's disease.METHODS: A middle-aged male with hepatic IPT and peripheral eosinophilia associated with autoimmune pancreatitis (AIP) was selected for this study and review of literature.RESULTS: A 59-year-old male was admitted with obstructive jaundice, marked eosinophilia (1 343/mm3)and hypergammaglobulinemia (4 145 mg/dL). Imaging techniques revealed dilatation of the intrahepatic bile duct,stenosis of the common bile duct with diffuse wall thickening, gallbladder wall thickening, irregular narrowing of the pancreatic duct, and swelling of the pancreatic parenchyma. Multiple liver masses were also demonstrated and diagnosed as IPT by biopsy specimens. Six months later, the abnormal features of the biliary tree remarkably improved by the oral administration of prednisolone, and the liver masses disappeared. The swelling of the pancreatic head also improved. The peripheral eosinophil count normalized. IPT associated with AIP, as we know,has not been reported in the literature. The clinical features of the present case mimicked those of pancreatic cancer with liver metastasis. This case deserves to be documented to prevent misdiagnosis of similar cases.

To screen or not to screen? Celiac antibodies in liver diseases

Celiac disease(CD) is a systemic immune-mediated disorder triggered by dietary gluten in genetically predisposed individuals. The typical symptoms are anemia, diarrhea, fatigue, weight loss, and abdominal pain. CD has been reported in patients with primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, aminotransferase elevations, nonalcoholic fatty liver disease, hepatitis B, hepatitis C, portal hypertension and liver cirrhosis. We evaluate recommendations for active screening for CD in patients with liver diseases, and the effect of a gluten-free diet in these different settings. Active screening for CD is recommended in patients with liver diseases, particularly in those with autoimmune disorders, steatosis in the absence of metabolic syndrome, noncirrhotic intrahepatic portal hypertension, cryptogenic cirrhosis, and in the context of liver transplantation. In hepatitis C, diagnosis of CD can be important as a relative contraindication to interferon use. Gluten-free diet ameliorates the symptoms associated with CD; however, the associated liver disease may improve, remain the same, or progress.

B cell depletion in treating primary biliary cirrhosis:Pros and cons

Primary biliary cirrhosis (PBC) is a progressive autoim- mune liver disease of unknown etiology that affects almost exclusively women.Ursodeoxycholic acid (UDCA) is currently the only approved drug by Food and Drug Administration for patients with PBC.Although the precise pathogenesis of PBC remains unclear,it has been postulated that many cell populations,including B cells,are involved in the ongoing inflammatory process,which implicates,not surprisingly,a potential thera- peutic target of depleting B cell to treat this disorder.Rituximab is a chimeric anti-CD20 monoclonal antibody that has been approved for the treatment of lymphoma and some autoimmune diseases such as rheumatoid arthritis.Whether it is effective in the treatment of PBC has not been evaluated.Recently,Tsuda et al [1] demon- strated that B cell depletion with rituximab significantly reduced the number of anti-mitochondrial antibodies (AMA)-producing B cells,AMA titers,the plasma levels of immunoglobulins (IgA,IgM and IgG) as well as se- rum alkaline phosphatase,and it was well tolerated by all the treated patients with no serious adverse events.This observation provides a novel treatment option for the patients with PBC who have incomplete response to UDCA.

Hepatocellular carcinoma with chronic B-type hepatitis complicated by autoimmune hemolytic anemia:A case report

A 57-year-old man consulted a local hospital because of a persistent slight fever. At the age of 37 years he was diagnosed having B-type hepatitis, but left the liver dysfunction untreated. Twenty years later, he was diagnosed having chronic hepatitis B, hepatocellular carcinoma （HCC） and macrocytic anemia, and referred to our hospital for further investigation. A HCC with a maximum diameter of 5.2 cm was detected in segment 8. Results of blood tests included 1.8 mg/dL serum total bilirubin, 0.9 mg/dL bilirubin, less than 10 mg/dL haptoglobin, 7.9 g/dL hemoglobin, 130 fL MCV, and 14.5% reticuloo/tes. A bone marrow sample showed erythroid hyperplasia. The direct Coombs test gave a positive result. We diagnosed the anemia as autoimmmune hemolytic anemia （AIHA）, for which prednisolone could not be administered due to positivity for HBsAg and HBeAg. After preparation of washed blood cells for later transfusion, the patient underwent systematic resection of segment 8. The cut surface of the resected specimen demonstrated an encapsulated yellow-brownish tumor measuring 52 mmx 40 mm which was diagnosed pathologicaly as moderately differentiated HCC. On the 9th postoperative day, the patient＇s temperature rose to 38℃, and exacerbated hemolysis was observed. The maximum total bilirubin value was 5.8 mg/dL and minimum hemoglobin level was 4.6 g/dL. He tolerated this period without blood transfusion. Currently he is being followed up as an outpatient, and shows no signs of HCC recurrence or symptoms of anemia. AIHA associated with HBV infection has been described in only three previous cases, and the present case is the first in which surgery was performed for accompanying HCC.

Detection of anti-Helicobacter pyloriantibodies in serum and duodenal fluid in peptic gastroduodenal disease

AIM:To study the diagnosis of Helicobacter pylori(H pylori) infection through the determination of serum levels of anti- H pylori IgG and IgA antibodies,and the levels of anti-H pylori IgA antibodies in duodenal fluid. METHODS:Data were collected from 93 patients submitted to upper digestive endoscopy due to dyspeptic symptoms. The patients were either negative(group A)or positive (group B)to H pylori by means of both histological detection and urease tests.Before endoscopy,peripheral blood was collected for the investigation of anti-H pylori IgG and IgA antibodies.To perform the urease test,biopsies were obtained from the gastric antrum.For the histological evaluation,biopsies were collected from the gastric antrum (greater and lesser curvatures)and the gastric body. Following this,duodenal fluid was collected from the first and second portions of the duodenum.For the serological assaying of anti-Hpylori IgG and IgA,and anti-Hpylori IgA in duodenal fluids,the ELISA method was utilized. RESULTS:The concentration of serum IgG showed sensitivity of 64.0%,specificity of 83.7%,positive predictive value of 82.0%,negative predictive value of 66.6% and accuracy of 73.1% for the diagnosis of H pylori infection.For the same purpose,serum IgA showed sensitivity of 72.0%, specificity of 65.9%,positive predictive value of 72.0%, negative predictive value of 67.4% and accuracy of 69.8%. If the serological tests were considered together,i.e.when both were positive or negative,the accuracy was 80.0%, sensitivity was 86.6%,specificity was 74.2%,positive predictive value was 74.2% and negative predictive value was 86.6%.When values obtained in the test for detecting IgA in the duodenal fluid were analyzed,no significant difference(P=0.43)was observed between the values obtained from patients with or without H pylori infection. CONCLUSION:The results of serum IgG and IgA tests for H pylori detection when used simultaneously,are more efficient in accuracy,sensitivity and negative predictive value, than those when used alone.The concentration of IgA antibodies in duodenal fluid is not useful in identifying patients with or without H pylori.

Helicobacter pylori infection in patients with autoimmune thrombocytopenic purpura

AIM:To compare the prevalence of Helicobacter pylori (Hpylon)infection in autoimmune thrombocytopenic purpura (AITP)patients with that of nonthrombocytopenic controls, and to evaluate the efficacy of the treatment in H pylori(+) and H pylor(-)AITP patients. METHODS:The prevalence of gastric H pylori infection in 38 adult AITP patients(29 female and 9 male;median age 27 years;range 18-39 years)who consecutively admitted to our clinic was investagated. RESULTS:H pylori infection was found in 26 of 38 AITP patients(68.5%).H pylori infection was found in 15 of 23 control subjects(65.2%).The difference in H pylori infection between the 2 groups was not significant.Thrombocyte count of H pylori-positive AITP patients was significantly lower than that of H pylori-negative AITP patients(P<0.05). Thrombocyte recovery of H pylori-positive group was less than that of H pylori-negative group(P<0.05). CONCLUSION:H pylori infection should be considerecd in the treatment of AITP patients with H pylori infection.

A meta-analysis of soluble suppression of tumorigenicity 2 （sST2） and clinical outcomes in pulmonary hypertension

Suppression of Tumorigenicity 2 （ST2） is a member of the interleukin （IL）-1 receptor family The ST2 receptor exists in two isoforms - ST2 ligand （ST2L） and soluble ST2 （sST2）.ST2L is a membrane receptor and sST2 is a trun- cated receptor which is soluble in the blood, allowing it to be detected in serum. IL-33 is a member of the IL-1 family of ligand and is the fimctional ligand of ST2L receptor. It binds to the ST2L, thereby mediating its immune function.

Multiplex neuritis in a patient with autoimmune hepatitis:A case report

A 37oyear old woman presented with a 9oyear history of hepatitis of unknown origin and aminotransferases within a 3-fold upper limit of normal. Autoimmune hepatitis （AIH） was diagnosed on the basis of elevated aminotransferases, soluble liver antigen/liver pancreas （SLA/LP） autoantibodies and characteristic histology. Immunosuppressive therapy led to rapid normalization of aminotransferases. Two years later, the patient developed left sided hemisensory deficits under maintenance therapy of prednisolone and azathioprine （AZT）. Later she developed right foot drop and paraesthesia in the ulnar innervation territory on both sides. Magnetic resonance imaging （MRI） and cerebral panangiography suggested cerebral vasculitis. Neurological investigation and electromyography disclosed multiplex neuritis （MN） probably due to vasculitis. Consistent with this diagnosis, autoantibodies to extractable nuclear antigens were detectable in serum. Immunosuppression was changed to oral 150 mg cyclophosphamide （CPMO） per day. Prednisolone was increased to 40 mg/d and then gradually tapered to 5 mg. Oral CPM was administered up to a total dose of 40 g and then substituted by 6 times of an intervall infusion therapy of CPM （600 mg/m^2）. Almost complete motoric remission was achieved after 3 mo of CPM. Sensibility remained reduced in the right peroneal innervation territory. Follow-up of cranial MRI provided stable findings without any new or progressive lesions. This is the first report of multiplex neuritis in a patient with autoimmune hepatitis.

Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients

AIM: To report on our large German collective and updated data of 142 patients with autoimmune hepatitis (AIH) type 1. METHODS: Key investigations performed were liver biopsy, serum autoantibodies as well as serum markers such as IgG and elevated transaminases. Antinuclear antigen (ANA) and smooth muscle antigen (SMA) autoantibodies characterized type 1 AIH. Type 3 (AIH) was solely characterized by the occurrence of soluble liver antigen/liver-pancreas antigen (SLA/LP) autoantibodies either with or without ANA or SMA autoantibodies. RESULTS: Most prevalent HLAs were A2 (68 patients, 48%), B8 (63 patients, 44%), C7 (90 patients, 63%), DR3 (49 patients, 38%), DR4 (49 patients, 38%) and DQ2 (42 patients, 30%). Compared to the Italian and North American patients, we found fewer patients with a DQ2 subtype. Furthermore, the B8-DR3-DQ2 human leucocyte antigen (HLA) was also less prominent compared to the North American patients. However, prevalences of B8, DR3, DR4, DR7, DR11 and DR13 were comparable to the Italian and North American patients. Furthermore, we report on an additional subgroup of patients with SLA/LP positive AIH. Generally, in this subgroup of patients the same HLA subtypes were favoured as the AIH type 1. CONCLUSION: Although HLA subtypes were comparable between these three collectives, the German patients were distinct from the Italian and North American patients with respect to DQ2 and from the North American patients with respect to B8-DR3-DQ2HLA. A clinical correlation, e.g. difference in severity or treatability of AIH type 1, has yet to be determined.

Anti-enrofloxacin Antibody Production by Using Enrofloxacin-screened HSA as an Immunogen

A two-step zero-length cross-linking procedure using active esters was successfully adopted for conjugating en-rofloxacin (EF) to human serum albumin (HSA). The derived conjugate was characterized by UV spectrum and then usedfor immunization of BALB/C mice. In enzyme-linked immunosorbent assay (ELISA) and competitive inhibition ELISA ex-periments, the derived antiserum exhibited high antibody titer (greater than 1: 250 000) as well as varied cross-reactivity(from 97.8% to 161.7%) to three analogs of EF belonging to fluoroquinolones family. But over the concentration rangestudied, no significant cross-reactivity was observed to other group of antibiotics (chloramphenicol, oxytetracycline, sul-phamethoxazole and nysfungin). It was confirmed that the synthesized immunogen was highly antigenic and elicited specificantibody responses in BALB/C mice against EF.

Radiofrequency induction on sodium/iodide symporter expression of thyroid cancer

Objective; The aim of this study was to investigate the effects of radiofrequency treatment on sodium/iodide symporter expression of thyroid cancer ceils. Methods： In 29 thyroid cancer patients with low or no expression of soda ／ iodide symporter, the radio frequency combined 1311 therapy was used, the whole-body scintigraphy and serum Ig were detected before and after the radiofrequency treatment. Results： The whole-body scintigraphy showed that 4 cases （4/29） before radiofrequenc_y treatment had positive iodine uptake, 19 cases （19/29） two weeks after radiofrequency treatment had the positive iodine uptake, 12 cases （12/29） four weeks after radiofrequency treatment had the positive iodine uptake. Four weeks after radiofrequency treatment, 5 cases had increased serum Ig levels, 17 cases had decreased serum Ig levels, 7 cases showed no change. 25 cases （25/29） were effective, 15 cases （15/29） were cured. Conclusion： The radiofrequency induced the non-expressed the sodium/iodide symporter of thyroid cancer cells regain the iodine intake ability, it improved the clinical efficacy of 131I therapy in dedifferentiated thyroid cancer.

Immunologic changes to autologous transfusion after operational trauma in malignant tumor patients:Neopterin and Interleukin-2

Objective:To estimate the impact of autologous transfusion on the status of perioperative immune activation inmalignant tumor patients.The Serum Neopterin and Interleukin-2(IL-2)were measured.Methods:Sixty patients undergoingelective radical resection for malignant stomach tumor were enrolled in the prospective study and assigned to the following groups:(Ⅰ)Group A received autologous transfusion;(2)Group H received allogeneic transfusion.The perioperative course(Beforeinduction of anesthesia,after operation and 5 d after operation)of Neopterin and IL-2 was compared.Results:In group A,SerumNeopterin was significantly lower than baseline alter operation and IL-2 had no significant changes.In group H,both SerumNeopterin and IL-2 were significantly lower than baseline alter operation and 5 d after operation.Compared with group A,SerumNeopterin was significantly lower than baseline alter operation and 5 d after operation and IL-2 was significantly lower thanbaseline 5 d alter operation.Conchision:Autologous transfusion decreased the perioperative immune suppression in malignantstomach tumor patients.

Relationship of VEGF/VEGFR with immune and cancer cells:staggering or forward?

Vascular endothelial growth factor(VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown that VEGF also plays a vital role in the immune environment. In addition to the traditional growth factor role of VEGF and VEGF receptors(VEGFRs), they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis. Dendritic cells(DCs), macrophages, and lymphocytes further express certain types of VEGF receptors.VEGF can be secreted as well by tumor cells through the autocrine pathway and can stimulate the function of cancer stemness.This review will provide a paradigm shift in our understanding of the role of VEGF/VEGFR signaling in the immune and cancer environment.

Diagnosis and management of late hepatic allograft dysfunction

Late hepatic allograft dysfunction (LHAD) is common after liver transplantation (LT) and can cause graft failure,retransplantation,or even death.A variety of etiologies including rejection,vascular complications,bile duct complications,recurrent diseases,infections,de novo diseases,neoplasms and drug toxicity can result in LHAD.The recurrent diseases have the potential to become the most serious problems facing LT in the future.It is difficult to differentiate late acute rejection from recurrent viral or autoimmune hepatitis.Accurate diagnosis of the cause of LHAD has therapeutic importance.