Fcγ receptor expression on hepatic macrophages and histological activity of chronic hepatitis

Abstract: Aims/Background: Activated liver macrophages in chronic hepatitis express a high affinity receptor for IgG named FcγRI. This study was performed to find the difference in FcγRI expression between chronic hepatitis B (CHB) and C (CHC) with reference to histological activity. Methods: Consecutive patients with CHB (20 cases) and CHC (25 cases) were enrolled in the study. Inflammatory activity was evaluated using the modified histological activity index (HAI). FcγRI-positive macrophages were quantitatively measured by computer assisted morphometry. Results: Total HAI score was significantly higher in CHB than in CHC. Confluent necrosis was observed in significantly higher frequency in CHB at Stages 3–5 than in CHC. The percentage area of FcγRI-positive macrophages was significantly higher in CHB than in CHC. In CHB, the percentage area of FcγRI-positive macrophages correlated with total HAI (< 0.01) as well as the degree of confluent necrosis (< 0.01), interface hepatitis (< 0.05) and portal inflammation (< 0.05). FcγRI-positive macrophages accumulated mainly at the site of confluent necrosis. In CHC, no correlation was observed between activated macrophages and any histological categories. Conclusion: These results suggest that FcγRI-positive macrophages are associated with confluent necrosis in CHB, which is more common in CHB patients than in CHC.     

Addition of granulocyte colony-stimulating factor to chemotherapy in patients with AIDS-related lymphoma: effects on neutrophil Fcγ receptor expression and soluble FcγRIII plasma levels

AIDS-related neutropenia and neutrophil dysfunction can (partly) be reversed by granulocyte-colony stimulating factor (G-CSF). We studied the effect of G-CSF on neutrophil increment and levels of soluble Fcγ receptor type III in 15 patients with AIDS-related lymphoma (ARL) undergoing chemotherapy. In six of these patients we performed a detailed kinetic analysis of the membrane expression of the functionally important Fcγ-receptors type I, II and III. In all these patients G-CSF induced FcγRI positive neutrophils with a decreased expression of the FcγRIII receptor. These changes were similar to those seen both in healthy volunteers and in non-HIV-infected individuals treated with chemotherapy. Interestingly, the mean neutrophil and sFcγRIII increment were significantly lower and more patients had a nadir granulocyte count < 0.5 × 10⁹/l after the first cycle than after the second cycle of chemotherapy. This may be related to a therapy-associated decrease in HIV-1 viral load. The conclusion is that patients treated with chemotherapy for ARL have a qualitatively normal response to G-CSF.     

Determination of neutrophil Fcγ receptor IIIb antigens (HNA‐1a,HNA‐1b and HNA‐1c) by fluorescence‐primed allele‐specific polymerase chain reaction

We evaluate a technique for genotyping HNA‐1a, ‐1b and ‐1c antigens, resorting to fluorescence‐primed allele‐specific polymerase chain reaction (FPAS‐PCR), and determine the frequency of the different genotypes in a normal Portuguese population. Our results indicate that the FPAS‐PCR system is a reliable and simple tool for genotyping the neutrophil Fcγ receptor IIIB antigens. The HNA‐1a, ‐1b and ‐1c gene frequencies of 42.98, 84.21 and 6.14%, respectively, found in this study are similar to those reported for other white populations.     

类风湿关节炎患者红细胞C3b受体数目改变及基因多态性分析

目的　分析类风湿关节炎（ＲＡ） 患者Ｃ３ｂ受体（Ｃ３ｂＲ） 表达数目及Ｃ３ｂＲ 基因多态性分布规律,探讨Ｃ３ｂＲ 数目改变的可能原因。方法　分别测定６３ 例ＲＡ 患者及健康献血员６０ 人的红细胞Ｃ３ｂ 受体花环率（Ｃ３ｂＲＲ） 及免疫复合物花环率（Ｃ３ｂＩＣＲ） 。用限制性片段长度多态（ＲＦＬＰ） 分析及Ｓｏｕｔｈｅｒｎ ｂｌｏｔｔｉｎｇ 杂交技术检测Ｃ３ｂＲ基因多态性。结果　ＲＡ 患者红细胞Ｃ３ｂＲＲ 和Ｃ３ｂＩＣＲ 分别显著低于和高于正常对照组。Ｃ３ｂＲ基因的两个等位基因基因型和表现型频率在ＲＡ 组和对照组均无显著差异。结论　ＲＡ 患者Ｃ３ｂＲ数目下降可能与基因变异无关,可能是受体基因转录和翻译过程异常所致。设法增加红细胞Ｃ３ｂＲ 数目以加速免疫复合物的清除,可能是治疗ＲＡ的有效途径之一。     

Overexpression of peroxisome proliferator‐activated receptor γ and retinoid X receptor α in gastric carcinomatous tissue

OBJECTIVE: To investigate the expression of peroxisome proliferator‐activated receptor γ (PPAR‐γ) and retinoid X receptor α (RXR‐α) in chronic gastritis, gastric mucosal dysplasia and gastric carcinoma and to identify any correlations between PPAR‐γ and RXR‐α expression in this progression sequence. METHODS: Immunohistochemical methods (avidin? biotin?peroxidase complex) were used to examine the expression of PPAR‐γ and RXR‐α in 53 patients with gastric carcinoma, 18 with gastric mucosal dysplasia and 30 with chronic atrophic gastritis. Thirty‐one patients with chronic non‐atrophic gastritis acted as controls. RESULTS: The positive rates of PPAR‐γ and RXR‐α in gastric carcinoma were 41.5 and 54.7%, 27.8 and 38.9% in gastric mucosal dysplasia, 10.0 and 20.0% in chronic atrophic gastritis, and 6.5 and 16.1% in chronic non‐atrophic gastritis, respectively. The expression of PPAR‐γ and RXR‐α increased during the progression from chronic non‐atrophic gastritis to chronic atrophic gastritis, then to gastric carcinoma. Compared with chronic gastritis, the expression of PPAR‐γ and RXR‐α in gastric mucosal dysplasia and gastric carcinoma was significantly increased (P < 0.05, P < 0.01). In gastric carcinoma, the expression of PPAR‐γ and RXR‐α was not associated with tumor cell differentiation or metastasis in the lymph nodes (P > 0.05). There was a positive correlation between the expression of PPAR‐γ and RXR‐α in gastric carcinoma (r= 0.54, P < 0.01). CONCLUSIONS: Overexpression of PPAR‐γ and RXR‐α protein is apparent in human gastric cancer. This might be an early event in carcinogenesis, and both PPAR‐γ and RXR‐α may play independent and/or synergistic roles in the progression of gastric carcinoma.     

Gamma-chain heterogeneity in Greek (δβ)O-thalassemia.

Abstract: A molecular and biochemical population study of (δβ)^O thalassemia in central Greece is described. The molecular study was focused on the type of the deletion and the status of ^Gγ-Xmn***l polymorphism, whereas the biochemical approach was centered on the ^Gγ/^Aγ ratio as well as the frequency of the ^Aγ ^T chain in the fetal hemoglobin of 19 δβ-thalassemia heterozygotes and 3 homozygotes. This study includes individuals from the mountainous district of Epirus (northwestern Greece) where the trait was found to be concentrated along the river Arachthos. The Sicilian (δβ)^O thalassemia deletion was found in all subjects tested by direct PCR. The levels for the ^Gγ-chain presented values ranging from 29 to 83% of the total γ -chain content. Thirteen heterozygotes had the adult ^Gγ /^Aγ ratio (mean ^Gγ: 35% ± 10) of whom 10 were Xmnl-negative (-/-), 6 had the newborn ratio (mean ^Gγ: 70% ± 9) and were Xmnl-positive, while homozygotes had equal amounts of ^Gγ and ^Aγ. Five of the 19 heterozygotes were ^Aγ ^T-positive with low levels of this ^Aγ-chain variant, suggesting an in-trans to the δβ-thalassemia determinant production.     

Tγ Cell Deficiency in Idiopathic Thrombocytopenic Purpura (ITP)

A significant reduction in the proportion and absolute number of circulating T_γ (suppressor) lymphocytes was observed in 15 adult patients with idiopathic thrombocytopenic purpura (ITP). The proportion of T_γ cells was also reduced in the spleen of four patients so investigated. This abnormality was not seen in 5 patients cured by splenectomy whilst it persisted in 3 who remained thrombocytopenic after splenectomy. The proportion of Tμ (helper) lymphocytes in ITP was normal. These findings, similar to those reported in systemic lupus erythematosus, suggest that an inbalance of the immunoregulatory T-cell subsets may be important in the pathogenesis of ITP.     

Fc γ R IIIB polymorphisms: their association with clinical manifestations and autoantibodies in SLE patients from Western India

Background: Receptors for the Fc fragment of immunoglobulin G (Fc γ Rs) represent the link between the humoral and cellular immune responses. Polymorphisms of Fc γ R, mainly IIA, IIB, IIIA, IIIB have been identified as genetic factors influencing susceptibility to disease or disease course of a prototype autoimmune disease like systemic lupus erythematosus (SLE). Fc γ alleles may be associated with inefficient removal of apoptotic cells or antigens and hence may be associated with higher risk of SLE. Objective: This study was designed to look for Fc γ RIIIB polymorphisms of three different alleles, NA1, NA2 and SH in SLE patients and to correlate the distribution of Fc γ RIIIB genotypes with clinical presentation and autoantibody profile. Material and methods: Eighty SLE patients along with eighty normal individuals were studied. Fc γ RIIIB polymorphism was tested by allele‐specific primer amplification. Results: The percentage distribution of NA1/NA1, NA1/NA2 and NA2/NA2 was 22.5%, 40% and 37.5%, respectively, among the normal population; and among SLE patients it was 25%, 40% and 35%, respectively. The percentage distribution of SH allele was 68.8% among the normal population, while in SLE patients it was 60%. No statistical difference was found in the distribution of Fc γ R IIIB genotypes in patients of lupus nephritis and SLE without nephritis (P > 0.05). Conclusion: Among SLE patients studied, NA2 was the prominent allele. It was commonly associated with clinical manifestations such as skin rash, arthritis, hematological and immunological disorders. This suggests that the primary involvement of Fc γ R IIIB NA2 allele is more likely involved with disease susceptibility of SLE.     

Transforming growth factor-β (TGF-β) type I and type II receptors are both required for TGF-β-mediated extracellular matrix production in lung fibroblasts

Transforming growth factor-β (TGF-β) regulates a variety of cellular activities including cell growth, differentiation and extracellular matrix production. The TGF-β type I and type II serine/threonine kinase receptors (TβRI and TβRII) have been identified as signal-transducing TGF-β receptors. This study was undertaken to examine the role of the type I and type II receptors in TGF-β-induced extracellular matrix production of lung fibroblasts. We constructed expression plasmids containing truncated derivatives of TβRI and TβRII that lacked the cytoplasmic serine/threonine kinase domain (TβRIΔK and TβRIIΔK), and transfected them into lung fibroblasts. TβRIIΔK expressed by lung fibroblasts was able to bind ¹²⁵I-TGF-β1, whereas TβRIΔK was unable to bind ligand when expressed alone. Co-expression with TβRII was required for binding and cross-linking of TGF-β1 to TβRIΔK. Lung fibroblasts upregulate tenascin and fibronectin production when treated with TGF-β1. The kinase-defective deletions of both TβRI and TβRII were dominant-acting inhibitors of TGF-β signal transduction. Expression of either TβRIΔK or TβRIIΔK alone was sufficient to block TGF-β-induced tenascin and fibronectin production of lung fibroblasts. The results indicate that both TβRI and TβRII were required for TGF-β signaling in regulation of extracellular matrix production by lung fibroblasts.     

Thiazolidinedione‐independent activation of peroxisome proliferator‐activated receptor γ is a potential target for diabetic macrovascular complications

Macrovascular complications are responsible for the high morbidity and mortality in patients with diabetes. Peroxisome proliferator‐activated receptor γ (PPARγ) plays a central role in the process of adipocyte differentiation and insulin sensitization, and also possesses anti‐atherogenic effects. Recently, some statins, angiotensin II type 1 receptor blockers and calcium channel blockers have been reported to activate PPARγ. However, the impact of PPARγ activation on diabetic macrovascular complications is not fully understood. It has been reported that the activation of PPARγ by thiazolidinediones induces anti‐atherogenic effects in vascular cells, including monocytes/macrophages, endothelial cells and smooth muscle cells, in atherosclerotic animal models and in clinical studies. We have reported that hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), which are used for treatment of hypercholesterolemia, activate PPARγ and mediate anti‐atherogenic effects through PPARγ activation in macrophages. Also, telmisartan, an angiotensin type I receptor blocker, has been reported to have anti‐atherogenic effects through PPARγ activation. Furthermore, we have reported that nifedipine, a dihydropyridine calcium channel blocker, can activate PPARγ, thereby mediating anti‐atherogenic effects in macrophages. Therefore, statin therapy and part of anti‐hypertensive therapy might produce beneficial effects through PPARγ activation in hypercholesterolemic and/or hypertensive patients with diabetes, and PPARγ might be a therapeutic target for diabetic macrovascular complications. In the present review, we focus on the anti‐atherogenic effects of PPARγ and suggest potential therapeutic approaches to prevent diabetic macrovascular complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00182.x, 2012)     

De novo initiation codon mutation (ATG→ACG) of the β-globin gene causing β-thalassemia in a swiss family

Investigation of microcytic anemia with normal ferrous status in two members (father and daughter) of a Swiss family originating from Bern revealed high levels of HbA₂ (4%, 7.3%) and HbF (3.2%, 3.1%). Direct sequence analysis of asymmetrically amplified DNA showed the ATGǎG mutation in the initiation codon of the β-globin gene. Heterozygous β-thalassemia was not found in either of the propositus's parents or in any of his brothers and sisters. Extended restriction fragment length polymorphism haplotyping of the β chromosomes led us to the conclusion of a recent spontaneous mutation in the paternal germ cell. The results of routine HLA and blood group testing supported the stated paternity. We also found that the intragenic sequence polymorphisms (frameworks) are not always in linkage disequilibrium with the Bam HI polymorphism downstream from the β-globin gene as previously observed. This is the second family found to carry this initiation codon mutation in the β-globin gene. Unlike the first reported family, of Yugoslavian origin, our patients have high HbF levels and this in the absence of a C→T substitution at-158 site 5′to Gγ. © 1993 Wiley-Liss, Inc.     

Hb adana or α259(E8)Gly→Aspβ2, A severely unstable α1-globin variant,observed in combination with the -(α)20.5 KB α-thal-1 deletion in two Turkish patients

We have identified a severely unstable hemoglobin variant through sequencing of amplified DNA involving the α₁-globin gene; the mutation is located in codon 59 (CC G CA G) andresults in a Gly—Asp replacement. This amino acid substitution concerns a glycine residue at an internal position in the E helix, which is in close contact with a glycine residue of the B helix; introduction of the larger and charged aspartic acid residue greatly affects the stability of the molecule. This variant was present in association with a common α-thalassemia-1 deletion [-(α)20.5 kb] in two adults and caused a severe type of Hb H disease with anemia, low levels of Hb A₂, increased → chain, and Hb Bart's. In vitro chain synthesis in reticulocytes showed a high specific activity of the variant α chain. Only a minute quantity of Hb H was present but instead about 10% of Hb Bart's was observed. The increased synthesis of γ chains was likely due to specific characteristics of a chromosome with haplotype #3, which was present in both patients. The same family was studied 18 years ago [1]; the improved methodology presently available has led to a corrected diagnosis for these patients. © 1993 Wiley-Liss, Inc.