The Putative Role of Fibroblasts in the Pathogenesis of Graves' Disease: Evidence for the Involvement of the Insulin-like Growth Factor-1 Receptor in Fibroblast Activation

Graves' disease when fully expressed affects the thyroid gland and connective tissues of the orbit and pretibium. While the glandular disease is relatively well-characterized, the pathogenesis of the orbital and dermal components remains enigmatic. In the following article, we review some of the evidence suggesting that fibroblast activation in Graves' disease might play an integral role in the tissue remodeling associated with ophthalmopathy. The thyrotropin receptor (TSHR) is expressed at low levels in several connective tissue depots and by their derivative fibroblasts, including those from the orbit. Little direct evidence currently links extra-thyroidal TSHR expression with Graves' disease. Very recent observations now implicate the insulin-like growth factor-1 receptor (IGF-1R) as a fibroblast activating antigen. When immunoglobulins from patients with the disease, with or without clinical ophthalmopathy, bind IGF-1R on the surface of fibroblasts, the receptor becomes activated and upregulates the expression of two T lymphocyte chemoattractants, IL-16 and RANTES. Thus, IGF-1R may represent a second self-antigen with a pathogenic role in extra-thyroidal Graves' disease.     

Efficacy and limitations of the histological diagnosis of type 1 autoimmune pancreatitis with endoscopic ultrasound-guided fine needle biopsy with large tissue amounts

ObjectivesWe examined the efficacy and limitations of acquiring large specimens by endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for diagnosing type 1 autoimmune pancreatitis (AIP).MethodsPatients from 12 institutions with non-neoplastic diseases or pancreatic ductal adenocarcinoma (PDAC) with large EUS-FNB specimens were investigated. Slides stained with hematoxylin-eosin, elastic, IgG4, and IgG stains were evaluated. The IgG4- and IgG-positive cell numbers were counted in three foci. The diagnoses were based on the Japan Pancreas Society 2011 (JPS 2011) criteria and the International Consensus Diagnostic Criteria (ICDC).ResultsWe analyzed 85 non-neoplastic (definite type 1 AIP in 73/85 based on the ICDC) cases and 64 PDAC cases. IgG4-positive cells were numerous (>10 in 85.9%), and the IgG4/IgG ratios were high (>40% in 81.2%). Plasma cell crushing by an artifact caused unsuccessful immunostaining, notably in smaller samples. Tissue lengths were an important factor for the presence of storiform fibrosis and obliterative phlebitis, but storiform fibrosis was equivocal even in large tissues. A definite or possible histological diagnosis was achieved in 45.9% (39/85) and 41.2% (35/85), respectively, and contributed to the definite final diagnosis of type 1 AIP in 33.3% (ICDC) and 55.6% (JPS 2011) in cases with segmental/focal lesions. In the PDAC group, >10 IgG4-positive cells was rare (2/58), but elastic stains revealed fibrous venous occlusions in 10.3% (6/58).ConclusionsEUS-FNB with large tissue amounts was useful for diagnosing type 1 AIP, notably by facilitating successful IgG4 immunostaining, but definite diagnosis may not be achieved even in cases with large specimens.     

Wiskott–Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans

Wiskott–Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott–Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21^low B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells.In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients.     

The use of immunohistochemistry for IgG4 in the diagnosis of autoimmune pancreatitis: A systematic review and meta-analysis

BackgroundThe diagnosis of autoimmune pancreatitis (AIP) remains challenging, especially when serum IgG4 is normal or imaging features are indeterminate. We performed a systematic review and meta-analysis to evaluate the performance of IgG4 immunostaining of pancreatic, biliary, and ampullary tissues as a diagnostic aid for AIP.MethodsA comprehensive literature search of the PubMed, EMBASE, and Ovid MEDLINE databases was conducted until February 2020. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. A random-effects model was used to summarize the diagnostic odds ratio and other measures of accuracy.ResultsThe meta-analysis included 20 studies comprising 346 patients with AIP and 590 patients with other pancreatobiliary diseases, including 371 pancreatobiliary malignancies. The summary estimates for tissue IgG4 in discriminating AIP and controls were as follows: diagnostic odds ratio 38.86 (95% confidence interval (CI), 18.70–80.75); sensitivity 0.64 (95% CI, 0.59–0.69); specificity 0.93 (95% CI, 0.91–0.95). The area under the curve was 0.939 for tissue IgG4 in discriminating AIP and controls. Subgroup analysis revealed no significant difference in diagnostic accuracy according to control groups (pancreatobiliary cancer versus other chronic pancreatitis) and sampling site (pancreas versus bile duct/ampulla).ConclusionsCurrent data demonstrate that IgG4 immunostaining of pancreatic, biliary, and ampullary tissue has a high specificity but moderate sensitivity for diagnosing AIP. IgG4 immunostaining may be useful in supporting a diagnosis of AIP when AIP is clinically suspected, but a combination of imaging and serology does not provide a conclusive diagnosis.     

Breastfeeding: An overview of oral and general health benefits

Background

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Breastfeeding is the reference against which alternative infant feeding models must be measured with regard to growth, development and other health outcomes. Although not a systematic review, this report provides an update for dental professionals, including an overview of general and oral health–related benefits associated with breastfeeding.Types of Studies ReviewedThe authors examined the literature regarding general health protections that breastfeeding confers to infants and mothers and explored associations between breastfeeding, occlusion in the primary dentition and early childhood caries. To accomplish these goals, they reviewed systematic reviews when available and supplemented them with comparative studies and with statements and reports from major nongovernmental and governmental organizations.ResultsWhen compared with health outcomes among formula-fed children, the health advantages associated with breastfeeding include a lower risk of acute otitis media, gastroenteritis and diarrhea, severe lower respiratory infections, asthma, sudden infant death syndrome, obesity and other childhood diseases and conditions. Evidence also suggests that breastfed children may develop a more favorable occlusion in the primary dentition. The results of a systematic review in which researchers examined the relationship between breastfeeding and early childhood caries were inconclusive.Conclusions and Clinical ImplicationsThe American Academy of Pediatric Dentistry, Chicago, suggests that parents gently clean infants' gums and teeth after breastfeeding. The American Academy of Pediatrics, Elk Grove Village, Ill., recommends that breastfeeding should be exclusive for about the first six months of life and should continue, with the introduction of appropriate complementary foods, to at least age 12 months or beyond, as desired by mother and child. Dentists and staff members can take steps to ensure they are familiar with the evidence and guidelines pertaining to breastfeeding and to oral health. They are encouraged to follow the surgeon general's recommendations to promote and support optimal breastfeeding and oral health practices among their patients.     

Detecting viruses by using salivary diagnostics

BackgroundDiagnostics that involve the use of oral fluids have become increasingly available commercially in recent years and are of particular interest because of their relative ease of use, low cost and noninvasive collection of oral fluid for testing.Types of Studies ReviewedThe authors discuss the use of salivary diagnostics for virus detection with an emphasis on rapid detection of infection by using point-of-care devices. In particular, they review salivary diagnostics for human immunodeficiency virus, hepatitis C virus and human papillomavirus. Oral mucosal transudate contains secretory immunoglobulin (Ig) A, as well as IgM and IgG, which makes it a good source for immunodiagnostic-based devices.Clinical ImplicationsBecause patients often visit a dentist more regularly than they do a physician, there is increased discussion in the dental community regarding the need for practitioners to be aware of salivary diagnostics and to be willing and able to administer these tests to their patients.     

人免疫球蛋白联合更昔洛韦治疗小儿腺病毒肺炎的临床研究

目的探讨静注人免疫球蛋白(pH 4)联合注射用更昔洛韦治疗小儿腺病毒肺炎的临床疗效。方法选择2014年6月—2016年12月华中科技大学同济医学院附属武汉儿童医院收治的腺病毒肺炎患儿90例,所有患儿按随机数字表法随机分为对照组和治疗组,每组各45例。对照组静脉滴注注射用更昔洛韦,5 mg/kg,滴注时间1 h,2次/d。治疗组在对照组基础上静脉滴注静注人免疫球蛋白(pH 4),400 mg/kg,1次/d。两组患儿均连续治疗14 d。观察两组的临床疗效,比较两组的临床症状、肿瘤坏死因子-α(TNF-α)、分泌型磷脂酶A2(sPLA2)、克拉拉细胞分泌蛋白(CCSP)和白细胞介素-1(IL-1)水平情况。结果治疗后,对照组和治疗组的总有效率分别为71.11%、95.56%,两组比较差异有统计学意义(P0.05)。治疗后,治疗组退热时间、咳嗽停止时间、咽痛消失时间、肺部湿啰音消失时间和住院时间均明显短于对照组,两组比较差异有统计学意义(P0.05)。治疗后,两组血清TNF-α、sPLA2、CCSP和IL-1水平均明显降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标明显低于对照组,两组比较差异具有统计学意义(P0.05)。结论静注人免疫球蛋白(pH 4)联合注射用更昔洛韦治疗小儿腺病毒肺炎具有较好的临床疗效,可改善临床症状,降低TNF-α、sPLA2、CCSP和IL-1水平,具有一定临床推广应用价值。     

Carimune NF Liquid is a Safe and Effective Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency Diseases

Subjects with primary immune deficiency diseases treated with intravenous immunoglobulin (n=42) received intravenous infusions of Carimune NF Liquid every 3–4 weeks for 6 months without routine premedication. The mean dose/patient/infusion was 278.5–800.7 mg/kg. Also, 80.4% of infusions achieved maximum rates of ≥3.5 mg/kg/min; 32% of infusions were associated with adverse events during or within 48 h of their end (upper 95% confidence interval was 39.4%, meeting the Food and Drug Administration (FDA) criterion for acceptable tolerability), and 54.8% of subjects had at least one temporally associated adverse event considered at least possibly drug-related (headache: 35.7% of subjects, 12.4% of infusions; nausea: 14.3%, 3.5%; myalgia: 14.3%, 3.2%; fatigue: 11.9%, 5.7%). The frequencies of these were highest after the first infusion. There were no serious drug-related adverse events or acute serious bacterial infections. Serum IgG trough levels were unchanged from baseline. Carimune NF Liquid, a ready-to-use, high-concentration, liquid immunoglobulin preparation is safe and effective. On behalf of the study group