Specific immunotherapeutic strategy for myasthenia gravis: targeted antigen-presenting cells

The pathogenesis of myasthenia gravis (MG) involves a T cell-dependent antibody-mediated autoimmune response directed against acetylcholine receptors (AChR). Inactivation of AChR-specific T cells should interrupt the immune response, resulting in therapeutic benefit. Since each individual's repertoire of T cells responds to a heterogeneous and unique spectrum of AChR epitopes presented in association with self-major histocompatibility complex (MHC) class II, an individualized approach is required to target all relevant AChR-specific T cells. The individual's own antigen-presenting cells (APC) can be used for this purpose, since they process and present the antigen appropriately, and express the correct MHC class II. A novel method of binding AChR to surface immunoglobulin with a heterobifunctional antibody conjugate allows us to use all B cells as APC. Conjugate-plus-AChR-treated B cells (AChR-APC) effectively targeted AChR-specific T cells, stimulating vigorous proliferative responses in a rat cell culture system. If APCs are 'fixed' with cross-linking reagents, they induce long-lasting or permanent 'anergy' of the specific T cells. We prepared AChR-APC, allowed them to process AChR in vitro, and fixed them with paraformaldehyde. Pre-culture of these fixed AChR-APC with AChR-specific T cells induced anergy: when restimulated with fresh AChR-APC, the T cells exhibited markedly reduced proliferative responses and IL-2 production, compared with responses of T cells pre-cultured with control fixed B cells. Implications for the design of antigen-specific therapeutic strategies for MG and other immune disorders will be discussed.     

预防接种与自身免疫病的关系

感染与自身免疫性疾病之间的联系已引出一场争论 :疫苗是否也能激发自身免疫性疾病。有关这种风险有众多正反两方面的主张。在此复习感染诱导自身免疫病的相关机制 ,并对预防接种和自身免疫病之间的相对危险度进行评估。     

原发性胆汁性肝硬化-自身免疫性肝炎重叠综合征患者的临床分析

目的了解原发性胆汁性肝硬化(PBC)-自身免疫性肝炎(AIH)重叠综合征在PBC患者中的发生率及临床特点。方法对123例PBC患者的临床及病理资料进行回顾性的分析,根据国际自身免疫性肝炎小组修订的诊断标准,筛选出6例PBC-AIH重叠综合征患者,并分析其临床及病理特点。结果123例PBC患者中有6例按国际自身免疫性肝炎小组评分诊断标准积分≥10,PBC-AIH重叠综合征在PBC患者中的发生率为4.8%;6例患者中有4例伴发其他自身免疫性疾病;6例患者的实验室检查兼具有PBC(ALP、GGT、IgM升高)及AIH(ALT、AST、IgG升高)的特点,同时伴有多钟自身抗体阳性,病理表现上有不同程度的碎屑样坏死及胆小管受累。结论PBC-AIH重叠综合征并非罕见,应根据患者的临床表现及病理特征做出及时的诊断。     

鳞癌相关抗原的检测及临床意义

本文对７７例肺癌，４８例食管鳞癌和１４例良性疾病病人进行了鳞癌相关抗原（ＳｑｕａｍｏｕｓＣｅｌｌＣａｒｉｎｏｍａＡｎｔｉｇｅｎ，ＳＣＣ—Ａｇ）测定，肺鳞癌（４５例）阳性率为６８．８％（＞１．５ｎｇ／ｍｌ）；腺癌（１８例）阳性率１６．６％；小细胞癌（８例）阳性率１２．５％；大细胞癌（６例）阳性率１６．７％。食管鳞癌阳性率３１．３％。１４例良性疾病均阴性。治疗前ＳＣＣ—Ａｇ浓度与肿瘤分期呈对应关系，肺鳞癌Ⅰ期阳性率为２２．２％；Ⅱ期为６４．２％；Ⅲ期８２．３％；Ⅳ期则１００％。食管鳞癌Ⅰ～Ⅱ期阳性率为１３．４％；Ⅲ～Ⅳ期阳性率为４８％。在行肿瘤根治切除的病人，其ＳＣＣ—Ａｇ在术后７２小时内转阴，而行非根治手术的病人，其ＳＣＣ—Ａｇ仍为阳性。治疗后无转移和复发的鳞癌病人，其ＳＣＣ—Ａｇ持续阴性，该抗原在治疗后由阴性再次上升为阳性，临床均证实为复发。     

Autoimmune hepatitis type 1 and primary biliary cirrhosis have distinct bone marrow cytokine production

We have recently reported differences in the hematopoiesis between autoimmune hepatitis type 1 (AIH-1) and primary biliary cirrhosis (PBC). In view of the notion that cytokines are regulators of hematopoiesis, we investigated in our tertiary center the cytokine production in the bone marrow (BM) of the same consecutive cohort of patients (13 AIH-1, 13 PBC, 10 healthy and 7 patients with cirrhosis due to chronic hepatitis B). Interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) were determined in the supernatants of long-term BM cultures by ELISAs. IL-4, TNF-alpha and TGF-beta were found significantly increased in the BM of PBC patients compared to AIH-1 and both control groups. AIH-1 patients had significantly higher BM IL-10 compared to PBC patients and higher IL-10, IL-4 and TNF-alpha compared to controls. BM IFN-gamma was significantly higher in PBC and AIH-1 patients compared to controls. In AIH-1 patients, IL-10 was positively correlated with CD34+, CD34+/CD38- and CD34+/CD38+ cell proportions. In conclusion, the BM cytokine microenvironment of PBC and AIH-1 patients differs significantly compared to that of healthy individuals and cirrhotic patients of non-autoimmune etiology. Differences were also found between patients with PBC and AH-1. The implication of BM in the pathogenesis of autoimmune liver diseases is possible and needs further investigation.     

Historical evolution,overview, and therapeutic manipulation of co-stimulatory molecules

Co-stimulatory molecules are key mediators in the regulation of immune responses and knowledge of its different families, structure, and functions has improved in recent decades. Understanding the role of co-stimulatory molecules in pathological processes has allowed the development of strategies to modulate cellular functions. Currently, modulation of co-stimulatory and co-inhibitory molecules has been applied in clinical applications as therapeutic targets in diseases and promising results have been achieved.     

Low interleukin-2 receptor levels in serum of patients with insulin-dependent diabetes

Interleukin-2 receptors are released in the circulation in response to antigenic or mytogenic stimulation of T-lymphocytes. Abnormal serum interleukin-2 receptor levels have been found in young children with type 1 diabetes and prediabetes. We measured interleukin-2 receptor levels in 17 patients with newly diagnosed type 1 diabetes, 21 patients with long-standing type 1 diabetes, 19 patients with long-standing type 2 diabetes, 19 islet-cell antibody positive nondiabetic polyendocrine patients, 12 islet-cell antibody-positive first-degree relatives of patients with type 1 diabetes and compared the results to age- and sex-matched normal controls. We found significantly lower interleukin-2 receptor levels in patients with newly diagnosed and long-standing type 1 diabetes compared to normal controls (87 ± 11 and 93 ± 11 vs. 142 ± 25 and 132 ± 40 U/ml, P < 0.001 and P < 0.01). There were no significant differences in interleukin-2 receptor levels between prediabetic groups and normal controls or patients with long-standing type 1 or type 2 diabetes. There was no correlation between glycosylated hemoglobin, blood glucose levels, and interleukin-2 receptor in the groups with long-standing type 1 or type 2 diabetes. We conclude that patients with type 1 diabetes have low interleukin-2 receptor serum levels. This phenomenon is acquired close to disease onset and is unlikely to be an early markers of type 1 diabetes.Abbreviations JDf Juvenile Diabetes foundation - ICA⁺ islet-cell antibody positive - IDDM insulin-dependent diabetes mellitus - IL-2R® interleukin-2 receptors - NIDDM non-insulin-dependent diabetes mellitus Correspondence to: R. Wagner     

Architectural remodelling in lungs of rabbits induced by type V collagen immunization: a preliminary morphologic model to study diffuse connective tissue diseases

The pathogenesis of diffuse connective tissue diseases (DCTD) is still unknown and has been extensively studied regarding its autoimmunity aspects related to extracellular matrix (ECM) remodelling, with an emphasis on the collagens at the inflammatory site. The present paper describes the pulmonary architectural and repair/remodelling responses to injury after immunization of rabbits with human type V collagen. The animal model consisted of rabbits immunized with collagen mixed with Freund's adjuvant and sacrificed 7, 15, 30, 75, and 120 days after the first of four doses of antigen. Pulmonary architecture remodelling response was evaluated by histology, morphometry, and the immunofluorescence method, according to compartments of reference (parenchyma and interstitium) and injury: 1 inflammation (polymorphonuclear and mononuclear cells); 2-repair (fibrosis) and 3-ECM remodelling (collagen system). The results showed an intense inflammatory involvement of the pulmonary vascular and bronchiolar parenchyma, characterized by increased wall thickness in small arteries, infiltrations by pseudoeosinophils, and mononuclear cells. Progressive remodelling of the pulmonary ECM was characterized by collagen deposition in the septal and bronchovascular interstitium, especially in rabbits sacrifices at 75 and 120 days. The ECM remodelling process was not reproduced when rabbits were inoculated with collagen types I and III. We conclude that the model reproduces morphologic changes similar to those observed in many DCTD, encouraging realization of other experiments to gain a better understanding of the pathogenesis of these diseases.