BAFF分子在部分肾移植受者外周血淋巴细胞异常高表达及其可能的生物学意义

目的：分析BAFF分子在肾移植受者外周血淋巴细胞的表达情况以及初步分析其异常表达的生物学意义。方法：以来院随访的肾移植受者为研究对象,采集患者外周血,以EDTA-Na2抗凝。采用单色和多色标记的免疫荧光分析法,分析BAFF分子在外周血淋巴细胞的表达情况,同时检测淋巴细胞CD3、CD4、CD8、CD134、CD25和CD127的表达。结果：共分析了86位肾移植受者。BAFF分子在受者外周血淋巴细胞的表达率分别介于0.18%至76.97%之间。以15%为界将所有数据分成两组（表达率〉15%组和表达率〈15%组）,对所获得的数据进行统计分析。在BAFF分子表达率〉15%组其BAFF分子表达的平均值为36.91%;BAFF^＋细胞群的增加与外周血CD4^＋/CD8^＋比值、与循环中CD4^＋CD25^＋CD127^-/low T细胞群等没有显著相关性;但是与循环中CD134^＋ T细胞群和CD4^＋CD134^＋ T细胞群的增加存在显著相关性（P〈0.01和P〈0.05）,具有统计学意义。而BAFF表达率〈15%组所检测的相关指标均没有统计学意义。结论：BAFF分子在部分肾移植受者外周血淋巴细胞的异常高表达可能与移植排斥反应相关。     

BAFF supports human B cell differentiation in the lymphoid follicles through distinct receptors

B cell-activating factor of the tumor necrosis factor family (BAFF/BLys) plays a critical role in B cell survival and immune responses through its three receptors: BAFF receptor (BAFF-R/BR3), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA). Using specific antibodies, we have investigated the expression of BAFF-R on human tonsillar B cells and their functional roles in naive and germinal center (GC) B cell differentiation. Our studies show that BAFF-R is the dominant receptor on naive B cells. However, three receptors are differentially modulated during in vitro GC-B cell differentiation. BAFF-R expression increased initially and then decreased with a corresponding induction of TACI and BCMA expression during differentiation to plasma cells (PCs). Consistently, blocking of BAFF-R alone with specific mAb inhibited GC-B cell proliferation and PC generation in the early period of their differentiation, whereas depletion of BAFF with TACI-Ig exhibited consistent inhibition throughout the differentiation. Finally, histological and molecular analyses of human tonsil tissue revealed that follicular dendritic cells produce BAFF. In conclusion, BAFF in the GC plays an important role through more than one receptor, and the three known receptors are differentially modulated as GC-B cells differentiate to PCs.     

Expression of BAFF-R (BR3) in normal and neoplastic lymphoid tissues characterized with a newly developed monoclonal antibody

BAFF-receptor (BAFF-R) is required for the successful maturation and survival of B-cells. We developed an anti-human BAFF-R monoclonal antibody (mAb), 8A7. The reactivity of 8A7 in normal and neoplastic tissue was examined by performing immunohistochemistry on paraffin-embedded sections. 8A7 reacted with lymphocytes in the mantle and marginal zones, but not with lymphocytes in the interfollicular area. Lymphocytes in the germinal centers were found to be negative or occasionally weakly positive for 8A7. BAFF-R expression was found only in B-cell lymphoma (44/80, positive cases/examined cases): B-lymphoblastic lymphoma 0/3, B-chronic lymphocytic leukemia/small lymphocytic lymphoma 4/4, mantle cell lymphoma 9/11, follicular lymphoma 10/14, diffuse large B-cell lymphoma (DLBCL) 11/25, marginal zone B-cell lymphoma 8/10, lymphoplasmacytic lymphoma 2/2, plasma cell myeloma 0/2, and Burkitt lymphoma 0/9, but not in T/NK cell lymphomas (0/19) or Hodgkin lymphoma (0/10). BAFF-R was expressed in most low-grade B-cell neoplasms and a small number of DLBCL, suggesting that BAFF-R may play an important role in the proliferation of neoplastic lymphoid cells. Thus, the mAb is very useful for further understanding of both healthy B-cell biology and its pathogenic neoplasms.     

B cells and atherosclerosis in systemic lupus erythematosus

Introduction: Cardiovascular (CV) events, as a result of accelerated atherosclerosis, are an important cause of mortality in patients with Systemic lupus erythematosus (SLE). The etiology of SLE is multifactorial and still unclear; among other potential culprits, excessive B cell activation seems to play a crucial role. Accumulating evidence supports a contributory role of B cells in the pathogenesis of atherosclerosis as well.

Areas covered: This article focuses on the contribution of both B cells and autoantibodies in the pathogenesis of atherosclerosis in both general and lupus populations. Review of the published literature on experimental models has also been performed.

Expert opinion: Distinct B cell subsets seem to exhibit separate effects on the progression of atherosclerosis, with B2 B cells displaying a mainly atherogenic phenotype, while B1 B cells are mostly viewed as atheroprotective. Selective B2 inhibition by anti-B cell therapies seems a promising therapeutic strategy against atherosclerosis development in the setting of lupus.     

以BAFF/APRIL为靶点药物治疗系统性红斑狼疮临床研究进展

系统性红斑狼疮(SLE)是一种以致病性自身抗体和免疫复合物形成并介导器官、组织损伤的自身免疫性疾病,近年来不少国内外学者发现B淋巴细胞在SLE的发病中扮演了重要的角色,本文主要对以BAFF/APRIL为靶点的药物治疗SLE的临床试验进展进行综述。     

Predicting progression to lymphoma in Sjögren's syndrome patients

Although the inherent complexity of the multifactorial nature of primary Sjögren's syndrome (pSS) renders the process of disease prognostication and prediction ambiguous, certain clinical and immunological characteristics have been described as lymphoma predictors in several studies. While the association between pSS and mucosa-associated lymphoid tissue lymphomas is indisputable, recent studies report a predominance of diffuse large B-cell lymphomas implying that pSS-lymphoma association is less subtype-specific than previously considered. The considerable differences in both disease severity and prognosis between patients with various types of lymphoma demand the identification of risk factors that can predict the development of the distinct subtypes. Additionally, a recently discovered diverse range of biological variables appears to influence clinical behavior and lymphoma outcome. In this review, we venture into the area of lymphoma prognostication in pSS, outlining long-established predictors, analyzing currently available prognostic models, and exploring the predictive potential of recent biological and molecular advances.     

Emerging biotherapies for Sjögren's syndrome

Importance of the field: Sjögren's syndrome (SS) is an autoimmune epithelitis. This exocrinopathy is frequently associated with extraglandular complications, and the patients are at risk of developing B cell lymphoma. Given the lack of disease-modifying drugs, and the fact that SS is a quintessential B-cell mediated disease, attention has recently been focused on biotherapies.

Areas covered in this review: Despite negative grounds, TNF-α antagonists have been tested in the disease, and proven not be efficient. However, B-cell depleting therapy using anti-CD20 antibodies such as rituximab, which is a chimeric mAb, has shown promise in the field, while anti-CD22 mAb seems to be less active.

What the reader will gain: New treatments against the B-cell activating factor of the TNF family are about to be tested, or replaced by receptor immunoglobulin decay protein.

Take home message: B-cell depleting therapies seem promising in SS, but no data are, thus far, available on treatments targeting B-cell activating factor of the TNF family.     

Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE.     

Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Nontypeable Haemophilus influenzae (NTHi), a typical mucosal pathogen largely responsible for respiratory infections and pediatric otitis media, has been increasingly recognized as a significant cause of invasive disease, especially in immunocompromised individuals. Lipooligosaccharide (LOS) is a conserved molecule with an important role in H. influenzae virulence and immune evasion, and it may be considered as a vaccine candidate. However, abilities of H. influenzae LOS to induce protective immune response are poorly understood. The goal of this study was to determine whether antibodies against LOS isolated from H. influenzae strains Eagan, Rd and NTHi 375 are present in the sera of normal individuals. Antigen specific IgG and IgM were studied in sera of 71 and 30 healthy adults, respectively. IgG specific for LOS of all three strains was ubiquitously present in our sample population while IgM specific for Eagan, Rd and NTHi 375 LOS compounds was detected in 37%, 63%, and 40% of samples, respectively. All tested serum samples exhibited bactericidal activity against all three H. influenzae strains; the removal of anti-LOS antibodies from the sera resulted in significant increases in bacterial survival of the corresponding strain. NTHi 375 exhibited the highest serum resistance, whereas the Rd strain was the least resistant. Serum bactericidal activity of anti-LOS antibody was mediated via the classical complement pathway. These findings suggest that in healthy adults, naturally acquired complement-activating anti-LOS antibodies significantly contribute to the overall serum bactericidal activity against both encapsulated and non-encapsulated strains of H. influenzae.