Regulatory B cells as inhibitors of immune responses and inflammation

Summary: B cells positively regulate immune responses through antibody production and optimal CD4⁺ T-cell activation. However, a specific and functionally important subset of B cells can also negatively regulate immune responses in mouse autoimmunity and inflammation models. The lack or loss of regulatory B cells has been demonstrated by exacerbated symptoms in experimental autoimmune encephalitis, chronic colitis, contact hypersensitivity, collagen-induced arthritis, and non-obese diabetic mouse models. Accumulating evidence suggests that B cells exert their regulatory role through the production of interleukin-10 (IL-10) by either B-1, marginal zone (MZ), or transitional 2–MZ precursor B-cell subsets. We have recently found that IL-10-producing regulatory B cells predominantly localize within a rare CD1d^hiCD5⁺ B-cell subset that shares cell surface markers with both B-1 and MZ B cells. We have labeled this specific subset of regulatory B cells as B10 cells to highlight that these rare CD1d^hiCD5⁺ B cells only produce IL-10 and are responsible for most IL-10 production by B cells and to distinguish them from other regulatory B-cell subsets that may also exist. This review focuses on the recent progress in this field and the exciting opportunities for understanding how this unique B-cell subset influences diverse immune functions.     

肾上腺髓质素的抗感染和炎症调节作用

肾上腺髓质素 (adrenomedullin ,ADM )是 1993年从人的嗜铬细胞瘤中发现的一种活性肽 ,由 5 2个氨基酸残基组成 ,在 16位与 2 1位半胱氨酸残基间通过二硫键形成环状结构[1] 。ADM具有扩张血管、利钠利尿、抑制血管平滑肌细胞增殖等作用 ,是循环稳态重要的调节因子 ,在高血压、心力衰竭等过程中起保护效应[2 ] 。心血管活性肽是维持循环稳态的重要因素 ,近期研究发现活性肽参与机体的防御反应 ,本文综述ADM抗感染和炎症调节作用。1　肾上腺髓质素抗感染作用　　皮肤粘膜是机体防御微生物感染的第 1道屏障。皮肤及其表皮角质、毛囊、皮肤…     

Effects of a diphtheria-tetanus-acellular pertussis vaccine on immune responses in murine local lymph node and lung allergy models

We have previously shown that in mice, diphtheria-tetanus-acellular pertussis (DTaP) vaccination before Bordetella pertussis infection resulted in, besides effective clearance, immediate hypersensitivity (lung eosinophilia, increased total serum immunoglobulin E [IgE], and increased ex vivo Th2 cytokine production by cells from the bronchial lymph nodes). To better appreciate the extent of these findings, we measured DTaP vaccination effects in the local lymph node assay (LLNA) and an ovalbumin (OVA) lung allergy model. In the LLNA, mice were vaccinated or adjuvant treated before being sensitized with trimellitic anhydride (TMA; inducing a Th2-directed response) and dinitrochlorobenzene (DNCB; inducing a Th1-directed response). Compared to the adjuvant-treated controls, the vaccinated mice showed a decreased response to TMA and (to a much lesser extent) an increased response to DNCB. The decreased response to TMA coincided with increased transforming growth factor beta levels. With the exception of filamentous hemagglutinin, all vaccine constituents contributed to the decreased response to TMA. In the lung allergy model, sensitization induced OVA-specific IgE, lung pathology (peribronchiolitis, perivasculitis, and hypertrophy of the bronchiolar mucus cells) and increased the number of eosinophils, lymphocytes, and neutrophils in the bronchoalveolar lavage fluid. Vaccination failed to modulate these parameters. In conclusion, although DTaP vaccination may affect the LLNA response, we found no evidence of an effect on lung allergy.     

Effects of methotrexate on trophoblast proliferation and local immune responses

Methotrexate is a folic acid analogue that has been used successfully for the treatment of ectopic pregnancy and, in conjunction with misoprostol, for medical abortions of early intrauterine pregnancies. To administer the most efficacious treatment requires knowledge of the mechanism underlying the induction of methotrexate-induced abortion. This study was designed to ascertain trophoblast integrity, proliferation and differentiation following administration of methotrexate. In addition, to determine if methotrexate affects the local uterine immune response, we ascertained the numbers and identities of decidual leukocytes following treatment. Ten women with undesired intrauterine pregnancies of 42-49 days gestation were recruited to receive methotrexte 50 mg/m2 i.m. A suction aspiration was performed 7 days later. Tissues from gestational age-matched elective surgical abortions were used as controls. Additionally, specimens from women who received methotrexate and misoprostol for abortion in a clinical trial of oral methotrexate in combination with misoprostol, who had a suction abortion because of continued embryonic cardiac activity 14 days after the methotrexate, were evaluated. Immunoreactivity to proliferating cell nuclear antigen and cyclin D3 antibodies was used to demonstrate a marked reduction in the proliferation index of cytotrophoblasts from methotrexate-treated abortions. Methotrexate treatment failures and non-treated pregnancies had a much higher proliferation index. There was no direct destruction of the syncytiotrophoblast, as indicated by the continued presence of human placental lactogen and beta-human chorionic gonadotrophin proteins. A decrease in the total number of leukocyte cells was observed in the decidua of methotrexate-treated samples, with the large granular lymphocyte (LGL) cells showing the greatest decline in numbers. Our conclusions from this study are that methotrexate acts primarily to derail the normal developmental programme of the trophoblast stem cell population, as well as to decrease LGL cell numbers in the decidua.      

Effects of obesity on immune responses to renal tumors

Immunologic Research - Kidney cancer incidence in the USA has been steadily increasing over the past several decades. The reasons for this are not completely clear, but an increased prevalence of...     

Effects of evening primrose oil on serum lipoproteins and immune responses

The effects of evening primrose oil (EPO) on serum lipoprotein and immune response were studied in ICR mice fed an EPO‐supplemented diet (5% or 10% by weight) for six weeks. The results were that high density lipoprotein (HDL), immunoglobulin G and circulating leukocytes were significantly increased in EPO‐fed groups over those of the control group, and that the correlation between HDL and hemolysin litre was significantly positive in the EPO group. The data reported here indicate that EPO increased serum HDL, which increased circulating leukocyte cellularity and activated lymphocyte that secreted immunoglobulin.     

The role of serotonin and its receptors in activation of immune responses and inflammation

Serotonin or 5‐hydroxytryptamine (5‐HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS) and in the respective organ systems. Peripheral 5‐HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut‐resident cells produce much more 5‐HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5‐HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5‐HT signalling have been described in inflammatory conditions of the gut, such as inflammatory bowel disease. The association between 5‐HT and inflammation, however, is not limited to the gut, as changes in 5‐HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as ‘5‐HT’, ‘EC cell’, ‘immune cells’ and ‘inflammation’ in pubmed.gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5‐HT in biological functions with a particular focus on immune activation and inflammation.     

Impact of intranasal budesonide on immune inflammatory responses and epithelial remodeling in chronic upper airway inflammation

BACKGROUND: Histologic and immunohistologic features of nasal polyps (NP) are similar to those observed in asthma, thus suggesting a similar immunopathology. OBJECTIVE: The primary objective of this study was to further understand the anti-inflammatory and immunoregulatory effects of locally delivered corticosteroids. To this end, the effect of intranasal budesonide on the expression of specific cytokines, lymphocyte subsets, and epithelial remodeling in this model of airway tissue inflammation were studied. METHODS: We used immunohistochemical techniques to examine nasal mucosae (NM) from healthy individuals and nasal polyp (NP) tissues from patients with nasal polyposis obtained before and after intranasal budesonide treatment. RESULTS: First, the density of CD8(+) cells was markedly increased in NP tissues after intranasal budesonide treatment from 16.1 +/- 8.4 (M +/- SEM) per mm(2) to 39.9 +/- 24.1. Second, the density of cells immunoreactive for IL-4, IL-5, IFN-gamma, IL-12, and TGF-beta in NP was significantly greater than in control NM tissues. The density of IL-4(+) and IL-5(+) cells in NP tissues significantly decreased after budesonide treatment from 40 +/- 12 to 17.8 +/- 8 and from 19.3 +/- 11 to 10.4 +/- 7, respectively. In contrast, the density of IFN-gamma(+) and IL-12(+) cells remained unchanged. In addition, we found that the density of TGF-beta(+) cells significantly increased after intranasal budesonide from 18 +/- 5 to 41 +/- 9. Third, damage to the entire length of the NP epithelium was quantified using a grading system. The epithelium of untreated NP was substantially damaged; remarkable epithelial restitution with no apparent changes in stromal collagen deposition was observed after intranasal budesonide treatment. CONCLUSIONS: These findings demonstrate that intranasal budesonide induced an increase in CD8 population and a selective regulatory effect on tissue cytokine expression. Furthermore, intranasal budesonide promoted epithelial remodeling. We hypothesize that these immunoregulatory and remodeling effects elicited by steroids might be, at least in part, mediated by the induction of TGF-beta.     

Effects of partial hepatectomy on the immune responses in mice

Experiments were performed to investigate the immune responses occurring as a result of partial hepatectomy (HEP) in mice. On Day 12 mice subjected to HEP showed a twofold rise in serum levels of IgG when compared with sham-operated (ShO) controls. The effects of HEP on specific antibody production following a single immunization with sheep red blood cells (SRBCs) were investigated. An early appearance of direct (IgM) splenic plaque-forming cells (PFCs) and significantly elevated indirect (IgG) PFCs were found in HEP mice. Elevated, early-appearing mercaptoethanol-resistant (IgG) hemagglutinating antibodies were also demonstrated in the sera of HEP mice. In addition to these findings our study showed that humoral and cell-mediated responses are affected by HEP in opposing fashion. Partial hepatectomy performed immediately after skin grafting suppressed a first set allograft rejection in mice. Furthermore, inhibited delayed-type hypersensitivity (DTH) response against SRBCs, as evaluated by a footpad weight assay, was demonstrated in HEP mice compared with the ShO controls. When SRBC-primed mice were partially hepatectomized 15 days later, they responded in a manner typical of the secondary immune response, showing an increased production of indirect (IgG) splenic PFCs. A similar anamnestic response was observed in mice sensitized with leptospiral antigen 50 days prior to HEP or exposed to carbon tetrachloride (CCl4) hepatotoxin. The mice responded by elevated serum IgG-specific antibodies as measured by solid-phase enzyme-linked immunosorbent assay (ELISA). Since HEP induced in mice immunological disturbances similar to those associated with liver disease, it is suggested that partial hepatectomy creating liver deficiency followed by regeneration may be a useful experimental model to study the immune status of various forms of hepatic damage.     

Effects of anti-B7 monoclonal antibodies on humoral immune responses

The costimulatory interaction between CD28 on T cells and B7-related molecules on antigen presenting cells plays an important role in a broad range of functions of the immune system, including protective immunity, tolerance induction, allograft rejection, and the development of autoimmune diseases. Monoclonal antibodies to B7-1 and B7-2 have been used in vivo to examine the mechanisms underlying these processes and to evaluate costimulation antagonism as an approach to treatment of chronic autoimmune diseases. To determine whether anti-B7 mAb might elicit, or inhibit, a host immune response that could influence the effects of these antibodies in vivo, we assessed the immune response to rat anti-B7-1 and anti-B7-2 mAb in healthy (BALB/c) mice and in lupus-prone NZB/NZW F1(B/W) mice. In BALB/c mice, low doses (1-10 microg) of mAb to B7-1 and mAb to B7-2 elicited brisk immune responses that occurred earlier and were significantly greater than the immune response to an isotype-matched control rat mAb to ovalbumin. In contrast, at higher doses (100-500 microg), both anti-B7 mAb, but not the control mAb, blocked the mouse anti-rat response. No such blockade occurred in B/W mice, who generated a significant mouse anti-rat response even at very high doses of anti-B7 mAb (1,000-4,000 microg). Blockade of the immune response to the anti-B7 mAb in BALB/c mice apparently did not reflect generalized immune suppression, because high doses of these mAb had little, if any effect on the humoral immune response to another antigen. These findings indicate that: (1) mAb to B7-1 and B7-2 can elicit either a potent immune response or no immune response at all depending upon the dose administered; (2) blockade of the immune response to anti-B7 mAb may be more difficult in the setting of autoimmunity; and (3) neither anti-B7-1 nor anti-B7-2 causes generalized suppression of humoral immunity.     

Effects of housing and individual coping characteristics on immune responses of pigs

The impact of environmental factors on immune responses may be influenced by coping characteristics of the individuals under study. The behavioral response of pigs in a so-called Backtest early in life seems indicative of their coping style at a later age. The present study investigated the effects of housing, barren versus enriched, and coping style, as assessed by Backtest classification, on immune responses of pigs. Pigs were housed either without a rooting substrate (barren housing) or in identical pens enriched with deep straw bedding (enriched housing) from birth. During the suckling period, pigs were subjected to the Backtest. Each pig was restrained on its back for 1 min and the resistance (i.e., number of escape attempts) was scored. Pigs classified as 'high-' or 'low-resisting' (HR and LR, respectively) were immunized with di-nitrophenyl-conjugated keyhole limpet haemocyanin (DNP-KLH) at 9 weeks of age. Blood samples were drawn before immunization (Day 0) and weekly thereafter, until Day 35. KLH-specific lymphocyte proliferation following immunization was higher for HR pigs than for LR pigs. Housing did not affect proliferative responses. Housing and coping style interacted in their effect on KLH-specific humoral immune responses. LR pigs from barren housing showed higher KLH-specific antibody titers than LR pigs from enriched housing. Differently housed HR pigs, however, showed similar antibody titers. These findings support other research indicating that individual coping styles of pigs are reflected in their immune responses. More important, the present study demonstrates that effects of housing on humoral immune responses of pigs may differ for pigs with divergent coping styles.     

Atherogenesis and immune inflammation

Modern concepts on the role of inflammation in atherogenesis are reviewed. The evidence indicating that changes in cellular composition of the vascular wall are associated with the expression of mediators of inflammation and lead to the development of the protective-compensatory reaction under conditions of autoantigen production is presented. The hypotheses on the pathogenesis of atherosclerosis are discussed that associated the causes and conditions for emergence of leukocytes in the arterial intima against the background of apoprotein B-containing lipoprotein deposition. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 122, No. 7, pp. 4–8, July, 1996     

土茯苓对细胞免疫和体液免疫的影响

土茯苓水提取物在抗原致敏后及攻击后给药均明显地抑制了picryl chloride(PC)所致的小鼠接触性皮炎(PC-DTH)和绵羊红细胞(SRBC)所致的足蹠反应(SRBC-DTH),其中攻击后给药时作用较强.土茯苓还明显地抑制了二甲苯所致的耳壳及蛋清所致的小鼠足蹠炎症反应。此外,土茯苓对小鼠抗SR-BC 抗体形成的细胞数(IgM-及IgG-PFC 数)无明显影响,但其溶血空斑明显地较对照组为大,同时,血清溶血素水平未见降低,而呈增加趋势。以上结果表明,土茯苓对体液免疫反应无抑制作用,但可选择性地抑制细胞免疫反应,后者主要系影响致敏T 淋巴细胞释放淋巴因子以后的炎症过程。     

Effects on immune responses in rats after neuromanipulation with capsaicin

The effect of capsaicin treatment on the immune response, assessed as antibody formation in vivo and in vitro, was studied in ovalbumin (OA)-immunized rates. Rats were treated with capsaicin at 1-2 days of life or at adult age, before or after immunization. The levels of IgA, IgE and IgG antibodies as well as immunoglobulins were measured in serum and supernatants from cultured lymph node cells, spleen cells and peripheral blood lymphocytes. Capsaicin treatment affected the antibody levels depending on the timing of capsaicin treatment in relation to immunization. Different effects of capsaicin treatment were also observed on the different immunoglobulin isotypes. One of the most striking effects by capsaicin treatment was the reduction of IgA and IgG synthesis in cultured lymphoid cells from aerosol immunized animals treated with capsaicin after immunization. In contrast, in vivo the level of total serum IgA was increased in similarly treated animals. In this study we show that capsaicin treatment, which is known to decrease the levels of neuropeptides of sensory origin, has a time-dependent effect on both antibody levels in vivo as well as the formation of immunoglobulin in vitro. Although the mechanisms responsible for this are not obvious, we conclude a link between depletion of neuropeptides in sensory nerves and the antibody synthesis.     

Effects of IL6 on B cells in mucosal immune response and inflammation.

Freshly isolated surface IgA+ (sIgA+) B cells from human gut-associated lymphoreticular tissues (GALT), e.g. the appendix, express high levels of IL6 receptor (IL6R) and respond to IL6 with significant increases in the number of IgA-secreting cells. On the other hand, neither sIgM+ nor sIgG+ B cells from appendix express IL6R. When the effect of IL6 on IgA subclass antibody synthesis was examined, the numbers of both IgA1- and IgA2-producing cells were increased upon incubation of GALT B cells with IL6; however, 60-70% of IgA-secreting cells were IgA2 subclass. Aberrant local production of IL6 can contribute to increased B-cell responses that occur in mucosal inflammation such as gingiva of patients with adult periodontitis (AP). When gingival mononuclear cells (GMC) isolated from AP patients were cultured without any stimulus, GMC spontaneously produced biologically active IL6 which induced peripheral blood mononuclear cells (PBMC) from the same patients to become IgG- and IgA-producing cells. Further, mRNA extracted from GMC possessed high message for IL6. When the expression of IL6R was compared between GMC and PBMC isolated from AP patients, IL6R-bearing cells were only seen in the former population. Thus, a high production of IL6, which have the ability to regulate later stages of IL6R+ B-cell development and to induce them to become Ig-secreting plasma cells and to support plasmacytoma growth, are important immunopathological elements for the induction of the increased B-cell response region in inflamed mucosal tissues.