大动脉炎患者体液免疫功能、细胞免疫功能检测及意义

目的探讨大动脉炎患者体液免疫功能及T淋巴细胞亚群变化的临床意义。方法检测31例大动脉炎患者(观察组)和30例体检正常者(对照组)IgG、IgA、IgM、IgE、C3、C4、CD3+、CD4+、CD8+、CD4+/CD8+水平。结果观察组IgG、IgM、IgE、C3、CD4+CD4+/CD8+水平较对照组明显升高而C4、CD3+水平明显下降(P均<0.05);IgA、CD8+两组间无显著差异。结论大动脉炎患者的体液免疫和T淋巴细胞亚群水平在发病时变化明显,对该病的发病机制研究和临床诊断有重要意义。     

Coccidioidomycosis in acquired immune deficiency syndrome. Depressed humoral as well as cellular immunity

Progressive pulmonary coccidioidomycosis has not been previously reported in the setting of acquired immune deficiency syndrome (AIDS). A patient with AIDS, progressive pulmonary coccidioidomycosis, Pneumocystis carinii pneumonia, and disseminated cytomegalovirus is described. Diagnosis of these opportunistic pathogens was made by bronchoalveolar lavage and transbronchial lung biopsy. Results of traditional complement fixation serologic testing for cytomegalovirus were negative; however, the more sensitive enzyme-linked immunosorbent assay did indicate infection. Coccidioidal complement fixation tests, precipitin tests, counter-immunoelectrophoresis, and immunodiffusion tests demonstrated negative findings. These results provide additional evidence that some patients with AIDS have defects in humoral as well as cellular immunity.     

Dendritic cell-targeted protein vaccines: a novel approach to induce T-cell immunity

Current vaccines primarily work by inducing protective antibodies. However, in many infections like HIV, malaria and tuberculosis as well as cancers, there remains a need for durable and protective T-cell immunity. Here, we summarize our efforts to develop a safe T-cell-based protein vaccine that exploits the pivotal role of dendritic cells (DC) in initiating adaptive immunity. Focusing on HIV, gag-p24 protein antigen is introduced into a monoclonal antibody (mAb) that efficiently and specifically targets the DEC-205 antigen uptake receptor on DC. When administered together with synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly IC) or its analogue poly IC stabilized with carboxymethylcellulose and poly-L-lysine (poly ICLC), as adjuvant, HIV gag-p24 within anti-DEC-205 mAb is highly immunogenic in mice, rhesus macaques, and in ongoing research, healthy human volunteers. Human subjects form both T- and B-cell responses to DC-targeted protein. Thus, DC-targeted protein vaccines are a potential new vaccine platform, either alone or in combination with highly attenuated viral vectors, to induce integrated immune responses against microbial or cancer antigens, with improved ease of manufacturing and clinical use.     

苦参碱对溃疡性结肠炎患者T细胞亚群的影响

[目的]探讨苦参碱注射液对溃疡性结肠炎（UC）患者外周血T细胞免疫的影响.[方法]采用免疫组化（SAP）法检测30例UC患者用苦参碱注射液治疗1月前、后和10例健康志愿者外周血T细胞亚群.[结果]30例UC患者中治愈7例,好转12例,无变化11例;UC患者CD8^＋Ts细胞明显减少;用苦参碱治疗后UC患者外周血CD3^＋、CD8^＋Ts细胞较治疗前明显增高,有效组CD8^＋Ts细胞显著高于无效组（P＜0.05）.[结论]UC患者抑制性T细胞减低,免疫亢进;用苦参碱注射液治疗有较好疗效,外周血T细胞,尤其CD8^＋Ts细胞水平明显增高.     

细胞免疫参数对结直肠癌的评估价值

目的:评估结直肠癌患者抗肿瘤免疫状态.方法:应用流式细胞术检测100例未转移结直肠癌患者、100例伴有转移结直肠癌患者和100例健康志愿者外周血CD4+、CD8+、NK、B、CD4+CD25HighCD127lowTreg、Th/Treg值,采用单因素方差分析进行比较,分析差异.结果:转移性结直肠癌患者组分别与正常对照组和非转移性结直肠癌患者组相比,CD4+CD25HighCD127lowTreg细胞升高(7.72%±2.20%vs6.08%±1.47%,5.91%±1.55%,均P<0.05),CD4+T细胞降低(34.04%±8.71%vs37.83%±7.62%,37.68%±8.89%,均P<0.05),Th/Treg值降低(4.70±1.72vs6.47±2.54,6.81±4.09,均P<0.05).结直肠癌患者与正常对照组CD8+T细胞、NK细胞、B细胞三组两两相比,均无统计学意义.结论:转移性结直肠癌患者免疫功能紊乱,主要表现为CD4+T细胞、Th/Treg值降低,CD4+CD25HighCD127lowTreg细胞升高.     

极端气候变化对哮喘患者全身及气道局部细胞、体液免疫的影响

目的探讨极端气候变化对支气管哮喘（哮喘）患者全身及气道局部细胞、体液免疫的影响。方法将40例哮喘患者均分为两组,对照组用舒利迭干预,观察组用舒利迭＋斯奇康干预;分别于基线点、气温骤降点、气候极冷点检测其血浆CD3＋、CD4＋、CD8＋、CD4＋/CD8＋,血清及诱导痰IgG、IgA、IgM。结果与基线点、气候极冷点比较,两组气温骤降点血浆CD3＋、CD8＋降低,CD4＋、CD4＋/CD8＋升高（P均〈0.01）,血清IgG、IgA、IgM下降（P均〈0.01）。与对照组比较,观察组气温骤降点血浆CD3＋、CD8＋升高,CD4＋、CD4＋/CD8＋降低,血清及诱导痰中IgG、IgA、IgM升高（P均〈0.01）。结论气温骤降可影响哮喘患者的细胞、体液免疫功能,舒利迭＋斯奇康能增强其免疫力,改善气温骤降致机体免疫力下降诱发的哮喘。     

Influence of humoral immunity on leukotriene B4 production by neutrophils in response to Trichomonas vaginalis stimulation

Neutrophils are the predominant inflammatory cells found in vaginal discharges from patients with Trichomonas vaginalis infection. In this study, we investigated the effect of humoral immunity on leukotriene B4 (LTB4) generation by neutrophils in the inflammatory response of vaginal trichomoniasis. As quantitated by a radioimmunoassay, no release of LTB4 was detected from neutrophils (5 x l0⁶/ml) interacted with trichomonads (1 times 10⁶/ml). However, specific immunoglobulin G(IgG) but not F(ab¹)₂, at a titre of 1:256 directed against T. vaginalis, augmented LTB4 production (1·4 ± 0·4 ng/ml, n= 5) by neutrophils, suggesting that this enhancement is Fey receptor-mediated. Moreover, addition of the specific IgG (1 mglml) to C2-deficient serum or Factor B-deficient serum, but not C5-deficient serum, significantly increased LTB4 production by neutrophils in response to trichomonad stimulation. This indicates that the complement common pathway activation is crucial for the amplification of host defence mechanisms against T. vaginalis. An LTB4 receptor antagonist, SC-41930, completely abolished neutrophil chemotactic activity induced by LTB4. Taken together, these results indicate that humoral immunity could promote the interaction of neutrophils with T. vaginalis and augment the inflammatory response through the amplification of LTB4 production.     

Friends and foes of tuberculosis: modulation of protective immunity

Protective immunity in tuberculosis (TB) is subject of debate in the TB research community, as this is key to fully understand TB pathogenesis and to develop new promising tools for TB diagnosis and prognosis as well as a more efficient TB vaccine. IFN‐γ producing CD4⁺ T cells are key in TB control, but may not be sufficient to provide protection. Additional subsets have been identified that contribute to protection such as multifunctional and cytolytic T‐cell subsets, including classical and nonclassical T cells as well as novel innate immune cell subsets resulting from trained immunity. However, to define protective immune responses against TB, the complexity of balancing TB immunity also has to be considered. In this review, insights into effector cell immunity and how this is modulated by regulatory cells, associated comorbidities and the host microbiome, is discussed. We systematically map how different suppressive immune cell subsets may affect effector cell responses at the local site of infection. We also dissect how common comorbidities such as HIV, helminths and diabetes may bias protective TB immunity towards pathogenic and regulatory responses. Finally, also the composition and diversity of the microbiome in the lung and gut could affect host TB immunity. Understanding these various aspects of the immunological balance in the human host is fundamental to prevent TB infection and disease.     

The impact of different intensities of regular donor plasmapheresis on humoral and cellular immunity, red cell and iron metabolism, and cardiovascular risk markers

BACKGROUND AND OBJECTIVES: Major studies are still lacking on the impact of differing intensities of long-term donor plasmapheresis, not only on total serum protein, albumin and immunoglobulin G (IgG), but also on humoral and cellular immunity, red cell and iron metabolism, and biochemical cardiovascular risk markers. MATERIALS AND METHODS: Three groups of donors, comprising 483 individuals undergoing differing intensities of long-term serial plasmapheresis, were entered into a cross-sectional study. A fourth control group consisted of 100 non-donors. In addition to measuring total protein, albumin and IgG levels, we determined parameters of humoral and cellular immunity, red cell and iron metabolism and recognized biochemical cardiovascular risk factors. RESULTS: The median annual net amount of plasma donated by the three donor groups was 37, 16 and 10 l, respectively (P < 0.0001). Donors had significantly lower total serum protein, albumin and IgG levels than non-donors (P < 0.0001), but the intensity of plasmapheresis had no influence on those parameters. Like non-donors, all plasma donors had normal humoral and cellular immunity. No increased rates of iron store depletion were observed in the three groups of plasma donors. Plasma donors were not at increased cardiovascular risk. CONCLUSIONS: Regular donor plasmapheresis of up to 45 l of plasma per year appears to be as safe as more moderate plasmapheresis programmes, with respect to the parameters analysed in this study. Individuals donating under these conditions did not develop impaired humoral and cellular immunity, iron store depletion, or increased cardiovascular risk with regard to established biochemical risk markers. Prospective studies are required to determine more exactly than in retrospective analyses the reasons why donors withdraw from plasmapheresis programmes.     

Cysticercosis vaccine: cross protecting immunity with T. solium antigens against experimental murine T. crassiceps cysticercosis

Vaccination of mice with an antigen extract from Taenia solium cysticerci induced protection against challenge with T. crassiceps cysticerci as successfully as did antigen extracts from T. crassiceps. Vaccination was more effective in male than in female mice and in the resistant strain (BALB/B) more so than in the susceptible strain (BALB/c). While only the resistant strain was completely protected by vaccination, the parasite load of the susceptible strain was significantly reduced by vaccination. Cross immunity between the human and murine parasites establishes murine T. crassiceps cysticercosis as a convenient laboratory model in which to test promising T. solium antigens aimed at vaccine development against T. solium cysticercosis. Further, results point to strong interactions of the immune system with sexual and histocompatibility factors in the host's dealing with cysticercosis.     

Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG

Respiratory syncytial virus (RSV) is one of the leading causes of childhood hospitalization and a major health burden worldwide. Unfortunately, because of an inefficient immunological memory, RSV infection provides limited immune protection against reinfection. Furthermore, RSV can induce an inadequate Th2-type immune response that causes severe respiratory tract inflammation and obstruction. It is thought that effective RSV clearance requires the induction of balanced Th1-type immunity, involving the activation of IFN-γ-secreting cytotoxic T cells. A recognized inducer of Th1 immunity is Mycobacterium bovis bacillus Calmette–Guérin (BCG), which has been used in newborns for decades in several countries as a tuberculosis vaccine. Here, we show that immunization with recombinant BCG strains expressing RSV antigens promotes protective Th1-type immunity against RSV in mice. Activation of RSV-specific T cells producing IFN-γ and IL-2 was efficiently obtained after immunization with recombinant BCG. This type of T cell immunity was protective against RSV challenge and caused a significant reduction of inflammatory cell infiltration in the airways. Furthermore, mice immunized with recombinant BCG showed no weight loss and reduced lung viral loads. These data strongly support recombinant BCG as an efficient vaccine against RSV because of its capacity to promote protective Th1 immunity.     

胃溃疡发生和愈合中细胞免疫功能的变化

目的:探讨细胞免疫功能在胃溃疡(GU)发生和愈合中的变化。方法:胃镜及病理证实的GU患者26例。在西咪替丁(1g/d〕治疗5—8周前后测定外周血T细胞亚群(APAAP桥联酶标法)及NK细胞活性(LDH释放法〕。20例健康人作为对照。结果:活动期GU患者CD_3~ ,CD_4~ ,CD_4~ /CD_8~ 比值及NK细胞活性分别为(55.1％±6.4％,41.4％±5.2％,1.69±0.24和29.7％±6.0％)明显低于正常人(P<0.05)。随着西咪替丁治疗使溃疡愈合,上述指标较用药前明显升高(分别为58.8%±6.8%,43.2％±5.0％,1.79±0.33和34.2％±5.9％,P<0.05),与正常人相似(P>0.05)。CD_8~ 治疗后(25.0％±7.1%)较治疗前(25.5％±6.8％)无明显变化(P>0.05)。结论:细胞免疫功能在GU的发生和愈合中有一定变化。除抑制胃酸外,西味替丁还能影响机体的免疫功能而治疗GU。     

Regulation of humoral immunity by gut microbial products

The intestinal tract provides ideal niches for several different microbial species, which are collectively called the gut microbiota. A key host immune effector that controls the microbiota and prevents mucosal infection is IgA. Gut microbiota-derived factors are largely classified into molecular pattern recognition receptor ligands and nutrient-derived metabolites including short-chain fatty acids and adenosine triphosphate. Along with host-derived factors such as retinoic acid, various cytokines and cytokine-like molecules, gut microbial products profoundly shape B cell responses. Gut microbial products can directly regulate B cell activation and differentiation. They can also indirectly affect B cells through epithelial cells, T cells, and myeloid cell subsets. We highlight the various direct and indirect mechanisms by which microbial products regulate humoral immunity.     

Regulating immunity to malaria

The optimal outcome of a malaria infection is that parasitized cells are killed and degraded without inducing significant pathology. Since much of the pathology of malaria infection can be immune-mediated, this implies that immune responses have to be carefully regulated. The mechanisms by which anti-malarial immune responses are believed to be regulated were discussed at the recent Malaria Immunology Workshop (Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; February 2005). Potential regulatory mechanisms include regulatory T cells, which have been shown to significantly modify cellular immune responses to various protozoan infections, including leishmania and malaria; neutralising antibodies to pro-inflammatory malarial toxins such as glycosylphosphatidylinositol and haemozoin; and self-regulating networks of effector molecules. Innate and adaptive immune responses are further moderated by the broader immunological environment, which is influenced by both the genetic background of the host and by co-infection with other pathogens. A detailed understanding of the interplay between these different immunoregulatory processes may facilitate the rationale design of vaccines and novel therapeutics.     

T细胞免疫功能紊乱在小儿单纯性肾病发病中作用的初步探讨

本文测定了不同病期单纯性肾病(INS)的外周血T细胞亚群(CD_4~+/CD_~+)和ConA诱导的T抑制(Ts)细胞活性改变。并根据西咪替丁的免疫调节作用对6例初发的INS进行2周的试验治疗.结果量示,INS活动期存在CD_4~+/CD_~+降低Ts细胞活性增强.西咪替丁能纠正上述异常,但不能改善INS蛋白尿程度,推测T细胞免疫紊乱可能不是INS发病的始动因素.     

Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients

NY-ESO-1 is a cancer/testis antigen expressed in a range of human malignancies, and a number of vaccine strategies targeting NY-ESO-1 are being developed. In the present study, the safety and immunogenicity of recombinant vaccinia-NY-ESO-1 and recombinant fowlpox-NY-ESO-1 were analyzed in a series of 36 patients with a range of different tumor types. Each construct was first tested individually at two different dose levels and then in a prime-boost setting with recombinant vaccinia-NY-ESO-1 followed by recombinant fowlpox-NY-ESO-1. The vaccines were well tolerated either individually or together. NY-ESO-1-specific antibody responses and/or specific CD8 and CD4 T cell responses directed against a broad range of NY-ESO-1 epitopes were induced by a course of at least four vaccinations at monthly intervals in a high proportion of patients. CD8 T cell clones derived from five vaccinated patients were shown to lyse NY-ESO-1-expressing melanoma target cells. In several patients with melanoma, there was a strong impression that the natural course of the disease was favorably influenced by vaccination.     

Polyclonal B-cell activation by bacteria that induce nonsuppurative sequelae

Summary The polyclonal B cell activation (PBA) process induced by Klebsiella pneumoniae K34 (klebs) and Yersinia enterocolitica 03 (yers) was investigated. Both heat-inactivated bacteria and their cell wall biostructures (klebsM, muriene, protein I etc.) stimulate human blood B cells to differentiate into immunoglobulin-secreting cells without prior proliferation and without T cells. Klebs-activated B cells secrete mainly IgM and to a lesser degree IgG (mainly IgG₂). The PBA process was regulated by CD4⁺ cells and monocytes, but not by CD8⁺ cells. While interleukin 2 is able both to induce proliferation and to enhance differentiation in klebs-activated B cell cultures, the low-molecular-weight B cell growth factor (BCGF) did not lead to a significant amount of ³H-thymidine uptake. In addition, in klebs-activated B cell cultures various anti-polynucleotide autoantibodies and the 16/6 idiotype were detectable. Thus, bacteria that induce nonsuppurative sequelae (e.g. klebs, yers) can use several mechanisms to overcome tolerance in their host.     

Suppressed cellular immunity in patients with nasopharyngeal carcinoma

The subsets and functions of lymphocytes were investigated in patients with nasopharyngeal carcinoma (NPC). The patients were divided into two groups comprising tumor-bearing patients and those in remission. There was no difference in the proportion of T cells among tumor-bearing, remission and healthy control groups. The percentages of inducer/helper T cells and natural killer cells were smaller in the tumor-bearing group than in the control group whereas the percentage of suppressor T cells was greater in the tumor-bearing group. Phytohemagglutinin-stimulated blastogenesis was markedly suppressed in the tumor-bearing group. The responsiveness to interleukin-2 of blastogenesis and of natural killer and lymphokine-activated killer activities was lowered in the tumor-bearing group. These parameters in the remission group were intermediate between those of the tumor-bearing and control groups. These results suggest that cellular immunity is suppressed in patients with NPC and that the suppressed condition still remains even in remission. Immunotherapy is considered to be indispensable for the proper treatment of NPC.Abbreviations IL-2 interleukin-2 - LAK lymphokine-activated killer - NK natural killer - NPC nasopharyngeal carcinoma - PHA phytohem-agglutinin     

Advances in inducing adaptive immunity using cell-based cancer vaccines: clinical applications in pancreatic cancer

The incidence of pancreatic ductal adenocarcinoma(PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients.     

Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength

The humoral immune response, also called the antibody-mediated immune response, is one of the main adaptive immune systems. The essential micronutrient zinc (Zn) is known to modulate adaptive immune responses, and dysregulated Zn homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this Zn-mediated modulation are largely unknown. Here, we show that the Zn transporter SLC39A10/ZIP10 plays an important role in B-cell antigen receptor (BCR) signal transduction. Zip10-deficiency in mature B cells attenuated both T-cell–dependent and –independent immune responses in vivo. The Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. The perturbed signaling was found to be triggered by a reduction in CD45R phosphatase activity and consequent hyperactivation of LYN, an essential protein kinase in BCR signaling. Our data suggest that ZIP10 functions as a positive regulator of CD45R to modulate the BCR signal strength, thereby setting a threshold for BCR signaling in humoral immune responses.The humoral immune response is a major arm of the adaptive immune systems, in which B cells play a key role (1, 2). In the bone marrow (BM), the initial commitment to pro-B cells occurs, followed by their differentiation into pre-B cells and then into immature (IMM) B cells, which express the B-cell antigen receptor (BCR) on their surface. The IMM B cells then migrate to the spleen as transitional B cells, and further differentiate into follicular (FO) or marginal zone (MZ) mature B cells. FO B cells are a highly recirculating population, and are essential for T-cell–dependent (TD) immune responses, in which BCR-activated B cells enter the germinal center (GC), where they undergo massive expansion and Ig class-switch recombination (CSR). In contrast, MZ B cells are noncirculating and mediate rapid T-cell–independent (TI) immune responses against blood-borne pathogens. In addition to the conventional B-2 cell subset described above, a distinct B-1 cell subset resides mainly in the peritoneal cavity and produces natural antibodies (1, 2).The BCR is composed of membrane-bound Ig and associated Igα and Igβ subunits. Following BCR binding to its cognate antigen, the Igα and Igβ subunits are phosphorylated on tyrosines within their immunoreceptor tyrosine-based activation motifs (ITAMs) by SRC family kinases, including LYN (3). The SYK tyrosine kinase is then recruited to the phosphorylated ITAMs, resulting in SYK’s activation, and the subsequent activation of downstream molecules, such as ERK, PI3K, and NF-κB. BCR activation not only drives adaptive immune responses, but also mediates a “tonic” signal together with B-cell–activating factor (BAFF) receptor (BAFFR) signaling to help maintain immunocompetent mature B-cell pools in the steady state (4, 5). Thus, BCR signaling critically regulates the activation status and fate decisions of B cells.Zinc (Zn) deficiency leads to lymphopenia and to attenuations of both cellular and humoral immunity, resulting in an increased susceptibility to various pathogens (6, 7). Zn is reported to function as a signaling factor (8–11) and its homeostasis is tightly controlled by Zn transporters, the SLC39/ZIP and SLC30/ZnT family members, which contribute to Zn influx and efflux, respectively (12, 13). Notably, it was shown that Zn transferred by a specific Zn transporter can selectively fine-tune distinct intracellular signaling events (14) by targeting specific signaling molecules (15–20). Moreover, the disruption of a given Zn signaling axis can have pathogenic consequences in the absence of redundant machinery (21). However, the specific mechanisms involved in Zn and Zn transporter modulation of the immune system—in particular, the humoral immune response—are not well understood.In this study, we showed that the Zn transporter, ZIP10 (Zrt- and Irt-like protein 10), is required for proper antibody responses following BCR activation. Mice with a conditional knockout of ZIP10 in mature B cells showed dramatic attenuations of TD and TI antibody responses. In addition, GC development failed in these mice, resulting in a marked reduction in antigen-specific IgG1 responses. Moreover, ZIP10 deficiency led to hyperactivated BCR signaling, which reduced cell proliferation because of decreased CD45R protein tyrosine phosphatase (PTPase) activity. Our results establish a link between ZIP10 and humoral immunity, in which ZIP10 controls the BCR signal strength as a positive regulator of CD45R, thereby setting a threshold for B-cell signaling.