T cell regulation of the chronic peritoneal neutrophilia during mycobacterial infections.

Intraperitoneal infection of mice with mycobacteria induces the persistent mobilization of neutrophils to the infected peritoneal cavities. The recruitment of the neutrophils was mediated by the immune system since it was enhanced by immunization and reduced in T cell-deficient nude and SCID mice. Anti-mitotic treatments with cyclophosphamide or X-rays led to a reduction in the number of mononuclear cells in the peritoneal cavity of infected mice, followed by a reduction in neutrophil numbers despite the presence of a normal circulating pool of neutrophils. The depletion of T cells with antibodies during mycobacterial i.p. infection led to a reduction in the number of neutrophils. Such a reduction was more extensive if the antibodies were administered early. Our data suggest that T cells are partially involved in the direct recruitment of neutrophils during chronic mycobacteriosis but they also play a role in the priming of other cell types for the mobilization of these phagocytes.     

HIV感染者、发病者及HAART治疗者NK细胞亚群变化研究

目的探讨HIV感染者、发病者和进行高效抗逆转录病毒疗法(HAART)的治疗者NK细胞亚群的变化情况。方法取新鲜外周全血,用荧光标记的单克隆抗体进行染色,经流式细胞仪检测分析HIV感染者、发病者和HAART治疗者NK细胞亚群的变化。结果 HIV感染者、发病者CD56dimCD16+NK细胞的百分比显著低于HIV抗体阴性健康对照;CD56-CD16+、CD56briCD16-/+NK细胞的百分比显著高于HIV抗体阴性健康对照;HAART治疗者CD56dimCD16+、CD56-CD16+和CD56briCD16-/+NK细胞亚群的百分比与HIV抗体阴性健康对照相比不再有显著差异。结论 HIV感染改变了NK细胞亚群的构成,HAART治疗后NK细胞亚群的比例可得到部分恢复。     

Severe chronic urticaria is associated with elevated plasma levels of D-dimer

Background:  Patients with chronic urticaria (CU) frequently show signs of thrombin generation as a result of the activation of the extrinsic pathway of coagulation and signs of fibrinolysis as shown by slightly increased mean D-dimer plasma levels. Here, we studied patients with severe CU to see whether the activation of coagulation and fibrinolysis parallels the severity of the disease.
Methods:  Eight consecutive patients with severe exacerbations of CU and 13 with slight CU were studied. Plasma prothrombin fragment F₁₊₂ as well as D-dimer were measured by ELISA. Serum histamine-releasing activity was assessed by basophil histamine release assay. Seventy-four normal subjects were used as controls.
Results:  In patients with severe CU, median levels of both D-dimer (11.20 nmol/l) and F₁₊₂ (592 pmol/l) largely exceeded those found in patients with slight CU [D-dimer: 2.66 nmol/l ( P  = 0.001) and F₁₊₂: 228 pmol/l ( P  = 0.003)] and in normal subjects [D-dimer: 1.41 nmol/l ( P  = 0.0001) and F₁₊₂: 159 pmol/l ( P  = 0.0001)]. Sera from 25% of patients with severe CU and 31% of those with slight CU, but from none of normal subjects, showed in vitro histamine-releasing activity. D-dimer and F₁₊₂ levels were significantly correlated each other ( r  = 0.64, P  = 0.002) and with CU severity score ( r  = 0.80–0.90, P  = 0.0001), but no correlation was observed between serum histamine-releasing activity and coagulation parameters or severity score.
Conclusions:  Severe exacerbations of CU are associated with a strong activation of coagulation cascade and fibrinolysis. Whether this activation is the cause of CU or acts as an amplification system is still a matter of debate.     

The expression of dendritic cell subsets in severe chronic rhinosinusitis with nasal polyps is altered

Background

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized as a Th2-driven disease.Activated dendritic cells (DCs) are the main T-cell activators; their role in the chronic inflammatory process of nasal polyposis is still unclear.

Methods

The regulation of DC subsets was analyzed in nasal polyp tissue from CRSwNP patients and compared to inferior turbinate tissue from healthy subjects. Tissue localization and expression of both plasmacytoid and myeloid DCs were assayed by means of immunohistochemistry and flow cytometry. Plasmacytoid DCs were also assayed by PCR, and tissue homogenates were assayed for various inflammatory markers.

Results

The number of plasmacytoid (pDCs) and myeloid (mDCs) dendritic cells was significantly increased in nasal polyp tissue when compared to non-inflamed nasal mucosa. The number of pDCs, but not mDCs, was down-regulated in more severe cases (nasal polyps with asthma) and varied with the cytokine milieu. The amount of pDCs was significantly decreased in IL5+IFNγ – nasal polyp tissue compared to tissues with high IFNγ levels (IL5+IFNγ+). Furthermore, levels of indoleamine 2,3-dioxygenase were increased in nasal polyp compared to inferior turbinate tissue and correlated negatively with the number of pDCs.

Conclusions

There is an altered balance of pDC and mDC numbers in nasal polyp tissue. pDCs seem to be more susceptible to an inflammatory cytokine milieu and may play a crucial role in disease severity.     

iNKT cell frequency in peripheral blood of Caucasian children and adolescent: the absolute iNKT cell count is stable from birth to adulthood

Human invariant natural killer T cells (iNKT cells) are a unique population of T cells that express a semi-invariantly rearranged T cell receptor (TCR) and are involved in a variety of immunoregulatory processes. We assessed the frequency of peripheral blood iNKT cells in 64 healthy Caucasian children from 7 months to 18 years of age and five cord blood samples by flow cytometry. iNKT cells were measured as CD3(+) cells co-expressing TCRVα24 and TCRVβ11 and using the monoclonal antibody 6B11, which recognizes specifically their invariant TCR rearrangement. The absolute number of iNKT cells ranged from 86 to 10,499 (CD3(+) /TCRVα24(+) / TCRVβ11(+)) and 233 to 11,167 (CD3(+) /6B11(+)) iNKT cells per millilitre of blood. This range is stable from birth to adulthood. The relative iNKT cell count was found to be 0.003-0.71% (CD3(+) /TCRVα24/TCRVβ11) and 0.019-0.776% (CD3/6B11) of peripheral blood T cells and shows only a slight increase with age.     

Gamma–delta T cell subsets are differentially associated with granuloma development and organization in a bovine model of mycobacterial disease

The characteristic lesion in bovine tuberculosis is well‐organized respiratory granulomas. This is typically associated with a strong T‐helper 1 biased cell‐mediated immune response and eventual containment of the infection. In bovine paratuberculosis, the classic lesion is unorganized granulomatous intestinal inflammation. Clinical paratuberculosis is associated with a T‐helper 2 biased humoral immune response and eventual death because of inability of the host to contain the infection. Recent reports have suggested that gamma–delta (γδ) T cells play a significant role in granuloma development and/or maintenance during initial stages of infection and may influence the subsequent adaptive immune response. The objective of this study was to use an in vivo bovine model to evaluate γδ T cells during the early host immune response to mycobacterial infection. We used immunofluorescent staining, hyperspectral microscopy, and computerized assisted morphometry to evaluate staining and distribution of γδ T cells during development of organized and unorganized granulomas. Our data suggest that bovine γδ T cell subsets are differentially recruited to early infection sites, and may be instrumental during the initial antimycobacterial host immune response as well as for granuloma organization.     

Susceptibility to experimental autoimmune encephalomyelitis is associated with altered B-cell subsets distribution and decreased serum BAFF levels

B cells possess the ability to regulate either pathogenic or protective events in several autoimmune diseases such as multiple sclerosis (MS) and its experimental model, experimental autoimmune encephalomyelitis (EAE). Given the extensive use of B-cell-targeting treatments, it appears crucial to more precisely define the dual role of B cells in the progression of the disease. In the present study, we explored the impact of EAE induction on the distribution of potential regulatory B-cell subsets (CD5(+) B1a, marginal zone and transitional 2 B cells) over critical time points in the relapsing-remitting EAE model, SJL/J (H2s). The same approach was carried out in B10.S mice that are resistant to EAE induction, (H2s). The comparative data obtained from these experiments showed that the homeostasis of the regulatory B-cell subsets is altered during the EAE preclinical and acute phases. These observations were associated with a distortion of the BAFF response. All these data suggest the existence of a close relationship between B-cell homeostasis, BAFF response and the susceptibility to develop EAE.     

Immune regulation of gammadelta T cell responses in mycobacterial infections

Antigen-specific gammadelta T cells may play a role in anti-mycobacterial immunity. Studies done in humans and animal models have demonstrated complex patterns of gammadelta T cell immune responses during early mycobacterial infections and chronic tuberculosis. Recent studies have also shown a clinical correlation between major recall expansion of antigen-specific gammadelta T cells and immunity against fatal early mycobacterial diseases. Multiple host and microbial factors can regulate diverse immune responses of phosphoantigen-specific gammadelta T cells during mycobacterial infections.     

辅助性T细胞亚群在小鼠EAE模型视神经中的变化

目的:探讨辅助性T细胞亚群Th1、Th2、Th17及Treg在小鼠EAE模型视神经炎发病机制中的意义.方法:C57BL/6小鼠随机分为佐剂对照组(n=16)、EAE模型组(n=48),免疫后第11、15、19天分批处死小鼠,观察视神经组织的病理改变.ELISA方法检测视神经IFN-γ、IL-4、IL-17的蛋白含量;Real-time PCR方法检测视神经组织IFN-γ、IL-4、IL-17和Foxp3的基因表达.结果:免疫后第11天IL-17的蛋白及mRNA的表达比正常对照组明显增高(14.255±0.790 vs 10.615±0.664;0.798±0.137 vs 0.083±0.013,均P＜0.05),免疫后第19天IFN-γ的蛋白及mRNA的表达比对照组明显增高(21.060±1.821 vs 12.845±0.970;0.617±0.070 vs 0.089±0.014,均P＜0.05),IL-4的蛋白及mRNA的表达与对照组比较减少(10.227±0.767 vs 14.258±0.885;0.089±0.014 vs 0.250±0.047,均P＜0.05). Foxp3 mRNA的表达由免疫后11天、15天至19天与对照组比较均明显减少(1.068±0.121,0.495±0.064,0.605±0.021 vs 3.087±0.194, P＜0.01) .结论:EAE小鼠视神经Foxp3和Treg表达减少可能为视神经炎发生发展的重要因素;IL-17在EAE小鼠视神经炎的早期阶段介导炎症损伤,IFN-γ在发病的高峰期加重了EAE小鼠视神经的炎症损伤.     

An increase in epithelial cell apoptosis is associated with chronic intestinal nematode infection

It is well established that homeostasis of the intestinal epithelium becomes dysregulated during gastrointestinal helminth infection and is under immune control. An increase in both enterocyte proliferation and the subsequent generation of crypt hyperplasia are hallmarks of chronic infection with Trichuris muris, a large intestinal dwelling nematode. The effect of this parasitic infection on apoptosis induction in the large intestine and its regulation has been neglected. To address this, mice of resistant and susceptible phenotypes were infected with different doses of T. muris, and the levels of epithelial cell apoptosis were determined. It is clear that apoptosis is induced during chronic T. muris infection. This occurs mainly at the base of the cecal crypt, within the stem cell region. The level of apoptosis induced is independent of worm number, suggesting that it is not a consequence of worm-induced damage but rather a mechanism for controlling cell number within the crypt. Neutralization of both gamma interferon and tumor necrosis factor alpha caused a significant reduction in the levels of apoptosis, showing that proinflammatory cytokines generated in response to chronic infection play an important role in apoptosis induction in this system. It is proposed that the generation of proinflammatory cytokines during chronic T. muris infection may play a positive role, by promoting intestinal epithelial cell apoptosis, to counter infection-induced epithelial hyperplasia.     

Bacteroides are associated with GALT iNKT cell function and reduction of microbial translocation in HIV-1 infection

Invariant natural killer T (iNKT) cells are innate-like T cells that respond to lipid antigens presented by CD1d. These immunoregulatory cells have the capacity for rapid cytokine release after antigen recognition and are essential for the activation of multiple arms of the immune response. HIV-1 infection is associated with iNKT cell depletion in the peripheral blood; however, their role in the gastrointestinal-associated lymphoid tissue (GALT) is less well studied. Our results show that iNKT cells are found at a higher frequency in GALT compared with blood, particularly in HIV-1 elite controllers. The capacity of iNKT cells to produce interleukin-4 (IL-4) and IL-10 in the GALT was associated with less immune activation and lower markers of microbial translocation, whereas regulatory T cell frequency showed positive associations with immune activation. We hypothesized that the composition of the microbiota would influence iNKT cell frequency and function. We found positive associations between the abundance of several Bacteroides species and iNKT cell frequency and their capacity to produce IL-4 in the GALT but not in the blood. Overall, our results are consistent with the hypothesis that GALT iNKT cells, influenced by certain bacterial species, may have a key role in regulating immune activation in HIV-1 infection.     

Ultrastructural defects of respiratory tract cilia associated with chronic infections

Ultrastructural defects were demonstrated in nasal and bronchial cilia from a 12-year-old boy with repeated upper and lower respiratory tract infections. Numerous abnormalities were found, including single axonemes surrounded by excess cytoplasmic matrix, compound cilia, intracytoplasmic microtubular doublets, and cilia contained within a periciliary sheath. Dynein arms were missing from the majority of the peripheral microtubular doublets. The most striking abnormality, however, was a disorientation of cilia as judged by the increased variation in the orientation of central microtubules. Because of these ultrastructural abnormalities, it is highly likely that ciliary motility was markedly decreased and that defective mucociliary transport was responsible for chronic and repeated upper respiratory tract infections.     

Distinct T cell subsets in adipose tissue are associated with obesity

Adipose tissue inflammation is a driving factor for the development of obesity-associated metabolic disturbances, and a role of adipose tissue T cells in initiating the pro-inflammatory signaling is emerging. However, data on human adipose tissue T cells in obesity are limited, reflected by the lack of phenotypic markers to define tissue-resident T cell subsets. In this study, we performed a deep characterization of T cells in blood and adipose tissue depots using multicolor flow cytometry and RNA sequencing. We identified distinct subsets of T cells associated with obesity expressing the activation markers, CD26 and CCR5, and obesity-specific genes that are potentially engaged in activating pro-inflammatory pathway, including ceramide signaling, autophagy, and IL-6 signaling. These findings increase our knowledge on the heterogeneity of T cells in adipose tissue and on subsets that may play a role in obesity-related pathogenesis.     

The proportion of different interleukin‐17‐producing T‐cell subsets is associated with liver fibrosis in chronic hepatitis C

Studies have suggested the pivotal role of T helper type 1 (Th1) ‐related cytokines on the outcome of hepatitis C virus (HCV) infection. Nevertheless, the role of different interleukin‐17 (IL‐17) ‐secreting T cells on chronic hepatitis C (CHC) is less clear. Here, the in vivo IL‐1β, IL‐6, and IL‐17 levels were positively correlated with both alanine transaminase (ALT) levels and hepatic lesions. When compared with the control group, CHC patients showed a lower proportion of IL‐17‐secreting (CD4⁺ and CD8⁺) T cells capable of simultaneously producing IL‐21. Moreover, the percentage of IL‐10‐secreting Th17 cells was also lower in CHC patients. Notably, advanced liver lesions were observed among those patients with lower percentage levels of IL‐17‐producing T cells positive for IL‐21, interferon‐γ (IFN‐γ) and IL‐10. In contrast, the severity of hepatic damage was associated with peripheral single IL‐17⁺ T cells. The percentage of IL‐17⁺ IL‐21^– IFN‐γ⁺ (CD4⁺ and CD8⁺) T‐cell phenotypes was positively associated with plasma CD14 levels. Finally, elevated levels of circulating CD14 were detected among CHC patients with extensive liver damage. In summary, although preliminary, our results suggest that a balance between different IL‐17‐producing T cells, associated with peripheral levels of CD14, may be a progress marker for liver disease in chronically HCV‐infected patients.     

HLA-DR phenotypes and blood levels of T cell subsets

Blood mononuclear cell and T cell subsets values were analyzed in 53 Sicilian individuals according to HLA-DR phenotypes. The results demonstrate that DR1-positive subjects show a significant increase of blood T cell subsets whereas DR3-positive subjects show a non-significant decrease of these values. These results suggest that gene(s) associated with HLA-DR could be one of the factors which affect blood levels of T cell subsets.     

Immunosuppression associated with the development of chronic infections with Rickettsia tsutsugamushi: adherent suppressor cell activity and macrophage activation.

Measures of general immunocompetency such as lymphocyte responses to mitogens and alloantigens and the ability to produce antibody to T-dependent and T-independent antigens were evaluated during the development of chronic infections with Rickettsia tsutsugamushi resulting from subcutaneous infection of BALB/c mice. It was found that a transient immunosuppression was demonstrable regardless of the infecting strain of rickettsiae; however, the immunosuppression produced by the Karp and Kato strains was more pronounced and longer lived. As a marked splenomegaly resulting from inflammatory macrophage influx accompanied this immunosuppression, mitogen- and antigen-induced lymphocyte proliferation was also evaluated after adherent cell depletion or in the presence of indomethacin, and both treatments significantly improved the responses. Isolated splenic macrophages were shown to suppress the responses of lymphocytes from naive mice as well as to exhibit parameters of activation including tumor cell cytolysis and cytostasis and the ability to inhibit the replication of R. tsutsugamushi in vitro. These data suggest an association between macrophage activation involved in rickettsial clearance and a transient immunosuppression.     

Early HIV infection is associated with reduced proportions of gamma delta T subsets as well as high creatinine and urea levels

Renal dysfunctions are major predictors of co-morbidities and mortality in HIV-infected individuals. Unconventional T cells have been shown to regulate kidney functions. However, there is dearth of information on the effect of HIV-associated nephropathies on γδ and DN T cells. It is also not clear whether γδ T cell perturbations observed during the early stages of HIV infection occur before immune activation. In this study, we investigated the relationship between creatinine and urea on the number of unconventional T cells in HIV-infected individuals at the early and chronic stages of infection. Persons in the chronic stage of infection were divided into treatment naïve and exposed groups. Treatment exposed individuals were further subdivided into groups with undetectable and detectable HIV-1RNA in their blood. Creatinine and urea levels were significantly higher among persons in the early HIV infection compared with the other groups. Proportions of γδ T, γδ + CD8, γδ + CD16 cells were also significantly reduced in the early stage of HIV infection (P < .01). Markers of immune activation, CD4 + HLA-DR and CD8 + HLA-DR, were also significantly reduced during early HIV infection (P < .01). Taken together, our findings suggest that high levels of renal markers as well as reduced proportions of gamma delta T cells are associated with the early stages of HIV infection. This event likely occurs before systemic immune activation reaches peak levels. This study provides evidence for the need for early HIV infection diagnosis and treatment.     

Alteration of behavior in mice by muscimol is associated with regional electroencephalogram synchronization

We tested the hypothesis that the effects of GABAergic agonists on behavior and the electroencephalogram (EEG) result from an increased regional synchronization in cortical circuits. The relationship between regional EEG topography, EEG synchronization and alteration of behavior was investigated by administering male C57BL/6 mice (n=7) a high, 3 mg/kg i.p. dose of muscimol, a selective GABA(A) agonist. Parietal and frontal cortical EEG, electromyogram, infrared and running wheel activity were recorded for 3 h before and 9 h after injection. Muscimol consistently elicited biphasic behavioral changes. Initially, it induced a catalepsy-like state lasting 96.0+/-12.4 min. This state was followed by a hyperactivity period of 49.7+/-5.4 min, during which the mice engaged in vigorous wheel running. During catalepsy, the EEG exhibited high amplitude waves which showed a consistent phase relationship between the frontal and parietal derivation. Moreover, the typical regional differences between the EEG spectra of the two derivations were abolished, and a redistribution of EEG power toward lower frequencies (<3 Hz) occurred in both derivations. In contrast, during hyperactivity the parietal EEG was dominated by theta-activity (7-9 Hz), which is typical for running behavior, while high amplitude slow waves, resembling the normal non-rapid eye movement sleep EEG pattern, predominated in the frontal EEG. The data indicate that the GABAergic system is involved in the regulation of cortical synchronization of neuronal activity and suggest a link between regional EEG synchronization and behavioral states.     

Reduction of blood nitric oxide levels is associated with clinical improvement of the chronic pelvic pain related to endometriosis

The objective of this prospective study was to determine the plasma levels of nitric oxide (NO) in women with chronic pelvic pain secondary to endometriosis (n=24) and abdominal myofascial pain syndrome (n=16). NO levels were measured in plasma collected before and 1 month after treatment. Pretreatment NO levels (μM) were lower in healthy volunteers (47.0±12.7) than in women with myofascial pain (64.2±5.0, P=0.01) or endometriosis (99.5±12.9, P<0.0001). After treatment, plasma NO levels were reduced only in the endometriosis group (99.5±12.9 vs 61.6±5.9, P=0.002). A correlation between reduction of pain intensity and reduction of NO level was observed in the endometriosis group [correlation = 0.67 (95%CI = 0.35 to 0.85), P<0.0001]. Reduction of NO levels was associated with an increase of pain threshold in this group [correlation = -0.53 (-0.78 to -0.14), P<0.0001]. NO levels appeared elevated in women with chronic pelvic pain diagnosed as secondary to endometriosis, and were directly associated with reduction in pain intensity and increase in pain threshold after treatment. Further studies are needed to investigate the role of NO in the pathophysiology of pain in women with endometriosis and its eventual association with central sensitization.