Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-alpha

We have recently demonstrated that G-CSF promotes the generation of human T regulatory (T(REG)) type 1 cells. In this study, we investigated whether the immunomodulatory effects of G-CSF might be mediated by DC. CD14(+) monocytes were cultured with serum collected after clinical administration of G-CSF (post-G), which contained high amounts of IL-10 and IFN-alpha. Similar to incompletely matured DC, monocytes nurtured with post-G serum acquired a DC-like morphology, expressed high levels of costimulatory molecules and HLA-DR, and exhibited diminished IL-12p70 release and poor allostimulatory capacity. Importantly, post-G DC-like cells were insensitive to maturation stimuli. As shown by neutralization studies, IFN-alpha and, even more pronounced, IL-10 contained in post-G serum inhibited IL-12p70 release by post-G DC-like cells. Furthermore, phenotypic and functional features of post-G DC-like cells were replicated by culturing post-G monocytes with exogenous IL-10 and IFN-alpha. Post-G DC-like cells promoted Ag-specific hyporesponsiveness in naive allogeneic CD4(+) T cells and orchestrated a T(REG) response that was dependent on secreted TGF-beta 1 and IL-10. Finally, neutralization of IL-10 and IFN-alpha contained in post-G serum translated into abrogation of the regulatory features of post-G DC-like cells. This novel mechanism of immune regulation effected by G-CSF might be therapeutically exploited for tolerance induction in autoimmune disorders.     

Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset

Summary CD4+ CD25+ T regulatory cells (TReg), suppress antigen-specific immune responses and are important for allograft tolerance. During pregnancy the mother tolerates an allograft expressing paternal antigens (the fetus) requiring substantial changes in immune regulation over a programmed period of time. We analysed whether immune-suppressive TReg cells were altered during pregnancy and therefore might play a part in this tolerant state. The presence of TReg cells was assessed in the blood of 25 non-pregnant, 63 pregnant and seven postnatal healthy women by flow cytometry. We observed an increase in circulating TReg cells during early pregnancy, peaking during the second trimester and then a decline postpartum. Isolated CD25+ CD4+ cells expressed FoxP3 messenger RNA, a marker of TReg cells, and suppressed proliferative responses of autologous CD4+ CD25- T cells to allogeneic dendritic cells. These data support the concept that normal pregnancy is associated with an elevation in the number of TReg cells which may be important in maintaining materno-fetal tolerance.     

Immune function in intrauterine growth retardation

A one-year longitudinal study was carried out on 2 groups of Kenyan intrauterine growth retarded infants and normal weight full-term infants to determine the effects of intrauterine malnutrition and other nutrient deficiencies on immune function. Three birth weight groups were studied: <2500 gm (≤3rd percentile); 2500–2799 gm (3rd to 10th percentile); and ≥2800 gm (> 10th percentile). B cell function was studied by determination of B lymphocytes and serum levels of IgG, IgM, IgA and IgE. T-cell function was studied by measuring lymphocyte numbers, the percent and absolute number of T-cells by E-rosette technique, lymphocyte responsiveness to PHA and the intradermal PPD response to BCG vaccine. Maternal and infant nutritional studies were obtained concurrently. At birth B cells and immunoglobulins were normal and comparable in all groups except that seven of 41 infants had elevated IgE levels in their cord blood. By 7 months adult levels of IgG, IgM and IgE were achieved in the intrauterine growth retarded infants. Their mothers had significantly higher levels of IgG than the control mothers. Total lymphocyte counts, T-cells and percent T-cells were significantly reduced at birth in the IUGR groups. This abnormality persisted until one year in the smallest (≤2500 g) birthweight group. The IUGR infants had a higher incidence of cutaneous anergy to PPD than did control infants. Cell-mediated immunity correlated significantly with birthweight, blood levels of iron and thiamin at birth and with folate, hemoglobin, pyridoxine and riboflavin at 6 and 12 months.     

Sarcoidosis 2001

In every decade, sarcoidosis makes a chameleon-like change so its profile needs to be updated. It was first recognised as a dermatological curiosity which evolved into a multisystem disorder with bone cysts, uveitis, and intrathoracic involvement. New dimensions were uncovered by biochemistry and immunology, bringing it still nearer the elusive enigma, namely the cause of sarcoidosis. Aetiology includes an understanding of a genetic predisposition and environmental trigger factors. What was left undone in the 20th century will become evident in the 21st century with more sophisticated technology. Likewise, conventional treatments of the past will be superseded by cytokines and other magic bullets of the millennium.     

Modulation of B‐cell tolerance by Murine Gammaherpesvirus 68 infection: requirement for Orf73 viral gene expression and follicular helper T cells

Viruses such as Epstein–Barr virus (EBV) have been linked to mechanisms that support autoantibody production in diseases such as systemic lupus erythematosus. However, the mechanisms by which viruses contribute to autoantibody production remain poorly defined. This stems in part, from the high level of seropositivity for EBV (> 95%) and the exquisite species specificity of EBV. In this study we overcame these problems by using murine gammaherpesvirus 68 (MHV68), a virus genetically and biologically related to EBV. We first showed that MHV68 drives autoantibody production by promoting a loss of B‐cell anergy. We next showed that MHV68 infection resulted in the expansion of follicular helper T (Tfh) cells in vivo, and that these Tfh cells supported autoantibody production and a loss of B‐cell anergy. Finally, we showed that the expansion of Tfh cells and autoantibody production was dependent on the establishment of viral latency and expression of a functional viral gene called Orf73. Collectively, our studies highlighted an unexpected role for viral latency in the development of autoantibodies following MHV68 infection and suggest that virus‐induced expansion of Tfh cells probably plays a key role in the loss of B‐cell anergy.     

NK cells from pleural effusions are potent antitumor effector cells

Natural killer (NK) cells express a set of activating and inhibitory receptors which, after interaction with their ligands, determine whether or not the target cell will be lysed. Many studies have clearly demonstrated that NK cells have the capacity to lyse stressed cells (such as tumor or virally‐infected cells). However, NK cells that infiltrate tumors usually exhibit phenotypic and functional defects. In this issue of the European Journal of Immunology, Vacca et al. [Eur. J. Immunol. 2013. 43: 550?561] show that NK cells in pleural effusions of primary and metastatic tumors of various origins are not anergic, possibly because the downregulation of activating receptors and the upregulation of inhibitory receptors does not occur, as previously reported for tumor NK cells. Another major finding of this study is the capacity of these pleural NK cells to respond to IL‐2 stimulation, as the authors demonstrate that pleural NK cells stimulated by IL‐2 in long‐term culture acquire the capacity to lyse autologous tumor cells isolated from pleural effusions. These results support the treatment of primary or metastatic pleural tumors with IL‐2 or other innovative strategies currently being developed to stimulate NK cells in cancer patients as discussed in this Commentary.     

CD4+ T-cell anergy induced by lin− CD117(c-kit)+ stem cell-derived immature dendritic cells loaded with nuclear antigen derived from Trypanosoma equiperdum

Dendritic cells (DCs) are professional antigen-presenting cells, which have the extraordinary capacity to initiate naïve T-cell-mediated primary immune responses. To investigate the role of DCs in the induction of antigen-specific tolerance, the immature DCs (imDCs) and mature DCs (mDCs) were generated in vitro from lin^? CD117(c-kit)⁺ stem cells isolated from mice bone marrow. Flow cytometry and confocal microscopy were used to characterize the phenotypes of DCs. These cells were loaded with nuclear antigen derived from Trypanosoma equiperdum and then co-cultured with naïve CD4⁺ T cells. It was found that imDC-treated T cells had lower proliferation level and cytokine expression of interleukin (IL)-2, IL-4, IL-12, and interferon-γ compared with mDC-treated T cells. These results demonstrated that the maturation status of DCs is critical for preventing the production of autoantibodies.     

Differing antibody IgG isotypes in the polar forms of leprosy and cutaneous leishmaniasis characterized by antigen-specific T cell anergy.

Leprosy and American cutaneous leishmaniasis are tropical diseases which present a spectrum of clinical and immunological manifestations. Lepromatous leprosy and diffuse cutaneous leishmaniasis are the severe, progressive polar forms of disease characterized by persistent T cell anergy. Relative concentrations of antibodies belonging to the four IgG isotypes have been determined in these forms of disease as well as active visceral leishmaniasis, which presents transitory T cell anergy. Leishmania-specific IgG4 antibodies predominated in 19/20 sera from patients with diffuse cutaneous leishmaniasis, and IgG1 antibodies predominated in 9/10 cases of untreated visceral leishmaniasis. The predominant IgG isotype of Mycobacterium leprae-specific antibodies in untreated lepromatous leprosy was remarkably variable (IgG1, IgG2, IgG3 and IgG4 in 8, 6, 2 and 1 sera, respectively). Differing IgG antibody isotypes have been associated with distinct CD4+ T cell helper subpopulations and their characteristic lymphokine profiles in several pathologies. These results suggest that T cell anergy in chronic intracellular infections may be associated with as yet undefined mechanisms which modulate reported T helper cell-lymphokine isotype relationships.     

Immune and serologic profiles of HIV-infected and noninfected hemophilic children and adolescents

Objectives: To assess relationships among the effects of HIV on hemophilic children and adolescents' immunologic parameters and vaccine-related serology. Methods: We analyzed data from extensive baseline immunologic evaluations of 207 HIV antibody-positive (HIV+) and 126 HIV antibody-negative (HIV?) hemophilic children and adolescents. Results: HIV+ and HIV- participants differed significantly in T-lymphocyte subpopulation numbers, immunoglobulin levels, and seroprevalence rates for diphtheria toxoid, measles, and mumps antigens. IgG levels, IgM levels, and serologic titers to vaccine antigens showed little correlation with T-cell parameters. Proportionately more HIV+ participants were nonreactive to each and all of a panel of 7 skin test antigens (71 % vs 28% anerglc, RR 2.6). The odds of anergy increased 1.6 times for every decline of 200 CD4 ± cells/μTl. Conclusions: HIV had significant, largely independent T- and B-lymphocyte effects on this pediatric cohort. © 1994 Wiley-Liss, Inc.