Defective λ interferon production in leprosy reversal with antigen and interleukin 2

[No abstract available

Influence of delayed immune reactions on human epidermal keratinocytes

The epidermal changes that occur in human cutaneous immune responses have been investigated in the tuberculin reaction and in the lesions of tuberculoid and lepromatous leprosy and cutaneous leishmaniasis. In each situation, there was a dermal accumulation of monocytes and T cells, and the epidermis exhibited thickening. In the tuberculin response, the thickness of the epidermis sometimes doubled in 48-72 hr, and this was attributed to increases in both size and number of keratinocytes. In addition, the phenotype of the keratinocytes changed from Ia- to Ia+. Similar changes in keratinocyte Ia-antigen expression occurred in the epidermis overlying untreated tuberculoid leprosy and cutaneous leishmaniasis lesions, but not in lepromatous leprosy. We suggest that one or more epidermal growth factors may be generated in the course of a delayed immune reaction in the dermis

Identification of immunostimulatory dendritic cells in the synovial effusions of patients with rheumatoid arthritis

Dendritic cells in the circulation are leukocytes that are rich in Ia antigens and that actively stimulate T cell replication. We have identified dendritic cells in the joint effusions of patients with rheumatoid arthritis. By phase-contrast and immunofluorescence microscopy, synovial mononuclear cells contained 1-5% dendritic profiles that were rich in HLA-DR and DQ, had small amounts of C3bi receptor, and lacked a battery of monocyte and lymphocyte markers. These dendritic cells could be enriched to 60-80% purity by cytolytic depletion of monocytes and lymphocytes with a group of monoclonal antibodies (MAb) and complement. By transmission electron microscopy, the dendritic cell processes were bulbous in shape and lacked organelles. The cytoplasm had few lysosomes or endocytic vacuoles but contained a well-developed smooth reticulum that was comparable to that previously described in the Ia-rich interdigitating cells of lymphoid tissues. The growth of sodium periodate-modified T lymphocytes was used as a rapid quantitative assay of accessory cell function. Synovial mononuclear cells were some ten times more active than normal blood cells. Treatment with α-Ia MAb and complement ablated stimulatory function. In contrast, removal of monocytes (MAb, 3C10) or monocytes and B (MAb, BA-1) plus T (MAb, OKT3, or T101) lymphocytes did not significantly alter total activity, and the function per viable cell increased four- to eightfold. We conclude that rheumatoid arthritis synovial fluids contain cells that are comparable in function, phenotype, and structure to blood dendritic cells, although the frequency (1-5%) is 10 times greater in joints. The reason for their accumulation in the articular cavity is not known, but dendritic cells may be important in perpetuating the joint inflammation characteristic of this disease

Strain specific transcriptional response in Mycobacterium tuberculosis infected macrophages

<p>Abstract</p> <p>Background</p> <p>Tuberculosis (TB), a bacterial infection caused by <it>Mycobacterium tuberculosis </it>(<it>Mtb) </it>remains a significant health problem worldwide with a third of the world population infected and nearly nine million new cases claiming 1.1 million deaths every year. The outcome following infection by <it>Mtb </it>is determined by a complex and dynamic host-pathogen interaction in which the phenotype of the pathogen and the immune status of the host play a role. However, the molecular mechanism by which <it>Mtb </it>strains induce different responses during intracellular infection of the host macrophage is not fully understood. To explore the early molecular events triggered upon <it>Mtb </it>infection of macrophages, we studied the transcriptional responses of murine bone marrow-derived macrophages (BMM) to infection with two clinical <it>Mtb </it>strains, CDC1551 and HN878. These strains have previously been shown to differ in their virulence/immunogenicity in the mouse and rabbit models of pulmonary TB.</p> <p>Results</p> <p>In spite of similar intracellular growth rates, we observed that compared to HN878, infection by CDC1551 of BMM was associated with an increased global transcriptome, up-regulation of a specific early (6 hours) immune response network and significantly elevated nitric oxide production. In contrast, at 24 hours post-infection of BMM by HN878, more host genes involved in lipid metabolism, including cholesterol metabolism and prostaglandin synthesis were up-regulated, compared to infection with CDC1551.</p> <p>In association with the differences in the macrophage responses to infection with the 2 <it>Mtb </it>strains, intracellular CDC1551 expressed higher levels of stress response genes than did HN878.</p> <p>Conclusions</p> <p>In association with the early and more robust macrophage activation, intracellular CDC1551 cells were exposed to a higher level of stress leading to increased up-regulation of the bacterial stress response genes. In contrast, sub-optimal activation of macrophages and induction of a dysregulated host cell lipid metabolism favored a less stressful intracellular environment for HN878. Our findings suggest that the ability of CDC1551 and HN878 to differentially activate macrophages during infection probably determines their ability to either resist host cell immunity and progress to active disease or to succumb to the host protective responses and be driven into a non-replicating latent state in rabbit lungs.</p

An analysis of in vitro T cell responsiveness in lepromatous leprosy

[No abstract available

Identification of a novel cell-type in peripheral lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro

Steinman, R.M., Kaplan, G., Witmer, M.D., and Cohn, Z.A. Identification of a novel cell-type in peripheral lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro. J. Exp. Med. 149: 1-16, 1979.https://digitalcommons.rockefeller.edu/historical-scientific-reports/1003/thumbnail.jp

Identification of a novel cell type in peripheral lymphoid organs of mice: V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro*

[No abstract available

Induction of Granulysin and Perforin Cytolytic Mediator Expression in 10-Week-Old Infants Vaccinated with BCG at Birth

Background. While vaccination at birth with Mycobacterium bovis Bacilli Calmette-Guérin (BCG) protects against severe childhood tuberculosis, there is no consensus as to which components of the BCG-induced immune response mediate this protection. However, granulysin and perforin, found in the granules of cytotoxic T lymphocytes and Natural Killer (NK) cells, can kill intracellular mycobacteria and are implicated in protection against Mycobacterium tuberculosis. Methods. We compared the cellular expression of granulysin and perforin cytolytic molecules in cord blood and peripheral blood from 10-week-old infants vaccinated at birth with either Japanese or Danish BCG, administered either intradermally or percutaneously. Results. In cord blood, only CD56+ NK cells expressed granulysin and perforin constitutively. These cytolytic mediators were upregulated in CD4+ and CD8+ cord blood cells by ex vivo stimulation with BCG but not with PPD. Following BCG vaccination of neonates, both BCG and PPD induced increased expression of granulysin and perforin by CD4+ and CD8+ T cells. There was no difference in expression of cytolytic molecules according to vaccination route or strain. Conclusions. Constitutive expression of perforin and granulysin by cord blood NK-cells likely provides innate immunity, while BCG vaccination-induced expression of these cytolytic mediators may contribute towards protection of the neonate against tuberculosis

Innate Immune Response to Mycobacterium tuberculosis Beijing and Other Genotypes

Contains fulltext : 124335.pdf (publisher's version ) (Open Access)BACKGROUND: As a species, Mycobacterium tuberculosis is more diverse than previously thought. In particular, the Beijing family of M. tuberculosis strains is spreading and evaluating throughout the world and this is giving rise to public health concerns. Genetic diversity within this family has recently been delineated further and a specific genotype, called Bmyc10, has been shown to represent over 60% of all Beijing clinical isolates in several parts of the world. How the host immune system senses and responds to various M. tuberculosis strains may profoundly influence clinical outcome and the relative epidemiological success of the different mycobacterial lineages. We hypothesised that the success of the Bmyc10 group may, at least in part, rely upon its ability to alter innate immune responses and the secretion of cytokines and chemokines by host phagocytes. METHODOLOGY/PRINCIPAL FINDINGS: We infected human macrophages and dendritic cells with a collection of genetically well-defined M. tuberculosis clinical isolates belonging to various mycobacterial families, including Beijing. We analyzed cytokine and chemokine secretion on a semi-global level using antibody arrays allowing the detection of sixty-five immunity-related soluble molecules. Our data indicate that Beijing strains induce significantly less interleukin (IL)-6, tumor necrosis factor (TNF), IL-10 and GRO-alpha than the H37Rv reference strain, a feature that is variously shared by other modern and ancient M. tuberculosis families and which constitutes a signature of the Beijing family as a whole. However, Beijing strains did not differ relative to each other in their ability to modulate cytokine secretion. CONCLUSIONS/SIGNIFICANCE: Our results confirm and expand upon previous reports showing that M. tuberculosis Beijing strains in general are poor in vitro cytokine inducers in human phagocytes. The results suggest that the epidemiological success of the Beijing Bmyc10 is unlikely to rely upon any specific ability of this group of strains to impair anti-mycobacterial innate immunity

Transcriptional profiling of mycobacterial antigen-induced responses in infants vaccinated with BCG at birth

BACKGROUND: Novel tuberculosis (TB) vaccines recently tested in humans have been designed to boost immunity induced by the current vaccine, Mycobacterium bovis Bacille Calmette-Guérin (BCG). Because BCG vaccination is used extensively in infants, this population group is likely to be the first in which efficacy trials of new vaccines will be conducted. However, our understanding of the complexity of immunity to BCG in infants is inadequate, making interpretation of vaccine-induced immune responses difficult. METHODS: To better understand BCG-induced immunity, we performed gene expression profiling in five 10-week old infants routinely vaccinated with BCG at birth. RNA was extracted from 12 hour BCG-stimulated or purified protein derivative of tuberculin (PPD)-stimulated PBMC, isolated from neonatal blood collected 10 weeks after vaccination. RNA was hybridised to the Sentrix(R) HumanRef-8 Expression BeadChip (Illumina) to measure expression of >16,000 genes. RESULTS: We found that ex vivo stimulation of PBMC with PPD and BCG induced largely similar gene expression profiles, except that BCG induced greater macrophage activation. The peroxisome proliferator-activated receptor (PPAR) signaling pathway, including PPAR-gamma, involved in activation of the alternative, anti-inflammatory macrophage response was down-regulated following stimulation with both antigens. In contrast, up-regulation of genes associated with the classic, pro-inflammatory macrophage response was noted. Further analysis revealed a decrease in the expression of cell adhesion molecules (CAMs), including integrin alpha M (ITGAM), which is known to be important for entry of mycobacteria into the macrophage. Interestingly, more leukocyte genes were down-regulated than up-regulated. CONCLUSION: Our results suggest that a combination of suppressed and up-regulated genes may be key in determining development of protective immunity to TB induced by vaccination with BCG