The Berlin Declaration on tuberculosis and its consequences for TB research and control in the WHO-Euro region.

In his famous presentation 'Ueber Tuberculose', Robert Koch (1843-1910) changed the view on tuberculosis as disease, identified Mycobacterium tuberculosis as the etiologic agent and revolutionized the fight against infectious disease in diagnosis, therapy and prevention. Koch gave this presentation in Berlin on March 24, 1882 [1]. Exactly 100 years later, 1982, the International Union Against Tuberculosis and Lung Disease (IUATLD) proposed the 24th of March as 'World Tuberculosis Day'. Fourteen years later, in 1996, the World Health Organization (WHO) confirmed this day as the official day commemorating the disease and its victims, as well as the global endeavours to fight tuberculosis.

[Berlin Declaration on Tuberculosis: High Level Follow-Up of High Priority Countries for TB Control in the WHO-EURO Region 'Double Trouble or Double Success? Bringing Together Diseases and Programs' - a symposium report]. / Berlin Declaration on Tuberculosis: High Level Follow-Up of High Priority Countries for TB Control in the WHO-EURO Region 'Double Trouble or Double Success? Bringing Together Diseases and Programs' - ein Symposiumsbericht.

The global tuberculosis (TB) situation has deteriorated dramatically since the beginning of the 1990s. In 2007, the WHO identified 18 countries of the WHO European Region as 'high priority countries' and introduced a plan for these countries to improve the situation. To further promote solutions a WHO European Ministerial Forum 'All against Tuberculosis' took place in Berlin in 2007 and resulted in the 'Berlin Declaration' which was commonly endorsed. In October 2009 a meeting was organized by the German Ministry of Health under the title "Berlin Declaration on Tuberculosis: High Level Follow-Up of High Priority Countries for TB Control in the WHO-EURO Region 'Double Trouble or Double Success? Bringing together Diseases and Programs'". This article summarizes the symposium. Besides reporting on the recent epidemiological situation of the WHO-EURO Region (with partly dramatically developments) presentations on psychosocial issues, the role of the EU and the 'Global Fund to Fight AIDS, Tuberculosis and Malaria', the importance of new tools for the fight against tuberculosis and the need for further political commitment were given.

[Control of tuberculosis in Russia and other countries of the former Soviet Union]. / Die Kontrolle der Tuberkulose in den Nachfolgestaaten der Sowjetunion am Beispiel Russlands.

BACKGROUND: Tuberculosis (TB) remains a serious threat to public health in Russia and other former Soviet Union Countries. The purpose of this paper is to describe the current trends of TB and MDR-TB in Russia and identify the characteristics of the traditional Russian TB control model inherited from the Soviet Union. We discuss current challenges to TB control in the country. METHODS: WHO tuberculosis notification data were analysed for Russia and 14 other former Soviet Union countries. To investigate the characteristics of TB control in Russia, we performed a systematic literature review using MEDLINE/EMBASE databases. 136 articles were initially identified of which 66 fulfilled the inclusion criteria. Full texts were reviewed. Additionally, we reviewed non-systematically Russian state reports, guidelines and legislations. RESULTS: In 2006, nearly 125 000 TB cases and 28 000 TB deaths were notified in the Russian Federation. The TB notification rate was 13 times higher than in Germany. The characteristics of the traditional Russian TB control model include: a centralised disease-specific inpatient network for diagnosis and treatment of TB, countrywide population screenings using fluorography, a strong focus on X-ray for diagnosis and disease classification, individualised and lengthy inpatient care, high rates of drug resistance, and inefficient financing systems. CONCLUSIONS: Current challenges to TB control in Russia are: the implementation of a quality-assured laboratory network for sputum-smear microscopy, culture and drug susceptibility testing, ensuring MDR-TB treatment and control, prevention and management of TB/HIV, and reform of health care financing systems. For TB control to be successful in the Russian Federation, the characteristics of the traditional TB control model need to be taken into account.

[Immunology of tuberculosis and current status of vaccine development]. / Immunologie der Tuberkulose und Entwicklungsstand neuer Impfstoffe.

Even 125 year after the discovery of Mycobacterium tuberculosis as the aetiological agent of tuberculosis by Robert Koch, tuberculosis is still a global health emergency according to WHO. The high infection rate with M. tuberculosis that persists in the human host until a weakened host immune system allows a reactivation and complicated and expensive antituberculous chemotherapy urgently demand the development of new vaccines. Increasing numbers of multidrug-resistant tuberculosis, especially in the successor states of the former Soviet Union and China, further complicate an efficient tuberculosis control. For decades, there was no new release of an antituberculous drug to efficiently fight tuberculosis. Hence, also drug development has to keep up with the development of resistance by the pathogen. The following review describes the immune response to M. tuberculosis infection and the deduction of strategies for novel vaccines. Thanks to international financial support, several new vaccine candidates are already in the pipeline and close to clinical testing phases.

[Immunology of tuberculosis: impact on the development of novel vaccines]. / Immunologie der Tuberkulose. Konsequenzen für die Impfstoffentwicklung.

Tuberculosis is an ancient health problem that is still not under control worldwide. High infection rates with the etiologic pathogen, Mycobacterium tuberculosis, persisting within the host organism and waiting for the opportunity to disseminate when the immune system is suppressed, and the long and cost-intensive chemotherapeutic treatment urgently require the development of a novel vaccine. This article reviews the immune response to M. tuberculosis infection resulting in new strategies for the improvement of the available vaccine Mycobacterium bovis BCG or for the development of alternative vaccines. A new vaccine should elicit a better immune response than the natural infection and reliably protect from TB disease, regardless if given prior or post infection with M. tuberculosis.

Increased numbers of ESAT-6- and purified protein derivative-specific gamma interferon-producing cells in subclinical and active tuberculosis infection.

Numbers of gamma interferon (IFN-gamma)-producing cells reactive to ESAT-6 antigen were increased in recent converters to purified protein derivative positivity and in tuberculosis patients but not in unvaccinated or Mycobacterium bovis BCG-vaccinated healthy donors. ESAT-6-reactive IFN-gamma-producing cells in recent converters and tuberculosis patients recognized similar synthetic peptides. Thus, ESAT-6 is a potential candidate for use in detection of early, as well as active, tuberculosis and for control of the disease.

CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection.

The discovery of the CD1 antigen presentation pathway has expanded the spectrum of T-cell antigens to include lipids, but the range of natural lipid antigens and functions of CD1-restricted T cells in vivo remain poorly understood. Here we show that the T-cell antigen receptor and the CD1c protein mediate recognition of an evolutionarily conserved family of isoprenoid glycolipids whose members include essential components of protein glycosylation and cell-wall synthesis pathways. A CD1c-restricted, mycobacteria-specific T-cell line recognized two previously unknown mycobacterial hexosyl-1-phosphoisoprenoids and structurally related mannosyl-beta1-phosphodolichols. Responses to mannosyl-beta1-phosphodolichols were common among CD1c-restricted T-cell lines and peripheral blood T lymphocytes of human subjects recently infected with M. tuberculosis, but were not seen in naive control subjects. These results define a new class of broadly distributed lipid antigens presented by the CD1 system during infection in vivo and suggest an immune mechanism for recognition of senescent or transformed cells that are known to have altered dolichol lipids.

CD1 proteins: targets of T cell recognition in innate and adaptive immunity.

The CD1 family consists of antigen presenting molecules encoded by genes located outside of the major histocompatibility complex. CD1 proteins are conserved among mammalian species and are expressed on the surface of cells involved in antigen presentation. The CD1 system has been shown to be involved in activation of cell-mediated responses, and T cells specific for either CD1 molecules or antigens presented by CD1 have been isolated. Structural and biochemical analyses demonstrate that antigens presented by CD1 are nonpeptide lipid or glycolipid structures, including examples found in the cell walls of pathogenic mycobacteria. The hydrophobic part of these antigens most likely binds in the CD1 ligand-binding groove, whereas the polar headgroup of these antigens appears to make direct contact with the T cell receptor and determines specific recognition. Presentation of antigens by CD1 molecules requires uptake and intracellular processing by antigen presenting cells and can be achieved for both exogenous and endogenous antigens. T cells recognizing CD1 restricted antigens have a broad range of functional activities that suggest that the CD1 system is involved in both innate and adaptive immune responses against microbial infections.

Numbers of IFN-gamma-producing cells against ESAT-6 increase in tuberculosis patients during chemotherapy.

ESAT-6 is a specific Mycobacterium tuberculosis complex antigen and strong inducer of interferon-gamma (IFN-gamma) production by T cells from tuberculosis patient T-cells. We studied the frequency of IFN-gamma producing cells reacting to ESAT-6 during anti-tuberculosis chemotherapy. The numbers of IFN-gamma producing cells in the peripheral blood were higher in tuberculosis patients after discharge from specific anti-tuberculosis chemotherapy, compared with untreated patients. These results indicate that monitoring specific M. tuberculosis antigen reactivity during anti-tuberculosis chemotherapy may avoid premature termination of treatment and resistant strains.

Disease activity related catecholamine response of lymphocytes from patients with rheumatoid arthritis.

In patients with chronic rheumatic diseases, a decreased density of beta 2-adrenergic receptors (beta 2R) on peripheral blood mononuclear cells (PBMC) could be demonstrated negatively correlating with various disease activity parameters. The aim of the present study was to determine the impact of this decrease on catecholamine response of PBMC from patients with rheumatoid arthritis (RA) in vitro. PBMC from 17 patients with RA and 6 healthy blood donors (HD) were investigated. The effects of epinephrine (E) and norepinephrine (NE) on PBMC proliferation were studied using cells activated with phytohemagglutinin (PHA) and monoclonal anti-CD3-antibodies (OKT3), respectively. The results revealed that lymphocytes of patients with RA showed a significantly reduced influence of catecholamines on PBMC function. In RA patients with high disease activity only, a shift to alpha 1-adrenergic-mediated catecholamine effects upon PBMC reactivity could be observed. The study demonstrates the intricate relationship between PBMC reactivity and catecholamine effects that is mediated via alpha- and beta-adrenergic receptors due to disease activity. In this respect the altered catecholamine response of PBMC from patients with RA may contribute to the pathogenic process of RA.

Phenotypically activated gammadelta T lymphocytes in the peripheral blood of patients with tuberculosis.

Surface molecules with the potential relevance for resistance against Mycobacterium tuberculosis were investigated. The expression of lymphocyte function antigen-1, very late antigen (VLA)-4, l-selectin, intercellular adhesion molecule (ICAM)-1, major histocompatibility complex class II, Fas, and CD40 on alphabeta T cells, gammadelta T cells, NK cells, and monocytes of healthy donors and patients with tuberculosis were analyzed. A high activation status of gammadelta T cells and increased levels of soluble ICAM-1 in plasma of patients with tuberculosis versus healthy individuals was detected. Tuberculosis patients with and without an underlying systemic disease could be segregated by differential expression of VLA-4 and ICAM-1 on gammadelta T cells and on monocytes. The composition of peripheral blood mononuclear cells varied slightly, whereas the proportion of monocytes decreased significantly in patients with tuberculosis, compared with healthy controls. The activation phenotype of peripheral gammadelta T cells in patients with tuberculosis emphasizes the role of these T cells in controlling the inflammatory process during tuberculosis and perhaps other microbial infections.

Reduced catecholamine response of lymphocytes from patients with rheumatoid arthritis.

Catecholamines modulate lymphocyte function via stimulation of beta2-adrenergic receptors (beta2R). Previous investigations revealed a decreased density of beta2R on peripheral blood mononuclear cells (PBMC) in patients with chronic rheumatic diseases. Aim of the present study was to determine the impact of this decrease on catecholamine response of PBMC from patients with rheumatoid arthritis (RA) in vitro. PBMC from 17 patients with RA and 12 healthy blood donors (HD) were investigated. Beta2R were determined by a radioligand binding assay. The effects of epinephrine (E) and norepinephrine (NE) on PBMC proliferation were studied using cells activated with pokeweed mitogen (PWM) and monoclonal anti-CD3-antibodies (OKT3), respectively. In parallel, alpha1- or beta-receptor antagonist were added to the culture to determine the specificity of the catecholaminergic effects. The results showed that depending on the stimulus and the catecholamine concentration employed E and NE exert inhibitory (OKT3) or stimulatory signals (PWM) on lymphocyte proliferation. Inhibitory effects could be abolished by adding beta-antagonist, while stimulatory signals were diminished after addition of alpha1- of beta-antagonist. Patients with RA showed a significantly reduced density of beta2R compared to HD paralleled by a significantly reduced influence of catecholamines on lymphocyte function. The study demonstrates the intricate relationship between PBMC reactivity and catecholamine effects that are mediated via alpha1- and beta-adrenergic receptors. In this respect the reduced catecholamine response of PBMC from RA patients may contribute to the pathogenic process of RA.

Differential T cell responses to Mycobacterium tuberculosis ESAT6 in tuberculosis patients and healthy donors.

Vaccination against and diagnosis of tuberculosis are still insufficient. Proteins secreted by Mycobacterium tuberculosis induce strong immune responses in tuberculosis and constitute prime candidates for development of novel vaccines against tuberculosis as well as for immunodiagnostic assays. We investigated the role of the secreted proteins MPT63, MPT64 and ESAT6 from M. tuberculosis in healthy individuals and tuberculosis patients. None of the secreted proteins stimulated peripheral blood mononuclear cells from healthy donors. In contrast, CD4+ T cells from many tuberculosis patients were stimulated in an MHC class II-restricted fashion by ESAT6, but not by MPT63 or MPT64. T cell reactivities of tuberculosis patients were focused on the N-terminal region of ESAT6. The ESAT6 T cell epitopes were presented by different HLA-DR phenotypes. Cell cultures responding to either ESAT6 or synthetic peptides thereof showed mRNA transcripts for macrophage inflammatory protein (MIP)-1alpha, monocyte chemotactic protein (MCP)-1 or IL-8 and production of IFN-gamma and MIP-1alpha. Our results suggest that the secreted M. tuberculosis proteins MPT63, MPT64 or ESAT6 do not stimulate unprimed T cells, and that ESAT6 may be a potential candidate antigen for detection of clinical disease.