Host Immune Responses Differ between M. africanum- and M. tuberculosis-Infected Patients following Standard Anti-tuberculosis Treatment.

Epidemiological differences exist between Mycobacterium africanum (Maf)- and Mycobacterium tuberculosis (Mtb)-infected patients, but to date, contributing host factors have not been characterised. We analysed clinical outcomes, as well as soluble markers and gene expression profiles in unstimulated, and ESAT6/CFP-10-, whole-Maf- and Mtb-stimulated blood samples of 26 Maf- and 49 Mtb-HIV-negative tuberculosis patients before, and after 2 and 6 months of anti-tuberculosis therapy. Before treatment, both groups had similar clinical parameters, but differed in few cytokines concentration and gene expression profiles. Following treatment the body mass index, skinfold thickness and chest X-ray scores showed greater improvement in the Mtb- compared to Maf-infected patients, after adjusting for age, sex and ethnicity (p = 0.02; 0.04 and 0.007, respectively). In addition, in unstimulated blood, IL-12p70, IL12A and TLR9 were significantly higher in Maf-infected patients, while IL-15, IL-8 and MIP-1α were higher in Mtb-infected patients. Overnight stimulation with ESAT-6/CFP-10 induced significantly higher levels of IFN-γ and TNF-α production, as well as gene expression of CCL4, IL1B and TLR4 in Mtb- compared to Maf-infected patients. Our study confirms differences in clinical features and immune genes expression and concentration of proteins associated with inflammatory processes between Mtb- and Maf-infected patients following anti-tuberculosis treatment These findings have public health implications for treatment regimens, and biomarkers for tuberculosis diagnosis and susceptibility.

Hypothesis: an alternative pathway for the regulation of inflammation.

Regulation of inflammation is a crucial event since its alteration, such as in sepsis and chronic autoimmune (i.e. rheumatoid arthritis, lupus erythematosus) or infectious diseases (i.e. tuberculosis, leprosy), determines severe tissue damage. Although there is a general consensus that regulation of inflammation results from a balance between proinflammatory and antiinflammatory pathways, we arrived at the conclusion that well known chemoattractants/proinflammatory molecules such as bacterial formyl peptides or immune complexes (IC), could induce, paradoxically, strong antiinflammatory effects. Thus, we demonstrated that N-formyl-methionyl-leucyl-phenylalanine (FMLP) exerted a drastic antiinflammatory effect, inhibiting the secretion of tumor necrosis alpha (TNF-alpha) induced by lipopolysaccharides, a potent TNF-alpha inducer. We also determined that in human neutrophils FMLP and IC induced the downregulation of receptors for the Fc portion of IgG (FcgammaRII and FcgammaRIIIB). Moreover, FMLP inhibited interferon gamma (IFN-gamma)-induced FcgammaRI expression and IC downregulate class II molecules of the major histocompatibility complex on monocytes. Part of these effects were mediated by the release of aspartic-, serin-, or metalloproteases. All these results favor the postulation of a new concept on the regulation of inflammation carried out through an alternative and non conventional pathway, in which a chemoattractant/proinflammatory agent could, under certain circumstances, act as an antiinflammatory molecule.

Hypotesis: an alternative pathway for the regulation of inflammation

Hipótesis: una vía alternativa de regulación de procesos inflamatorios. La regulación de mecanismos inflamatorios es un evento crucial debido a que una alteración de los mismos, como sucede por ejemplo, en la sepsis, en enfermedades autoinmunes crónicas (artritis reumatoidea, lupus eritematoso) o en enfermedades infecciosas (tuberculosis, lepra), genera daños tisulares severos. Aunque hay un consenso general de que la regulación de procesos inflamatorios resulta de un balance entre vías proinflamatorias y antiinflamatorias, nosotros arribamos a la conclusión de que moléculas quimioatractantes / proinflamatorias como, por ejemplo, péptidos formilados bacterianos o complejos inmunes (CI), pueden también inducir, paradójicamente, potentes efectos ntiinflamatorios. Así, demostramos que el péptido formilado prototipo N-formilmetionil- leucil-fenilalanina (FMLP), ejerce un drástico efecto antiinflamatorio, inhibiendo la secreción de factor de necrosis tumoral alfa (TNF-α) inducido por lipopolisacáridos, un potente inductor de la secreción de TNF-α. También determinamos que el FMLP y los CI inducen la disminución de la expresión de receptores para el fragmento Fc de IgG (FcγRII and FcγRIIIB) en neutrófilos humanos. Más aún, el FMLP inhibe la inducción de la expresión de los FcγRI por interferón gamma (IFN-γ) y los CI disminuyen la expresión de moléculas de clase II del complejo mayor de histocompatibilidad en monocitos humanos. Parte de esos efectos fueron mediados por la liberación de aspártico-, serino-, o metaloproteasas. Todos estos resultados nos permiten especular sobre un nuevo concepto en el cual la regulación de los procesos inflamatorios también puede llevarse a cabo por una vía alternativa, no convencional, en la cual un agente quimioatractante / proinflamatorio, bajo determinadas circunstancias, puede actuar como una molécula antiinflamatoria.(AU)

Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement.

Sarcoidosis, a chronic granulomatous disease of unknown etiology, is treated with immune suppressive drugs such as corticosteroids. Sarcoidosis patients have been reported to benefit clinically from treatment with thalidomide. We administered thalidomide for 16 weeks to eight patients with chronic skin sarcoidosis and evaluated the drug's effects before and with treatment. After thalidomide treatment, all skin biopsies showed decreases in granuloma size and reduction in epidermal thickness. We also observed extensive T cell recruitment into the granulomas, the appearance of multinucleated giant cells, and increased numbers of dermal Langerhans cells (CD1a(+)) and mature dendritic cells (CD83(+) or DC-LAMP(+)). Plasma IL-12 levels increased and remained elevated during the treatment period. We noted increased HLA-DR expression on peripheral blood lymphocytes and a corresponding drop in the naive T cell marker CD45RA. Our data suggest that thalidomide treatment of sarcoidosis results in granuloma differentiation to a Th1-type cellular immune response usually associated with protective immunity to tuberculosis and tuberculoid leprosy.