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Recent studies have revisited the roles of prime players in the immune response to tuberculosis (TB) and have highlighted novel functions of these players. Specifically, immunoregulatory mechanisms mediated by IFNγ have been delineated as well as a novel role for neutrophils in promoting antigen presentation. New insights into the interaction between the bacterium and phagocyte indicate that the bacterium actively promotes phagocyte necrosis rather than apoptosis and that this impacts generation of the acquired response. There are also many new examples of how the phagocyte responds to the bacteria and how it mediates control. The phenotype of protective T cells is also being re-examined. These developments provide promise for improved vaccine design and highlight the complexity of this disease.

Cells of the innate immune system produce cytokines and lipid mediators that strongly influence the outcome of mycobacterial infection. In the case of Mycobacterium tuberculosis, the lung is a critical site for this interaction. Here, we review current information on the role of the major innate cytokine pathways both in controlling initial infection as well as in promoting and maintaining adaptive T-cell responses that mediate host resistance or immunopathology. Understanding this important feature of the host-pathogen interaction can provide major insights into the mechanisms of virulence and can lead to new approaches for immunological intervention in tuberculosis and other mycobacterial diseases.

IL-12p40 is known as a component of the bioactive cytokines interleukin (IL)-12 and IL-23 but it is not widely recognized as having intrinsic functional activity. Recent publications have altered this perception and support an independent role for IL-12p40. IL-12p40 is induced in excess over the other subunits of IL-12 and IL-23 and can exist in a monomeric or homodimeric form. Its most widely appreciated function is to provide a negative feedback loop by competitively binding to the IL-12 receptor. However, IL-12p40 acts as a chemoattractant for macrophages and promotes the migration of bacterially stimulated dendritic cells. It is associated with several pathogenic inflammatory responses such as silicosis, graft rejection and asthma but it is also protective in a mycobacterial model. An appreciation of the independent function of IL-12p40 is important for improving our understanding of both protective and pathogenic immune responses.

Setting : Members of the Mycobacterium avium complex (MAC) are responsible for mycobacterial disease in children, the aged and in immunocompromised individuals. The complex consists of different species, serovars and morphologic forms that vary in virulence. One isolate of the MAC is currently being sequenced (MAC 104) and was chosen based on its derivation from an AIDS patient and the fact that it could be genetically manipulated. Objective : MAC 104 was therefore analyzed for virulence, colony morphotype and expression of the glycopeptidolipid (GPL) responsible for serotying differences and the rough to smooth morphological switch. Results : The isolate was found to be virulent in the murine model of low-dose aerosol infection in that it could colonize the lung, proliferate within the tissue and disseminate to other organs. MAC 104 expressed a variety of colony morphotypes, the most prevalent of which were smooth opaque, smooth transparent and rough. All three morphotypes could persist in the lung; however, the transparent and rough morphotypes grew more rapidly in vivo . The rough morphotype was unusual in that it expressed an atypical form of the GPL usually absent from rough morphotypes. Conclusion : This characterization complements the genome data and confirms that MAC 104 behaves similarly to other MAC isolates.

Mice which have disrupted genes for important components of the immune system have been used to study the role of these components in the immune response to infection with Mycobacterium tuberculosis . This has resulted in the identification of interleukin-12 (IL12), interferon-γ (IFNγ), tumour necrosis factor-α (TNFα) and inducible nitric oxide synthase (iNOS) as being essential to the protective response. Less crucial but perhaps more intriguing roles for other molecules such as intercellular adhesion molecule (ICAM) and IL6 have also been suggested by this kind of analysis.

Objective: Use gene disrupted mice to examine the possible role of secretory antibody on resistance to re-exposure to pulmonary tuberculosis. Design: Mice deficient in B cells due to targeted gene disruption were infected by aerosol exposure with Mycobacterium tuberculosis. A further set were identically exposed then given isoniazid to clear the infection and establish a state of memory immunity. Results: Control of the aerosol infection and generation of gamma interferon proceeded in a similar manner in both naive and memory immune mice, regardless of B cell deficiency. Conclusions: The absence of antibody responses did not affect the course of infection, thus confirming the classical literature that antibody plays no significant protective role.

S UBMITRAL aneurysms occur in the left ventricle adjacent to the mltral annulus. They are the most common subannular aneurysms of the left ventricle. The aneurysms are often large and multiloculated and contain thrombi. They tend to grow into the pericardial space, behind the left atrium, bulging through its floor) A significant segment of the posterior mitral annulus is involved that leads to loss of support for the posterior leaflet with prolapse and consequent regurgitation 2 It may also compress the circumflex coronary artery, leading to angina pectoris or myocardial infarction. Submitral aneurysms are not uncommon in the black population of Africa, and occasional cases have been described m the white population outside of Africa. 2-6 They have also been reported in the Indmn population. 7 The incidence of this condmon is 1% to 2% of isolated mitral valve disease in the African population as reported by Antunes. I The cause is unknown but appears to be related to a defect or developmental weakness between the muscular ventricular wall and the fibrous annulus. The hemodynamlc impairment is related to the systolic expansion of the aneurysm, to valve regurgitation, or to both. The symptoms are those of congestive heart failure and angina pectorls. Occasionally they rupture, s Reported is an experience with two such patients and highlighted are the assocmted problems that might influence the successful anesthetic management of such patients. The authors believe this to be the first report describing the anesthetic management of such cases. A case of grant submitral aneurysm was reported about 6 years ago. 7 The patient died of low cardiac output syndrome after surgery However, the patient is not included in this report due to the unavailability of the anesthetic details.

Recent advances have characterized the protective immune response against Mycobacterium tuberculosis. These include identification of the phenotype of some protective cells, the antigens to which these cells respond and the cytokines produced in response to infection which modulate disease. Progress has also been made in inducing this response by vaccination.

We would concur with Professor Toossi that there are multiple facets to the immune response to tuberculosis (TB). We also believe that understanding the causes of immunopathogenesis in TB is crucial for the development of effective therapeutic and preventative interventions. With regard to the role of interferon (IFN)-γ in human disease, a recent review of patients deficient in components of the interleukin (IL)-12/IFN-γ macrophage-activation pathway [1xHeterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-γ production pathway. Lammas, D.A. et al. Int. J. Exp. Pathol. 2002; 83: 1–20Crossref | PubMed | Scopus (50)See all References[1] reports that there are clear differences in the histological consequences of mycobacterial infection that depend on where in the IL-12/IFN-γ pathway the patient is deficient. In addition, in the absence of IFN-γ signalling, there is a high circulating level of IFN-γ, supporting the hypothesis that IFN-γ might downregulate its own production during mycobacterial infection in patients. Further studies of the cellular responses in these patients could help determine whether the absence of IL-12/IFN-γ signalling not only compromises anti-mycobacterial activity but also contributes to tissue damage.