One third of the world's population is infected with Mycobacterium tuberculosis (Mtb). Although most infected people remain asymptomatic, they have a 10% lifetime risk of developing active tuberculosis (TB). Thus, the current challenge is to identify immune parameters that distinguish individuals with latent TB from those with active TB. Using human and experimental models of Mtb infection, we demonstrated that organized ectopic lymphoid structures containing CXCR5 + T cells were present in Mtb-infected lungs. In addition, we found that in experimental Mtb infection models, the presence of CXCR5 + T cells within ectopic lymphoid structures was associated with immune control. Furthermore, in a mouse model of Mtb infection, we showed that activated CD4 + CXCR5 + T cells accumulated in Mtb-infected lungs and produced proinflammatory cytokines. Mice deficient in Cxcr5 had increased susceptibility to TB due to defective T cell localization within the lung parenchyma. We demonstrated that CXCR5 expression in T cells mediated correct T cell localization within TB granulomas, promoted efficient macrophage activation, protected against Mtb infection, and facilitated lymphoid follicle formation. These data demonstrate that CD4 + CXCR5 + T cells play a protective role in the immune response against TB and highlight their potential use for future TB vaccine design and therapy.

Rationale: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. Objectives: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. Methods: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/ A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. Conclusions: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.Keywords: inflammation; tuberculosis; neutrophil; S100A8/A9 proteins; granuloma A hallmark of pulmonary tuberculosis (TB) in humans and experimentally infected animals is the formation of granulomas. However, the immune factors that drive the formation of the protective granuloma during latent TB, and the factors that drive the inflammatory granulomas formed during active TB, are not well defined. What This Study Adds to the FieldThis study demonstrates the dominant presence of neutrophils producing S100 proteins within the inflammatory lung granulomas of patients with active TB. This study also describes a link between S100A8/A9 protein induction, neutrophil accumulation, and pathology associated with the inflammatory granuloma formed during TB, because S100A8/A9 deficiency in mice reverses exacerbated inflammation during TB. In addition, this study demonstrates the potential use of S100A8/A9 proteins along with neutrophilattracting chemokines in serum as surrogate biomarkers to assess inflammation and disease severity in TB in humans.

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Renaut bodies are well-demarcated cylindrical (circular in cross section) hyaline structures attached to the inner layer of the perineurium that can be found in normal and pathological nerves of various animals and humans. They are composed of spidery fibroblasts and perineurial cells immersed in an extracellular matrix that contains randomly oriented collagen fibers and elastin precursors but not axons or Schwann cells. Frequently, they are associated with thickened subperineurial capillaries. As Renaut bodies are mainly located at sites of nerve compression, it is hypothesized they may act as 'protective cushions' for endoneurial components, and that they may be formed as a secondary reaction to trauma. Herein, we report the presence of Renaut bodies within numerous small dermal nerve trunks in an amputated finger. By immunohistochemistry, Renaut bodies expressed markers identical to those of perineurial cells (epithelial membrane antigen, Glut-1, and claudin-1), supporting the concept of a closely associated perineurial but not endoneurial origin. In addition, expression of hypoxia-inducible factor 1 alpha (which has been shown to increase Glut-1 transcription), neurofibromatosis 1 gene related product and NF-2, were also detected in these peripheral nerve structures.

Our results suggest that NO and peroxynitrite could be involved in the nerve damage following borderline leprosy.