Fungal Recognition and Host Defense Mechanisms.

Fungi have emerged as premier opportunistic microbes of the 21st century, having a considerable impact on human morbidity and mortality. The huge increase in incidence of these diseases is largely due to the HIV pandemic and use of immunosuppressive therapies, underscoring the importance of the immune system in defense against fungi. This article will address how the mammalian immune system recognizes and mounts a defense against medically relevant fungal species.

CD4(+) T-cell survival in the GI tract requires dectin-1 during fungal infection.

Dectin-1 is an innate antifungal C-type lectin receptor necessary for protective antifungal immunity. We recently discovered that Dectin-1 is involved in controlling fungal infections of the gastrointestinal (GI) tract, but how this C-type lectin receptor mediates these activities is unknown. Here, we show that Dectin-1 is essential for driving fungal-specific CD4(+) T-cell responses in the GI tract. Loss of Dectin-1 resulted in abrogated dendritic cell responses in the mesenteric lymph nodes (mLNs) and defective T-cell co-stimulation, causing substantial increases in CD4(+) T-cell apoptosis and reductions in the cellularity of GI-associated lymphoid tissues. CD8(+) T-cell responses were unaffected by Dectin-1 deficiency. These functions of Dectin-1 have significant implications for our understanding of intestinal immunity and susceptibility to fungal infections.

Ocular Inflammatory Diseases: Molecular Pathogenesis and Immunotherapy.

Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases of infectious or autoimmune etiology and accounts for more than 10% of severe visual handicaps in the United States. Pathology derives from the presence of inflammatory cells in the optical axis and sustained production of cytotoxic cytokines and other immuneregulatory proteins in the eye. The main therapeutic goals are to down-regulate the immune response, preserve the integrity of the ocular architecture and eventually eliminate the inciting uveitogenic stimuli. Current therapy is based on topical or systemic corticosteroid with or without second line agents and serious adverse effects of these drugs are the impetus for development of less toxic and more specific therapies for uveitis. This review summarizes the pathophysiology of uveitis, molecular mechanisms that regulate the initiation and progression of uveitis and concludes with emerging strategies for the treatment of this group of potentially blinding diseases.

Efficacy of membrane TNF mediated host resistance is dependent on mycobacterial virulence.

TNF is required for protection against virulent and non-virulent mycobacterial infections. Here we compared the effect of Tm-TNF and sTNF, two different molecular forms of TNF, in virulent and non-virulent murine challenge models. Using non-virulent Mycobacterium bovis BCG intranasal infection we established that immunity is durably compromised in Tm-TNF mice, with augmented bacilli burden, leading to chronic but non-lethal infection. Acute infection by a virulent Mycobacterium tuberculosis low-dose aerosol challenge was controlled in Tm-TNF mice with bacilli burdens equivalent to that in WT mice and pulmonary pathology characterised by the formation of well-defined, bactericidal granulomas. Protective immunity was however compromised in Tm-TNF mice during the chronic phase of M. tuberculosis infection, with increased lung bacterial growth and inflammatory cell activation, dissolution of granulomas associated with dispersed iNOS expression, increased pulmonary IFNgamma and IL-10 expression but decreased IL-12 production, followed by death. In conclusion, membrane TNF is sufficient to control non-virulent, M. bovis BCG infection, and acute but not chronic infection with virulent M. tuberculosis.