Mawieh Hamad

Patterns of Expression of Vaginal T-Cell Activation Markers during Estrogen-Maintained Vaginal Candidiasis

The immunosuppressive activity of estrogen was further investigated by assessing the pattern of expression of CD25, CD28, CD69, and CD152 on vaginal T cells during estrogen-maintained vaginal candidiasis. A precipitous and significant decrease in vaginal fungal burden toward the end of week 3 postinfection was concurrent with a significant increase in vaginal lymphocyte numbers. During this period, the percentage of CD3+, CD3+CD4+, CD152+, and CD28+ vaginal T cells gradually and significantly increased. The percentage of CD3+ and CD3+CD4+ cells increased from 43% and 15% at day 0 to 77% and 40% at day 28 postinfection. Compared with 29% CD152+ vaginal T cells in naive mice, > 70% of vaginal T cells were CD152+ at day 28 postinfection. In conclusion, estrogen-maintained vaginal candidiasis results in postinfection time-dependent changes in the pattern of expression of CD152, CD28, and other T-cell markers, suggesting that T cells are subject to mixed suppression and activation signals.

Novel Antifungal Therapies

Advances in cancer medicine, transplantation biology, management of AIDS patients, and diabetics are responsible for the alarming expansion rates in the number of immunocompromised patients susceptible to life-threatening fungal infections. In response to these concerns, researchers have successfully labored at modifying some of the existing antifungals (polyenes and azoles) and introducing novel therapies (peptides, oligonucleotides, and monoclonal antibodies (MAbs)) that have collectively expanded the spectrum of activity and minimized associated side effects. Nonetheless, the classical approach of dealing with fungal infections by targeting the pathogen remains prone to failure over time owing to the extensive genetic flexibility of fungi to evade or resist antifungal therapeutics. Conditioning or modulating the immune system of the host may help circumvent the resistance problem. Vaccines, cytokines, and adoptive T cell transfer are the backbone of this approach.

Estrogen-Dependent Downregulation of Hepcidin Synthesis Induces Intracellular Iron Efflux in Cancer Cells In Vitro

It is well accepted that intracellular iron overload that associate with various forms of cancer fuels tumor mutagenesis and growth. Hence, iron chelation therapy is being increasingly used to minimize iron overload in cancer patients despite significant safety and efficacy concerns. Mounting evidence suggests that estrogen (E2) downregulates hepcidin synthesis and increases serum iron concentration. It is postulated therefore that, by downregulating hepcidin synthesis, E2 may maintain ferroportin integrity and enhance intracellular iron efflux. Here, MCF-7 and SKOV-3 cancer cells treated with increasing concentrations (5, 10 and 20 nM) of E2 were assessed for intracellular labile iron content, the expression of hepcidin, ferroportin, and transferrin receptors 1 and 2 along with cell viability at different time points post treatment. In MCF-7 cells, E2 treatment resulted in a significant reduction in hepcidin synthesis, most noticeably at the 20 nM/24 h dose, a significant increase in ferroportin expression and a marked decrease in transferrin receptors 1 and 2 expression. E2-treated cells also showed reduced intracellular labile iron content most evidently at 20 nM/48 h dose and reduced viability especially at 20 nM/72 h dose. E2-treated SKOV-3 showed slightly reduced intracellular labile iron content, reduced expression of hepcidin and significantly increased expression of TFR1 but not TFR2; FPN expression was overall similar to that of controls. The effects of E2 on intracellular iron metabolism in SKOV-3 were most evident at 5 nM/24 h dose. These findings suggest that E2 treatment induces intracellular iron efflux, which may minimize intracellular iron overload in cancer cells; disrupted expression of transferrin receptor 1 and/or 2 may help sustain a low intracellular iron environment.

The Re-Emerging Role of Iron in Infection and Immunity

Much has been achieved over the past three decades in the quest to understand iron homeostasis and the mechanisms governing it. Several proteins including hepcidin, ferroprtin, transferrin receptors, and ferritin have been identified as key players in iron metabolism and homeostasis. This has provided for a thorough revisiting of the role of iron in various disease states including cancer, cardiovascular diseases, and susceptibility to infection to name few. Regarding the later, although the idea that iron is essential for microbial pathogenesis has been known for a long time, knowledge regarding key mechanisms employed by pathogens to extract iron and counter mechanisms employed by the immune system to sequester iron has expanded in a significant way. Furthermore, there is renewed interest in the role of iron in immunity and the extent and ramifications of the reciprocal effects of either on the other. This mini-review starts by introducing the reader to the basics of iron metabolism and goes on to briefly, but non-exhaustively, recount the epic fight for iron between pathogen and host.

Modeling Acquired Immunity as an Outcome of the Interaction between Host-related Factors and Potential Antigen Repertories.

In an attempt to understand why different organisms defend against potential antigens differently, the influence of possible interactions between host-related factors and respective antigen repertoires on the complexity of host defense mechanisms was investigated. A compartmental model coupling these two variables was developed and tested. Data analysis suggests that the more complex the organism, the larger the size of its antigen repertoire. The two variables seem to advance in a parallel fashion suggesting that they could reach a state of equilibrium. Therefore, host-related factors may play a role in determining the size of the antigen repertoire on the one hand; on the other hand, increased antigen repertoire size may dictate the evolution of more complex mechanisms of immunity. Although the interplay between the two variables maintains some common themes in different groups of organisms, it results in clear differences pertinent to immunologic specificity, diversity, memory and self nonself discrimination.