Journal Club: Recent Research by UCSF Scientists
By Alexandra Greer
Science Editor
IMMUNOLOGY: Differential requirements for Th1 and Th17 responses to a systemic self-antigen. Katzman, S.D.; Gallo, E.; Hoyer, K.K.; Abbas, A.K. Journal of Immunology. Mar 14. [Epub ahead of print]
When activated by dendritic cells (DCs), T helper cells coordinate the immune response to a particular pathogen by releasing inflammatory cytokines that help to activate other cells upon recognition of the pathogen or pathogen product. In different types of infection, these T helper cells take on different sets of characteristics. For example – in many viral or bacterial infections, T helper cells secrete lots of interferon and are called Th1, while other bacterial infections create Th17 cells that secrete more IL-17 and lead to more inflammation. However, what causes a T helper cell to become one subtype over the other is poorly understood. In this paper, researchers provided the same antigen (which can be considered a surrogate for a pathogen product) to mice that had either ‘mature’ or ‘immature’ DCs – which essentially means DCs that readily interact with T helper cells, or DCs that are not as efficient. They found that the mature DCs were more likely to cause the T helper cells to become Th17 cells instead of Th1 cells, indicating that DC maturity plays a role in the T helper type decision and immune response.
GENETICS: Differential genetic associations for Systemic Lupus Erythematosus based on anti-dsDNA autoantibody production. Chung, S.A. et al. (Criswell). PLoS Genetics. 7(3):e1001323.
Systemic lupus erythematosus is a very heterogeneous autoimmune disease characterized by a variable level of inflammation in many organs due to the presence of auto-antibodies (antibodies specific to our own tissues). For largely unknown reasons, the body generates antibodies to harmless self-protein; when these antibodies bind to that protein, it initiates inflammation- resulting in joint pain, skin rashes, lung problems, nephritis, and even anemia. Genome-wide association studies have found multiple genes associated with an increased risk of the disease, but no one gene that accounts for most of the risk. In this paper, researchers undertook a new genome-wide association study that separates lupus cases based on the presence of double-stranded DNA-specific autoantibodies, which are a destructive autoantibody found in many cases of lupus. They found that if they separate the association study results based on the presence of DNA autoantibodies, many of the genes associated with a higher risk of disease are only significant for those with DNA autoantibodies, indicating that cases of lupus lacking DNA autoantibodies may have more of an environmental component to the disease.
CELL BIOLOGY: Progesterone activates the principal Ca2+ channel of human sperm. Lishko, P.V.; Botchkina, I.L.; Kirichok, Y. Nature. 471(7338):387-91.
In higher mammals including humans, an unfertilized egg is surrounded by a gelatinous layer of cells called the cumulus oophorus. These contribute to the mature follicle that must be penetrated by a sperm cell in order for the egg cell to be fertilized. It has been known that the cumulus oophorus expresses high levels of progesterone. Typically, progesterone acts through a nuclear receptor that induces changes in gene expression; however, sperm cells – the cells likely to approach the cumulus oophorus – are transcriptionally inactive, and therefore would have no use for a nuclear progesterone receptor. In this paper, researchers have identified a new progesterone receptor in sperm that is also a calcium channel, called CatSper. CatSper is found near the flagellar tail of sperm and when activated by progesterone, induces hyperactivation and chemotaxis towards the egg. As the authors point out, the discovery of this channel provides the possibility for novel, non-hormonal contraceptives through inhibition of this progesterone receptor.
CANCER BIOLOGY: Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems. More, S.S. et al. (Giacomini). Clinical Cancer Research. Mar 18. [Epub ahead of print]
Neuroblastoma is an extra-cranial metastatic cancer that primarily affects children; it involves metastasis of neural crest cells into a variety of tissues and is not only difficult to detect, but difficult to treat. Currently, treatments have focused on the fact that as neural crest cells, neuroblastoma express norepinephrine transporters (NET) – one treatment involves administration of radioactive meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine that accumulates in cells with NET and cause death of the cancerous cells. However, non-cancerous neural crest cells also express NET, meaning that this type of treatment can include significant side-effects. In this paper, researchers wanted to alter the expression profile of NET to maximize neuroblastoma uptake of radioactive MIBG. They administered vorinostat, an inhibitor of histone deacetylation, to cancer cells expressing NET and found an increase in NET in these cells. Furthermore, when administered in mice, they found that vorinostat caused an increased uptake of MIBG in neuroblastoma tumors and in slightly in the liver, but not in other tissues, indicating that this may enhance MIBG treatment.
This article appeared in the April 7, 2011 issue of Synapse.
