Readings for Week 4 – Leonore A. Herzenberg Summary

Apologies for the (very) late posting - I was convinced that I was scheduled to post next week's summary instead of this one. It wasn't until I checked GoogleDocs that I realized my mistake. My deepest regrets.

Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis, LVS challenge

Francisella tularensis (Ft) the etiologic agent of tularemia, is a gram-negative bacterium with an extremely low infectious dose. Respiratory forms of human tularemia may have a mortality rate exceeding 30%. Most research into Ft pathogenesis therefore focuses on understanding immune responses to a “Live Vaccine Strain” (LVS) of Ft. Herzenberg and her colleagues demonstrate that injecting wild-type mice with as little as 0.1 ng of Ft LVS lipopolysaccharide (Ft-LPS) is sufficient to generate a rapid antibody response. All wild-type mice pretreated with 100 ng (Ft-LPS) two days prior to challenge with 1000 CFU of the live virus survived the infection, while all wild-type mice pretreated with saline died (Fig 1a). These results showed that (Ft-LPS) confers protection against lethal Ft LVS infection in wild-type mice, effectively immunizing them against the pathogen. Subsequent tests showed that the glycolipod compound lipid A, purified from Ft-LPS, is not sufficient to induce the same protective response (Fig 1b). Herzenberg deduces that the core carbohydrate component of Ft-LPS, missing from lipid A, is essential for recognition of the antigen and induction of a protective immune response. Finally, Herzenberg demonstrates that uMT mutant mice, which lack mature B cells, are unable to mount a protective immune response against Francisella tularensis , even when pretreated with Ft-LPS (Fig 1c). She concludes that B cells are necessary for Ft-LPS immunization and protection against the live virus.
Taking this research a step further, Herzenberg shows that Ft-LPS immunization is sufficient to stimulate the production of antigen-specific B-1a cells in the spleen and Per C as soon as three days after the initial injection. The presence of the IgK light chain bound to each cell makes them easily detectable by Hi-D FACS analysis (Fig 2A). These cells rapidly proliferate and bind flurochrome-labeled Ft-LPS, as evidenced by concurrently increasing levels of Anti Ft-LPS in serum.
Herzenberg and her colleagues found that the magnitude of this antibody response was equivalent in wild-type, T-deficient, and Toll-like receptor (TLR4)-deficient mice. They conclude that Ft-LPS immunization is therefore both T-Cell independent and TLR-independent, and that the response is governed exclusively by B-1a lymphocytes. T-deficient mice do eventually succumb to the virus, however, suggesting that T-cells are nonetheless important for long-term survival of Ft infection.
Summary: Herzenberg concludes that antigen-specific B-1a antibody responses are required for the immune system to mount a protective response against a live vaccine strain of Francisella tularensis. The causative antigen is Ft-LPS, not Ft-lipid A. The protective antibody response is T-Cell and TLR-4 independent, but cannot persist when B cell development is disrupted.

I also found some cool (albeit somewhat dated) articles on other research applications for B1a cells, including their role in autoimmunity and the mechanisms of their development. Check them out if you like.

"Role of B1a cells in autoimmunity"
http://www.ncbi.nlm.nih.gov/pubmed/16890894

"CD11b expression distinguishes sequential stages of peritoneal B-1 development."
http://www.ncbi.nlm.nih.gov/pubmed/18375763