Editors' ChoiceAutoimmunity

The Rise and Fall of an Immune Response

See allHide authors and affiliations

Science Translational Medicine  05 Dec 2012:
Vol. 4, Issue 163, pp. 163ec221
DOI: 10.1126/scitranslmed.3005331

That screeching noise you hear when someone first turns on a microphone—called audio feedback—happens because the mic picks up the sound from the speaker. Yoshizaki et al. now report that immune responses experience feedback as well: The same processes that initiate autoimmunity driven by B and T cells are responsible for restraining this pathogenic immune response. The investigators found in a model of multiple sclerosis (MS) that factors critical for induction of B cell–T cell interactions such as interleukin-21 (IL-21) and CD40 were also critical for the restraint of autoimmunity. These findings indicate that inhibition of these molecules, classically thought of as immunostimulatory, may not modulate all forms of immunity equally.

Yoshizaki et al. found that B cell expression of IL21 and CD40 molecules was necessary for the differentiation and proliferation of regulatory B cells, which suppress immune responses. The authors found that regulatory B cells lacking CD40 or the receptor for IL-21 failed to suppress development of experimental autoimmune encephalitis (EAE)—a mouse model of MS. In addition, using regulatory B cells from mice that cannot present antigen to T cells, they provided evidence that the function of regulatory B cells is antigen-specific.

In addition to the usual caveats regarding extrapolation from mouse data to human disease, two additional qualifications are in order for this work. The acute induction EAE model used in these experiments may not replicate human MS, and several investigators have shown that biologics that block the CD40 system and IL-21 pathways can blunt autoimmune disease. Reconciling these factors will be necessary to move forward with the hypothesis that regulatory B cells play a crucial role in systems beyond acute mouse MS models. That said, Yoshizaki et al. have unraveled critical mechanisms of regulatory B cell differentiation and function and show that the relationship between immune activation and suppression is complex from the start.

A. Yoshizaki et al., Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264–268 (2012). [Abstract]

Navigate This Article