Editors' ChoiceAutoimmunity

Autoimmune TSA

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Science Translational Medicine  05 Sep 2012:
Vol. 4, Issue 150, pp. 150ec157
DOI: 10.1126/scitranslmed.3004839

The airport safety screening process is complex, and the rules at the checkpoint can change and be applied differently by different inspectors. Such flux in immune cell developmental checkpoints may result in failure of the immune system to identify pathogenic organisms but conversely may also cause autoimmunity—when the immune system attacks the body’s own tissue. Fortunately, the rules that govern immune cell development, although they are complex, are consistent. Work by Zikherman et al. has unraveled some of the complexity underlying lymphocyte development by using a mouse model. Their studies show that the developmental programs of B cells and T cells are surprisingly different.

A central question in autoimmunity is how immune cells distinguish invading pathogens from endogenous tissues. Tolerance of both B and T cells is intrinsic to their initial differentiation in the bone marrow and thymus, respectively. However, autoreactive B and T cells that escape these early checkpoints have long been known to populate lymphoid tissues. In lymph nodes, these potentially autoreactive cells could be pathogenic.

Zikherman et al. used a mouse that expresses a fluorescent protein when B cell receptors or T cells receptors are activated to show that the mechanisms for lymph node B and T cell tolerance differ. The checkpoints for B cell tolerance are dependent on intrinsic B cell processes, even in circulating B cells. B cell receptor signaling was identified as critical to tolerance in circulating B cell populations. Importantly, many potentially autoreactive B cells that are rendered tolerant are not deleted. Rather, they are left in an unresponsive or anergic state. For T cells, the data support a different model. Tolerizing T cell receptor stimulation occurred during thymic T cell development but not in peripheral T cells.

The authors provide a hint of how this tool could be used in disease-oriented models in the supplemental data. They examined how a variety of clinical and experimental immunomodulatory agents affect B cell and T cell receptor signaling in vitro. Going forward, this model could provide a useful system to dissect how we manipulate the immune checkpoints with immunomodulatory drugs.

J. Zikherman et al., Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature, 19 August 2012 (10.1038/nature11311). [Abstract]

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