Membrane repair and immunological danger

Abstract

Antigens are able to elicit productive immune responses only when second signals are provided by adjuvant molecules. It is well established that exogenously acquired, pathogen-associated molecular patterns fulfil this adjuvant role when recognized by specific receptors on antigen-presenting cells. Recent evidence points to the existence of another class of adjuvant, which is apparently released from injured cells. Such endogenous adjuvants, referred to as 'danger' signals, could alert the immune system to situations that cause cell damage, but not necessarily those that involve infections. Endogenous adjuvants provide a good explanation for immune responses generated against tumours and autologous tissues, but it has been difficult to explain how a constant activation of the immune system is avoided, considering the frequency at which cells are injured in vivo. Here, we suggest that the efficiency with which cells reseal wounds in their plasma membrane might be an important factor in the balance between tolerance and autoimmunity. Recent observations in synaptotagmin-VII-deficient mice suggest that defective membrane repair could lead to autoimmunity in tissues that are more susceptible to mechanical injury.

Figure 1

Resealing efficiency and release of endogenous adjuvants. Recent evidence suggests that the cytosol of mammalian cells contains molecules with adjuvant activity that are able to stimulate maturation of antigen-presenting cells (APCs) and activate naive T cells. Plasma-membrane repair might have a role in preventing immunostimulation, by limiting the release of cytosol from accidentally injured cells. (Modified from Rock et al, 2005).