After the elimination of infection, termination of immune response is necessary. This process can occur only when B-cell activation is shut down otherwise autoimmunity can occur. Recently researchers from University of Maryland and Harvard Medical School USA tried to analyze the process involved in inactivation of B-cells after infection has been cleared from the body. The main focus was on Wiskott-Aldrich syndrome protein (WASP) and neural WASP (N-WASP). Wiskott-Aldrich syndrome is X-linked disorder and results in immune dysregulation. WASP is entirely expressed in hematopoietic cells and N-WASP in neuronal cells.
Which molecules are involved in activation or inhibition of N-WSAP and how the latter affects B-cell activation were some key areas of enquiry and research in this study. The role of N-WASP in BCR (B-cell receptor) activation was analyzed by devising an experiment that activates human B cells and mouse BCR in a similar way. Results of this experiment revealed that at places where BCRs interact with antigen similar to WASP, transient activation of N-WASP occurs. In other words BCR stimulation causes N-WASP activation following WASP activation. Earlier studies lead this team to hypothesize that N-WASP has a compensatory role in WASP KO B-cells. For investigating this hypothesis KO mice were used. Results revealed that for antigen-induced BCR clustering both N-WASP and WASP are critical. Also B-cell morphology and B-cell spreading are affected. However N-WASP in the absence of WASP, supports B-cell spreading and in presence of WASP, B-cell contraction.
The effects of N-WASP and WASP KO on B-cell morphology led the team of researchers to dig into the BCR signaling. Experiments revealed that attenuation as well as stimulation of BCR signaling involves N-WASP. Earlier study from the same authors had shown that BCR signaling and clustering are in a two-phase relationship. Since cNKO had effects on both B-cell contraction and clustering, the researchers thought of N-WASP regulating signaling via cluster modulation of surface BCRs. Data from experiments showed role of N-WASP in promoting growth of BCR micro-clusters into the central cluster by down-regulating the BCR signaling system. Infact authors of this paper have clearly demonstrated that N-WASP has role in both positive and negative regulation of BCR signaling. However negative regulation suggested that B-cell self tolerance could also be affected by N-WASP. For clarification serum levels of anti- dsDNA and anti-nuclear DNA antibody were measured in cKNO (N-WASP deleted) mice and were found to be elevated, suggesting a clear role in self-tolerance. Moreover activation of BCR induces receptor internalization which in turn involves reorganization of actin. To elaborate the role of N-WASP and WASP in internalization and co-localization and immmunoflorescence studies were done with a marker named as LAMP-1 and surface-labeled BCRs respectively.
WASP and N-WASP involvement in activation of BCR led to understanding of their relationship. The experimental data suggests that both of them regulate each other negatively during activation of B-cells. However, BCR signaling inversely regulates both WASP and N-WASP activation.
On the whole the results have shown that B cells lacking N-WASP protein are activated for extended periods of time than the normal B-cells. Also mice with B-cells deficient in making N-WASP show increase in number of self-reactive B cells.
Open Access Article Under Creative Commons Attribution License.
Chaohong Liu, Xiaoming Bai, Junfeng Wu, Shruti Sharma, Arpita Upadhyaya, Carin I. M. Dahlberg, Lisa S. Westerberg, Scott B. Snapper, Xiaodong Zhao, and Wenxia Song. N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling. PLoS Biol. doi: 10.1371/journal.pbio.1001704.