Role of WASP and N-WASP in B Cell Receptor Signaling.

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.

References:

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.

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