Integrins control the trafficking of autoantigens in B cells 

In lupus, B cells play a critical role by producing autoantibodies that mistakenly target a person’s own cells and tissues. B cells also can present small pieces of pathogens (foreign invaders), called antigens, to other immune cells like T cells, initiating an immune response. In lupus, B cells present self-antigens (parts of the body’s own tissues), initiating an ongoing attack that can lead to chronic inflammation and organ damage.

Antigen presentation by B cells is crucial in lupus development, but what triggers B cells to present self-antigens is unknown. Dr. Lagos Orellana will study whether molecules called integrins, involved in the trafficking (or relocating) of antigens, play a role in the recognition and processing of self-antigens.

Two integrins, called αv integrin and CD11b integrin, are known to have roles in autoimmunity. Dr. Lagos Orellana will test whether these integrins are involved in antigen trafficking and if this process is disrupted in lupus. He predicts that these integrins control the route of antigen trafficking, and that this process is disrupted in self-reactive B cells in lupus, leading to an uncontrolled response to self-antigens.

By genetically deleting αv and CD11b in human B cells, he will explore how these integrins impact antigen trafficking and degradation (breakdown). He predicts that defects in these integrins result in changes to the route of trafficking of antigens in lupus, driving the presentation of self-antigen. Lastly, Dr. Lagos Orellana will test whether blocking other integrins with opposing functions can compensate for defects in integrins αv and CD11b.

What this means for people with lupus
Antigen processing by B cells is important in the development of lupus, but the link between self-reactivity (the ability to participate in an autoimmune response) and antigen processing is not well understood. Dr. Lagos Orellana’s findings will define how changes in how B cells process antigens contribute to the activation of self-reactive B cells in lupus and may help to identify new integrin-related therapeutic targets for people with this autoimmune disorder.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that could potentially affect any organ in the body, and it has a higher prevalence in young women during their childbearing years. B cells have a central role in the pathogenesis of SLE by several mechanisms, including secretion of autoantibodies, secretion of pro-inflammatory cytokines, and presentation of autoantigens. Antigen recognition and presentation are essential to B activation, and factors that modify this process will have consequences in the posterior differentiation and replication of B cells. During the BCR engagement by their cognate antigen, integrins have a role in stabilizing the interaction of B cells with the antigen-presenting cells. Some genetic variations in integrin genes, such as CD11b and αv, have been associated with inflammatory diseases. Our lab has studied the integrin αv, which has a role in the trafficking of pattern recognition receptors, controlling their signaling and degradation. The absence of this integrin in B cells promotes TLR-driven autoimmunity in mice. Other groups have shown that CD11b-KO macrophages increased TLR signaling via a similar mechanism. However, whether these integrins also have a role during antigen recognition and internalization is unknown. Our preliminary results show that αv integrin also has a role in trafficking the antigen to compartments where it can be processed and presented to T cells. αv-KO B cells lead to antigens to peripheral LAMP2 compartments in contrast to a central classical compartment and, therefore, have a permissive control of the peptide processing. We hypothesize that αv and CD11b integrins have a role in modulating the recognition, processing, and presentation of autoantigens. This could explain the dysregulation of B cells from SLE patients, which present an increased number of activated B cells mediated by increased autoantigen presentation. Our main aims are to 1) determine how integrins change the trafficking of antigens in B cells. 2) Compare the trafficking of BCR antigens in B cells from healthy controls and lupus subjects. 3) Determine if antigen trafficking in lupus B cells can be changed by integrin ligation. To do this, we will use two genetically modified human B cell lines and PBMC-isolated B cells from control and SLE patients to study the trafficking of antigens and autoantigens in αv-KO B cells by advanced microscope techniques. We will investigate if the phenotypes observed in integrin-KO human cell lines correlated with phenotypes observed in cells from SLE patients and then measure their correlation with the expression of different integrins. Finally, we will use diverse ligands of integrins to see if we can modify antigen trafficking. The results from this project will help us to understand how antigen recognition by B cells is initiated and could allow new strategies to modify the activation of autoreactive lymphocytes.