Objective/Rationale:
LRRK2 expression has been demonstrated in the brain and several organs, including the thymus and spleen, which are major immune system organs for B and T lymphocyte maturation and selection. LRRK2 expression has also been described in different cells of the immune system, including B lymphocytes. The presence of autoantibodies is a common finding in Parkinson’s Disease (PD) patients, suggesting that a deregulation of the immune response –in particular B lymphocyte differentiation and function- might be associated with PD. This project aims to: 1) determine if LRRK2 mutations influence the expression of LRRK2 in peripheral blood B lymphocytes of PD patients and how this expression relates to the presence of autoantibodies; 2) understand the role of LRRK2 expression during the cell differentiation and antibody production processes of human B lymphocytes.
Project Description:
In this project, peripheral blood and serum samples from PD patients (with and without LRRK2 mutations) and age/gender matched with healthy controls will be gathered from different cohorts around the world. To accomplish the 1st objective, we will detect the presence of several autoantibodies in the serum samples and isolated peripheral blood B lymphocytes will be characterized for cell surface markers of activation, memory and plasma cell stages and for the activation of several proteins linked to LRRK2 function. Moreover, the changes in LRRK2 expression on B lymphocytes will be analyzed by gene expression analysis. Changes in phenotype and LRRK2-expression will be correlated to LRRK2-mutation type and clinical manifestations. To achieve the 2nd objective, peripheral blood naïve B lymphocytes from control individuals and LRRK2-mutated PD patients will be stimulated in vitro with a B lymphocyte differentiation cocktail to compare their capacity to fully develop into antibody-secreting plasma cells.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Understanding how LRRK2 and its mutations relate to autoantibody production and B lymphocyte differentiation and function in PD, will provide new biomarkers for disease progression and pre-clinical diagnosis. More importantly, the present proposal will pave the ground for the development of novel immunotherapeutic strategies for PD patients, aiming at blocking/ reducing the autoantibody titers, thus stopping their contribution to the neurodegenerative process and/or the secondary systemic manifestations of the disease.
Anticipated Outcome:
This will be the first study on PD patients to correlate LRRK2 mutations with the presence and titers of serum autoantibodies and clinical manifestations. The present proposal will also provide valuable insights on LRRK2 role in B lymphocyte function and how it is involved in (auto)antibody production.
Final Outcome
B cells are cells of the immune system that have a dual function: they produce antibodies to fight disease causing agents, and they participate in the regulation of the immune response by interacting with other cells. However, genetic mutations might cause alterations in these functions, and B cells end up have a role in disease exacerbation by reacting against the person’s own organs and/or cells. In this project we studied how the LRRK2 mutations had an influence on the function of B cells. For that purpose we analyzed blood samples from Parkinson’s patients with and without the LRRK2-G2019S mutation and matched healthy volunteers. We found out that the LRRK2-G2019S mutation seems to stimulate the pathways leading to the death of B cells, and impairs the communication between B cells and other cells of the immune system. We also found that LRRK2-G2019S B cells produce, more frequently, antibodies that react with the patient’s own tissues or cells. Whether such self-reactive antibodies are clearing the by-products of neurodegeneration, or if they are causing further damage to the central nervous system remains to be established. Altogether we have shown that LRRK2 plays an important, and hitherto unknown, role in regulating B cell function.