This grant builds upon the research from a prior grant: LRRK2 Role on Auto-Antibody Production by Human B Cells
Objective/Rationale:
B lymphocytes 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 – such as the LRRK2 mutations found in Parkinson’s disease patients – might cause alterations in these functions, and B lymphocytes end up have a role in disease exacerbation by reacting against the person’s own organs and/or cells.
Project Description:
In this follow-up project we will complete our studies on how the LRRK2-G2019S mutation influences the function of B cells, leading to the production of antibodies against brain proteins. For that purpose, we will analyze blood samples from Parkinson’s patients with and without the LRRK2-G2019S mutation and matched healthy volunteers. We will focus on how LRRK2-G2019S mutation stimulates the pathways leading to the death of B cells, and impairs the communication between B cells and other cells of the immune system. We will also try to understand how LRRK2-G2019S mutation impact the way B cells produce antibodies that end up reacting with the patient’s own tissues or cells.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Even though we do not expect to develop any direct new diagnostic and/or treatment method for Parkinson’s disease, we do hope to identify which pathways in B lymphocyte function are under the influence of LRRK2 and how they become altered in the presence of the typical Parkinson’s disease mutations. This knowledge may later serve as a starting point to develop new immune-based therapies for Parkinson’s disease, in particular by influencing antibody production.
Anticipated Outcome:
We anticipate that LRRK2-G2019S mutation influences B lymphocytes to such an extent that their normal function and communication capacity with other cells of the immune system are severely deregulated. Such deregulation, in particular the production of auto-reactive antibodies, might become a major contributor to the neurodegenerative process observed in Parkinson’s disease.
Final Outcome
B cells are part of the immune system. They have two major functions: produce antibodies against foreign antigens and participate in the regulation of the immune response. When the neurodegeneration occurs in PD, some proteins from tissues and cells of the central nervous system are released, and might be recognized by the immune system as potential antigens, leading to the production of specific antibodies. LRRK2 is expressed in B cells and its mutations are related to early development of PD. Thus, the main objective of this study was to determine how LRRK2 G2019S-mutation impact B cell function and the production of antibodies against alpha-synuclein. For this purpose we gathered a group of PD patients with LRRK2 G2019S mutation, PD patients without LRRK2 mutations and healthy age and gender-matched controls.
We have observed that LRRK2 G2019S mutation influenced B cells at various levels: 1) it impaired the expression of several molecules involved in the maturation and proliferation of B cells; 2) it reduced the expression of molecules used by B cells to communicate with other immune cells; 3) the reduction of such “communication” molecules lead to a poor regulation of the response by other immune cells, namely CD4 T cells; 4) it appeared to reduce the metabolic capacity of B cells. Furthermore, PD patients bearing the LRRK2 G2019S mutation had high serum titers of antibodies against the pathogenic alpha-synuclein fibrils, which presented characteristic properties of antigen-adapted antibodies, suggesting a long-standing immune response directed against those fibrils. Apparently, our data suggest that these antibodies may have a protective effect in reducing inflammation, as blocking their interaction with specific receptors on monocytes (immune cells sharing similarities with microglia) has increased the inflammatory potential of those cells. However, the means by which these antibodies regulate the immune response needs to be further explored. Finally, a preliminary statistical analysis combining all these data on B cell alterations was able to define clusters of patients, based on the observed changes. Overall, we believe that studying LRRK2-mutation-induced B cell alterations improves our understanding of the peripheral immune response in PD and how it might contribute to the neurodegenerative process.