While transcriptional events in brain tissues from deceased PD patients have shed light on disease pathogenesis, recent studies have demonstrated the potential of PBL as a surrogate tissue in PD research. Mammalian lymphocytes are capable of synthesizing dopamine (DA) and other catecholamines, as well as DA receptors and transporters (DAT) [26, 27]. Furthermore, when PBL from PD-patients were compared to controls, differences in DA signaling, including reduced DA content, impaired DAT immunoreactivity  and higher levels of dopamine D1-like and D2-like receptors, were observed . The hypothesis that PBL can echo some of the changes occurring in the substantia nigra of PD-patients is also supported by our results. Changes in expression levels, in the same direction (up- or down-regulation), of the ADCY2, CCDC92, CELSR1, HECTD2 and KIF1B genes, were demonstrated both here, in patients' PBL, and previously, in the substantia nigra of PD-patients [6, 19]. In addition, genes involved in PD-related pathways, such as the ubiquitin-proteasome and apoptosis, and mitochondrial function were differentially expressed in patients' PBL both in our study and in recent reports [9, 10]. These results suggest that PBL from PD-patients serve as an important, easily accessible tool, that might help in the study of mechanisms underlying Parkinson's disease pathogenesis. Our data also demonstrated that the selection of a relatively homogeneous group of RNA samples from Ashkenazi women that do not carry either GBA or LRRK2 founder mutations [14, 15] increased the ability to detect novel expression changes in PD patients' PBL.
The involvement of the immune system, and particularly T cells, in PD has been recognized (reviewed by ). Our expression analysis of PBL from PD-patients demonstrated that the most prominent group of differentially expressed genes were those involved in immune system processes. Notably, a significantly decreased expression of innate and humeral immune response genes was detected, mainly of genes related to B cell functions. The down-regulation of dozens of genes encoding the CD surface molecules, the B cell specific immunoglobulins IGHM and IGHD, and regulators of B cell differentiation and activation, suggest a decrease in the B cell population among women with PD. Such a decrease in the number and percentage of peripheral CD19+ B cells was previously demonstrated in PD-patients . Indeed, decreased mRNA levels of CD19 were confirmed in our study by both microarray and quantitative real-time PCR analyses. Changes in peripheral B and T lymphocytes were also described in other neurodegenerative disorders, such as Alzheimer's disease  and amyotrophic lateral sclerosis . Our findings suggest that B cells might in fact be an additional tissue involved in PD, which has been recently appreciated as multi-systemic, beyond the central nervous system, involving the enteric and autonomic nervous systems as well as the eye (reviewed by  and ).
The detection of expression changes in tissues taken from patients under pharmacotherapy raises the question of whether changes are related to the disease, therapy, or both. Therefore, the quantitative expression confirmation analysis included both treated and untreated (naïve) patients. Our data demonstrated that the reduced expression levels of B cell-related genes did not result from anti-parkinsonian medications, but were related to the presence of PD. This is in agreement with the decreased number and percentage of CD19+ B cells observed in both treated and untreated PD-patients .
While our initial microarray expression study tested only women, we greatly expanded the number of samples for the confirmation analysis, testing six B cell-related genes in male and female PD-patients and controls. Interestingly, the expression levels of all six genes were significantly under-expressed only in women patients compared to women controls, whereas in men, the expression levels were similarly lower in both patients and controls. Such a gender-dependent differential expression of B cell-related genes is reminiscent of the variations detected in the levels of different subsets of lymphocyte populations between healthy men and women [36, 37], specifically, the higher count of CD19+ B cells in healthy women compared to men . Additionally, since our analysis of Ashkenazi PD women samples demonstrated an expression changes in B cell related genes both in the initial stage and in the confirmation study, and given that we could not detect the same changes in expression patterns in non-Ashkenazi PD women (in Jewish women with PD from Eastern and North-African origin, as well as in Scherzer et al.  cohort), it is possible that these changes might be specific to Ashkenazi PD women.
Gender-associated phenotypes are well recognized in PD, particularly the greater prevalence and the younger age of motor symptom onset in men . Specific differences were also detected in peripheral blood, where serum uric acid levels have been inversely correlated with disease duration and daily levodopa dosage in male, but not female PD patients . Recently, gender-dependent gene expression changes were demonstrated in the SN of PD-patients, with only a small overlap of the differentially expressed genes between males and females . The expression changes detected in B cell-related genes in our study are yet another example of molecular variations between men and women with PD. It will be important to explore the relationship between the down regulation of B cell-related genes and the development of PD: Are women with down regulation of B cell-related genes more prone to develop PD, with a higher expression of B cell-related genes possibly carrying a protective effect? or is it the disease process itself that decreases the expression of B cell-related genes in women?