The Role of Home Practice Engagement in a Mindfulness-Based Intervention

Over the last three decades, there has been a precipitous rise in curiosity regarding the clinical use of mindfulness meditation for the self-management of a broad range of chronic health conditions. Despite the ever-growing body of evidence supporting the use of mindfulness-based therapies for both medical and psychological concerns, data on the active ingredients of these mind-body interventions are relatively scarce. Regular engagement in formal mindfulness practice is considered by many to be requisite for generating therapeutic change; however, previous investigations of at-home practice in MBIs have produced mixed results. The equivocal nature of these findings has been attributed to significant methodological limitations, including the lack of standardized, systematic practice monitoring tools, and a singular focus on practice time, with little attention paid to the nature and quality of one’s practice. The present study used a prospective, observational design to assess the effects of home-based practice on dispositional mindfulness, self-compassion, and psychological functioning in twenty-eight people enrolled in an MBSR or MBCT program. To address some of the aforementioned limitations, the present study collected detailed weekly accounts of participants’ home-based practice engagement, including information about practice time (i.e., frequency and duration), exercise type, perceived effort and barriers to participation, and practice quality. Hierarchical multiple regression was used to examine the relative contribution of practice time and practice quality on treatment outcomes, and to explore possible predictors of adherence to at-home practice recommendations. As anticipated, practice quality and perceived effort improved with time; however, rather unexpectedly, practice quality was not a significant predictor of treatment-related improvements in psychological health. Home practice engagement, however, was predictive of change in dispositional mindfulness, in the expected direction. Results of our secondary analyses demonstrated that employment status was predictive of home practice engagement, with those who were unemployed completing more at-home practice on average. Mindfulness self-efficacy at baseline and previous experience with meditation or other contemplative practices were independently predictive of mean practice quality. The results of this study suggest that home practice helps generate meaningful change in dispositional mindfulness, which is purportedly a key mechanism of action in mindfulness-based interventions.

IL-10-producing Regulatory B Cell Development in Human Autoimmune Disease

B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of costimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of “regulatory B cells” has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported with interleukin-10 (IL-10) being the most studied. IL-10-producing regulatory B cells predominantly localize within a rare CD1dhiCD5+ B cell subset in mice and the CD24hiCD27+ B cell subset in adult humans. This specific IL-10-producing subset of regulatory B cells have been named “B10 cells” to highlight that the regulatory function of these rare B cells is primarily mediated by IL-10, and to distinguish them from other regulatory B cell subsets that regulate immune responses through different mechanisms. B10 cells have been studies in a variety of animal models with autoimmune disease and clinical settings of human autoimmunity. There are many unsolved questions related to B10 cells including their surface phenotype, their origin and development in vivo, and their role in autoimmunity.

In Chapter 3 of this dissertation, the role of the B cell receptor (BCR) in B10 cell development is highlighted. First, the BCR repertoire of mouse peritoneal cavity B10 cells is examined by single cell sequencing; peritoneal cavity B10 cells have clonally diverse germline BCRs that are predominantly unmutated. Second, mouse B10 cells are shown to have higher frequencies of λ+ BCRs compared to non-B10 cells which may indicate the involvement of BCR light chain editing early in the process of B10 cell development in vivo. Third, human peripheral blood B10 cells are examined and are also found to express higher frequencies of λ chains compared to non-b10 cells. Therefore, B10 cell BCRs are clonally diverse and enriched for unmutated germline sequences and λ light chains.

In Chapter 4 of this dissertation, B10 cells are examined in the healthy developing human across the entire age range of infancy, childhood and adolescence, and in a large cohort of children with autoimmunity. The study of B10 cells in the developing human documents a massive transient expansion during middle childhood when up to 30% of blood B cells were competent to produce IL-10. The surface phenotype of pediatric B10 cells was variable and reflective of overall B cell development. B10 cells down-regulated CD4+ T cell interferon-gamma (IFN-γ) production through IL-10-dependent pathways and IFN-γ inhibited whereas interleukin-21 (IL-21) promoted B cell IL-10 competency in vitro. Children with autoimmunity had a contracted B10 cell compartment, along with increased IFN-γ and decreased IL-21 serum levels compared to age-matched healthy controls. The decreased B10 cell frequencies and numbers in children with autoimmunity may be partially explained by the differential regulation of B10 cell development by IFN-γ and IL-21 and alterations in serum cytokine levels. The age-related changes of the B10 cell compartment during normal human development provide new insights into immune tolerance mechanisms involved in inflammation and autoimmunity.

These studies collectively demonstrate that BCR signals are the most important early determinant of B10 cell development in vivo, that human B10 cells are not a surface phenotype defined developmental B cell subset but a functionally defined regulatory B cell subset that regulates CD4+ T IFN-γ production through IL-10-dependent pathways and that human B10 cell development can be regulated by soluble factors in vivo such as the cytokine milieu. The findings of these studies provide new insights into immune tolerance mechanisms involved in human autoimmunity and the potent effects of IL-21 on human B cell IL-10 competence in vitro open new horizons in the development of autologous B10 cell-based therapies as an approach to treat human autoimmune disease in the future.