BLyS plays a critical role in integrating B cell homeostasis with specificity-based tolerance mechanisms. This is evidenced by the effects of manipulating BLyS or its receptors, as well as the links between the BLyS/BLyS receptor family and humoral autoimmunity. Recent data and our preliminary results show that the proportion of newly formed B cells surviving transitional selection can be varied based on homeostatic demands. Thus, the stringency of negative selection is relaxed when the demand for newly formed lymphocytes is high, allowing autoreactive clonotypes to mature and enter the follicular and marginal zone pools. These observations suggest that upon cessation of treatments that ablate peripheral pools, altered homeostatic demands will compromise the normal balance of selection and homeostasis. Accordingly, we hypothesize that during lymphoid reconstitution following curtailed marrow output or peripheral B lymphopenia, selective thresholds will be relaxed. We further hypothesize that this will be governed by available BLyS and BLyS receptor levels, and that the emergence of autoreactive specificities can thus be modulated by controlling available BLyS. The studies herein will address these ideas.
In aim 1, we will determine how transitional B cell throughput is influenced by reduced marrow output and peripheral B lymphopenia. These experiments will employ BrdU labeling coupled with lymphoid autoreconstitution, drug-induced peripheral B lymphopenia, and mixed marrow chimera studies to determine the throughput and fate of cells under these conditions.
In aim 2 we will determine whether the stringency of transitional repertoire selection is relaxed during peripheral lymphopenia or reduced BM output. We will assess selection stringency by monitoring changes in repertoire composition, diversity and specificity across transitional and mature subsets. In addition, we will directly test whether autoreactive specificities normally eliminated at the transitional checkpoint are afforded entry to mature compartments. These experiments will use flow cytometry, limiting dilution and single cell specificity analyses in normal and transgenic mice.
In aim 3, we will establish whether normal selection can be restored by adjusting BLyS levels or responsiveness during replenishment of peripheral pools. We will assess whether reduced available BLyS levels will restore normal selective stringency by in vivo treatment with soluble TACI Ig or neutralizing anti-BLyS antibody in normal and autoimmune models.
|Naradikian, Martin S; Perate, Alison R; Cancro, Michael P (2015) BAFF receptors and ligands create independent homeostatic niches for B cell subsets. Curr Opin Immunol 34:126-9|
|Goenka, Radhika; Scholz, Jean L; Sindhava, Vishal J et al. (2014) New roles for the BLyS/BAFF family in antigen-experienced B cell niches. Cytokine Growth Factor Rev 25:107-13|
|Goenka, Radhika; Matthews, Andrew H; Zhang, Bochao et al. (2014) Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation. J Exp Med 211:45-56|
|Scholz, Jean L; Diaz, Alain; Riley, Richard L et al. (2013) A comparative review of aging and B cell function in mice and humans. Curr Opin Immunol 25:504-10|
|Jacob, Chaim O; Yu, Ning; Guo, Shunhua et al. (2013) Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor. Arthritis Rheum 65:1043-54|
|Naji, Ali; Noorchashm, Hooman; Cancro, Michael P (2012) New wine in old bottles: expanding roles for B cells in transplantation tolerance. Semin Immunol 24:75-6|
|Dosenovic, Pia; Soldemo, Martina; Scholz, Jean L et al. (2012) BLyS-mediated modulation of naive B cell subsets impacts HIV Env-induced antibody responses. J Immunol 188:6018-26|
|Scholz, Jean L; Cancro, Michael P (2012) Resolve, revise, and relax: the 3 Rs of B cell repertoire adjustment. Immunol Lett 143:2-8|
|Jacob, Chaim O; Guo, Shunhua; Jacob, Noam et al. (2012) Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. Arthritis Rheum 64:1610-9|
|Stohl, William; Scholz, Jean L; Cancro, Michael P (2011) Targeting BLyS in rheumatic disease: the sometimes-bumpy road from bench to bedside. Curr Opin Rheumatol 23:305-10|
Showing the most recent 10 out of 26 publications