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Biomedical subjects

Michael P Cancro

Publications and source records attributed to Michael P Cancro.

At least 19 recordsLinked to original sources
PubMed2006

BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells.

The BLyS family of receptors includes two cytokines, BLyS and APRIL; and three receptors, BR3, BCMA and TACI. Together, these regulate the size and composition of peripheral B cell pools. The multiplicity of ligand-receptor sets, in conjunction with differential receptor expression, alternative binding partners and disparate downstream signaling characteristics, affords the potential to establish independently regulated homeostatic niches among primary and antigen-experienced B cell subsets. Thus, BLyS signaling via BR3 is the dominant homeostatic regulator of primary B cell pools, whereas APRIL interactions with BCMA likely govern memory B cell populations. Short-lived antibody forming cell populations and their proliferating progenitors express a TACI-predominant signature. Further, within each niche, relative fitness to compete for available cytokine is determined by exogenous inputs via adaptive and innate receptor systems, affording intramural hierarchies that determine clonotype composition.

Animals↗
PubMed2006

Cutting edge: impaired transitional B cell production and selection in the nonobese diabetic mouse.

Developing B cells undergo selection at multiple checkpoints to eliminate autoreactive clones. We analyzed B cell kinetics in the NOD mouse to establish whether these checkpoints are intact. Our results show that although bone marrow production is normal in NOD mice, transitional (TR) B cell production collapses at 3 wk of age, reflecting a lack of successful immature B cell migration to the periphery. This yields delayed establishment of the follicular pool and a lack of selection at the TR checkpoint, such that virtually all immature B cells that exit the bone marrow mature without further selection. These findings suggest that compromised TR B cell generation in NOD mice yields relaxed TR selection, affording autoreactive specificities access to mature pools.

Aging↗
PubMed2006

Space, selection, and surveillance: setting boundaries with BLyS.

The BLyS family of ligands and receptors governs B cell homeostasis by controlling survival, differentiation, and lifespan. This family consists of multiple receptors and ligands, allowing independent regulation of different B cell subsets by varying the combination and levels of receptors expressed. Multiple downstream signaling pathways are implicated in these activities, reflecting this receptor complexity as well as cross-talk with other B cell signaling systems. BLyS levels are associated with multiple forms of humoral autoimmunity and can modulate tolerogenic elimination at the transitional checkpoint. BLyS responsiveness thus balances peripheral selection against cell numbers, providing an elastic system that varies selective stringency based on homeostatic demands.

Animals↗
PubMed2006

Unraveling the warp and weft of B cell fate.

Two recent Immunity articles (Enzler et al., 2006; Sasaki et al., 2006) probe the roles of Nuclear Factor kappa-B (NF-kappaB) pathways in survival and differentiation mediated by B cell activation factor of the TNF family (BAFF).

Animals↗
PubMed2005

Homeostatic niche specification among naïve and activated B cells: a growing role for the BLyS family of receptors and ligands.

B lymphocyte homeostasis encompasses the establishment and maintenance of independently regulated niches, within which cells compete for viability promoting resources. The BLyS/BLyS receptor family controls the size and composition of these niches, by governing the selection and survival of most peripheral B cells. Moreover, different receptor-ligand sets from this family dominate the regulation of various B cell subsets. These observations suggest a model whereby the regulation of BLyS receptors by differentiative and stimulatory cues yield characteristic BLyS receptor signatures, thus specifying homeostatic niche and competitive advantage.

Animals↗
PubMed2005

Dwindling competition with constant demand: can homeostatic adjustments explain age-associated changes in peripheral B cell selection?

The close relationship between specificity-based selection and homeostatic processes in maintaining peripheral B cell pools has become increasingly evident. Thus, age-associated changes observed within these pools may reflect homeostatic responses to proximal primary lesions. Marked shifts in the size and dynamics of most B lymphocyte subsets and their progenitors occur with age: perturbations in B lineage precursors result in reduced production of immature B lymphocytes in the bone marrow and transitional pools in the periphery, but these effects appear to be offset by compensatory homeostatic processes at the marrow-periphery interface. We propose a model whereby these "distal" homeostatic adjustments relax the stringency of specificity based selection, affording a potential explanation for the increased frequency of autoreactive specificities with age.

Aging↗
PubMed2005

B cells and aging: gauging the interplay of generative, selective, and homeostatic events.

Lymphocyte homeostasis encompasses a continuum of processes that together determine the production, turnover, composition, and representation of lymphocyte pools. These processes include commitment to lymphoid lineages, expansion of progenitor pools, successful transit through intermediate maturation stages, negative and positive selection based on receptor specificity, steady-state maintenance of peripheral lymphocytes, and regulation of antigen-driven activation. Understanding the impact of aging on lymphocyte homeostasis thus requires appreciation of not only the mechanisms responsible for generating and sustaining antigen-reactive B and T cells but also how age-related events can subvert these. Even under the influence of normally operating homeostatic mechanisms, lesions yielding perturbations outside of evolutionarily anticipated boundaries will yield aberrant lymphoid function and representation both upstream and downstream of the primary defect. Accordingly, determining the relative contribution of lineage-intrinsic versus compensatory homoeostatic processes throughout the continuum of lymphoid system development, selection, and maintenance are critical first steps towards understanding age-associated alterations in the immune system.

Aging↗
PubMed2004

Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice.

During aging, adaptive immunity is severely compromised, due in part to decreased production of B lymphocytes and loss of immunoglobulin (Ig) diversity. However, the molecular mechanisms that underlie age-associated diminished B cell production remain unclear. Using in vivo labeling, we find that this reduction in marrow pre-B cells reflects increased attrition during passage from the pro-B to pre-B cell pool. Analyses of reciprocal bone marrow chimeras reveal that the magnitude and production rates of pre-B cells are controlled primarily by microenvironmental factors, rather than intrinsic events. To understand changes in pro-B cells that could diminish production of pre-B cells, we evaluated rag2 expression and V(D)J recombinase activity in pro-B cells at the single cell level. The percentage of pro-B cells that express rag2 is reduced in aged mice and is correlated with both a loss of V(D)J recombinase activity in pro-B cells and reduced numbers of pre-B cells. Reciprocal bone marrow chimeras revealed that the aged microenvironment also determines rag2 expression and recombinase activity in pro-B cells. Together, these observations suggest that extrinsic factors in the bone marrow that decline with age are largely responsible for less efficient V(D)J recombination in pro-B cells and diminished progression to the pre-B cell stage.

Aging↗
PubMed2004

B cell positive selection: road map to the primary repertoire?

Accumulating evidence indicates that positive selection events mediate differentiation, lineage commitment, and longevity of B lymphocytes. The BCR plays a central role, dictating the likelihood that newly formed cells will complete maturation, as well as whether cells persist within mature pools. Competition among B cells for limited, life span-promoting resources, which include self-ligands, lineage-specific cytokines, and innate receptor ligands, underlie these selective processes. Together, these observations suggest that positive selection is a critical feature in the establishment and maintenance of all lymphocyte pools, prompting re-evaluation of the underlying biological rationale for this process.

Animals↗
PubMed2004

Screening of alternative models for transitional B cell maturation.

Several functional and phenotypic B cell populations have been described in the spleen. These include the 'transitional' subsets, which are thought to be late differentiation intermediates of marrow-derived, mature follicular B cells. The exact progenitor-successor relationships of these transitional subsets, as well as whether a proliferative step is requisite for follicular B cell maturation, remain controversial. Moreover, whether late B cell differentiation might involve branched or asynchronous maturation pathways, thus allowing some cells to 'skip' one or more of these stages, has not been investigated. Herein we have used mathematical modeling to interrogate these possibilities. Using mathematical models that numerically simulate splenic B cell population dynamics, we have determined which alternative models of differentiation best fit existing in vivo labeling data. Our results indicate that follicular differentiation does not involve a proliferating splenic intermediate. Our results further suggest that some developing cells move directly from the immature marrow pool to more advanced semi-mature peripheral subsets without passing through the least mature subset in the spleen.

Animals↗
PubMed2004

An increased frequency of autoantibody-inducing CD4+ T cells in pre-diseased lupus-prone mice.

Pathogenic autoantibody production in murine models of lupus is dependent on autoreactive CD4+ helper T cells. However, the mechanisms which permit the selection and maintenance of this autoantibody-inducing CD4+ T-cell repertoire are currently unknown. We hypothesized that the peripheral CD4+ T-cell repertoire of lupus-prone mice was enriched with autoantibody-inducing specificities. To test this, we utilized the splenic focus assay to determine if pre-diseased lupus-prone (NZB x NZW)F(1) mice have an elevated frequency of autoreactive CD4+ T lymphocytes capable of supporting autoantibody production. The splenic focus limiting dilution assay permits anti-nuclear antibodies to be generated from contact-dependent T-B interactions in vitro. We show that young, pre-diseased lupus-prone mice have an elevated frequency of autoantibody-inducing CD4+ T cells. Interestingly, these autoantibody-inducing CD4+ T-cell responses are also present in the thymus. Therefore, an elevated frequency of autoantibody-inducing CD4+ T cells predisposes lupus-prone mice to the development of autoantibodies.

Animals↗
PubMed2004

Tipping the scales of selection with BAFF.

Two recent Immunity papers link peripheral tolerance with the ability of developing B cells to capture BAFF. These findings suggest that an increase in effective BAFF levels leads to autoreactive B cell maturation.

B-Cell Activating Factor↗
PubMed2004

The BLyS family of ligands and receptors: an archetype for niche-specific homeostatic regulation.

Discovery and characterization of the tumor necrosis factor (TNF) family member B-lymphocyte stimulator (BLyS) has opened a novel chapter in the role of TNF family members in the homeostatic control of lymphocyte populations. BLyS and its sister cytokine APRIL (a proliferation-inducing ligand) act primarily as soluble trimers and serve to regulate the steady-state numbers of nearly all B-cell compartments. This homeostatic regulation is accomplished through the regulation of B-cell production rates, selection thresholds, and lifespan. Differential expression of the three BLyS receptors during differentiation and activation provides related yet distinct homeostatic niches for follicular, marginal zone, and memory B-cell subsets.

B-Cell Activating Factor↗
PubMed2004

Peripheral B-cell maturation: the intersection of selection and homeostasis.

B cells complete maturation after migrating to the periphery, where they transit several intermediate developmental stages prior to recruitment into the long-lived primary pool. Because B-lineage commitment is not regulated by peripheral pool size and most peripheral B cells are quiescent, the primary factors governing steady-state numbers are the proportion of immature B cells surviving transit through later developmental stages and the longevity of mature B cells themselves. Substantial evidence indicates that the B-cell receptor (BCR) plays an essential role in all these processes, but recent findings suggest a central role for the recently described tumor necrosis factor (TNF) family member, B-lymphocyte stimulator (BLyS). Signaling through one of the BLyS receptors, BLyS receptor 3 (BR3), controls B-cell numbers in two ways: by varying the proportion of cells that complete transitional B-cell development and by serving as the primary determinant of mature B-cell longevity. The recent discovery that BCR signaling is selectively coupled to BR3 expression in a developmentally regulated fashion links BCR- and BLyS-mediated events, suggesting that specificity-based selection and survival may be mechanistically similar processes.

Animals↗
PubMed2003

Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling.

The Rac1 guanosine triphosphatase (GTPase) has been implicated in multiple cellular functions, including actin dynamics, proliferation, apoptosis, adhesion, and migration resulting from signaling by multiple receptors, including the B cell antigen receptor (BCR). We used conditional gene targeting to generate mice with specific Rac1 deficiency in the B cell lineage. In the absence of both Rac1 and the highly related Rac2, B cell development was almost completely blocked. Both GTPases were required to transduce BCR signals leading to proliferation, survival and up-regulation of BAFF-R, a receptor for BAFF, a key survival molecule required for B cell development and maintenance.

Animals↗