The specificity of humoral immune responses relies on the huge DIVERSITY of antigen combining sites present in antibodies, diversity which is generated in an antigenindependent fashion. The process by which antigen (during an immune response) stimulates the clonal expansion and differentiation of antibody-forming cells of predetermined specificity is known as CLONAL SELECTION. The basic princip...

Strings of bits (bitstrings) are a common first-order representation in the design and preliminary investigation of computational intelligence algorithms given (1) the ease in mapping the strings to arbitrary domains (such as real numbers), and (2) in terms of mathematical analysis. This work considers the use of bitstrings in the context of the clonal expansion and antigenic selection in a gen...

The role of PI3K in T cell activation and costimulation has been controversial. We previously reported that a kinase-inactivating mutation (D910A) in the p110delta isoform of PI3K results in normal T cell development, but impaired TCR-stimulated cell proliferation in vitro. This proliferative defect can be overcome by providing CD28 costimulation, which raises the question as to whether p110del...

Aging of the hematopoietic stem cell compartment is believed to contribute to the onset of a variety of age-dependent blood cell pathophysiologies. Mechanistic drivers of hematopoietic stem cell (HSC) aging include DNA damage accumulation and induction of tumor suppressor pathways that combine to reduce the regenerative capacity of aged HSCs. Such mechanisms do not however account for the chang...

Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predictin...

Tumor promoters stimulate the selective expansion of initiated mouse keratinocytes in the two-stage model of skin carcinogenesis. However, it is not clear whether these promoters directly modulate the growth of initiated cells or rather permit clonal expansion of initiated cells by modifying the environment of adjacent normal cells. The goal of this study was to further understand the mechanism...

Clonal diversity in multiple myeloma (MM) includes both MM-related and MM-unrelated clonal expansions which are subject to dominance exerted by the MM clone. Here we show evidence for the existence of minor but highly expanded unrelated B-cell clones in patients with MM defined by their complementary determining region 3 (CDR3) peak. We further characterize these clones over the disease and sub...

BACKGROUND Mesenchyme-derived airway cell populations including airway smooth muscle (ASM) cells, fibroblasts and myofibroblasts play key roles in the pathogenesis of airway inflammation and remodeling. Phenotypic and functional characterisation of these cell populations are confounded by their heterogeneity in vitro. It is unclear which mechanisms underlie the creation of these different sub-p...

Although it is well documented that feeding Ag can tolerize or prime systemic humoral and cell-mediated immune responses, the mechanisms involved remain unclear. Elucidation of these mechanisms remains, in part, complicated by the inability to assess responses by individual lymphocyte populations. In the past, in vivo studies have examined T cell responses at the gross level by examining their ...

Peripheral tolerance mechanisms normally prevent delivery of T cell help to anergic self-reactive B cells that accumulate in the T zones of spleen and lymph nodes. Chronic exposure to self-antigens desensitizes B cell antigen receptor (BCR) signaling on anergic B cells so that they are not stimulated into clonal expansion by CD4(+) T cells but instead are eliminated by Fas (CD95)-induced apopto...