Analysis of aberrant somatic hypermutation (SHM) in non-Hodgkin's lymphomas of patients with chronic HCV infection

Hepatitis C virus (HCV) and aberrant somatic hypermutation (SHM) have each been suggested to contribute to the development of B-cell non-Hodgkin's lymphoma (NHL). The incidence of PIM-1, PAX-5, RhoH/TTF, and c-MYC mutations in tumour biopsy specimens from 32 HCV-infected B-cell NHL patients was analysed to determine whether the extent of aberrant SHM among these patients differed from that previously reported for HCV-negative B-cell NHL patients. Mutation of PIM-1, PAX-5, RhoH/TTF, and c-MYC was detected in 4 (13%), 5 (16%), 4 (13%), and 4 (13%) of 32 samples, respectively. In HCV-positive B-cell NHL patients, the frequency of aberrant SHM was lower than that already found in HCV-negative B-cell NHL patients. This indicates that, unlike B-cell lymphomas from HCV-negative patients, aberrant SHM may not contribute significantly to malignant transformation in HCV-associated B-cell lymphomas.     

The molecular basis of Natural Killer (NK) cell recognition and function

Natural Killer cells are likely to play an important role in the host defenses because they kill virally infected or tumor cells but spare normal self-cells. The molecular mechanism that explains why NK cells do not kill indiscriminately has recently been elucidated. It is due to several specialized receptors that recognize major histocompatibility complex (MHC) class I molecules expressed on normal cells. The lack of expression of one or more HLA class I alleles leads to NK-mediated target cell lysis. Different types of receptors specific for groups of HLA-C, HLA-B, and, very recently, HLA-A alleles have been identified. While in most instances, they function as inhibitory receptors, an activatory form of the HLA-C-specific receptors has been identified in some donors. Molecular cloning of HLA-C-, HLA-B- or HLA-A-specific receptors has revealed new members of the immunoglobulin superfamily with two or three Ig-like domains, respectively, in their extracellular portion. While the inhibitory form is characterized by a long cytoplasmic tail associated with a non-polar transmembrane portion, the activatory one has a short tail asociated with a Lys-containing transmembrane portion. Thus, these human NK receptors are different from the murine Ly49, that is a type II transmembrane protein characterized by a C-type lectin domain. A subset of activated T lymphocytes expresses NK-type class I-specific receptors. These receptors exert an inhibiting activity on T cell receptor-mediated functions and may provide an important mechanism of downregulation of T cell responses.     

Requirement for tumor necrosis factor receptor 2 expression on vascular cells to induce experimental cerebral malaria

Using tumor necrosis factor receptor type 2 (TNFR2)-deficient mice and generating bone marrow chimeras which express TNFR2 on either hematopoietic or nonhematopoietic cells, we demonstrated the requirement for TNFR2 expression on tissue cells to induce lethal cerebral malaria. Thus, TNFR2 on the brain vasculature mediates tumor necrosis factor-induced neurovascular lesions in experimental cerebral malaria.     

Group‐specific component (GC) in curiaú and pacoval,two african‐derived brazilian populations

The group‐specific component (GC) system is of interest in anthropological genetic studies because the distribution of its subtypes distinguishes among major ethnic groups. The GC system was analyzed in Curiaú and Pacoval, two remnant Quilombo populations (African‐derived populations) from the Brazilian Amazon. There was no significant statistical difference in allelic frequencies between the two populations or between them and three other African‐derived Brazilian populations (Mimbó, Sítio Velho, and Gaucinha in Northeastern Brazil). These populations share similarities among themselves and with African populations (high frequencies of GC*1F and lower frequencies of GC*1S), which may reflect the influence of a high level of African contribution to their formation, but there is a clear difference between them and Europeans and South American Indians. It is suggested that the GC system is a useful marker for studying relationships between single populations and major ethnic groups, but does not discriminate between populations which share the same parental stock. Am. J. Hum. Biol. 13:718–720, 2001. © 2001 Wiley‐Liss, Inc.     

Behavioral and hormonal responses to stress in the newborn mouse: Effects of maternal deprivation and chlordiazepoxide

These studies investigated behavioral and hormonal responses to stress in developing mice. Experiment 1 examined the effects of 24-hr maternal deprivation on corticosterone (CORT) secretion and ultrasonic vocalization (UVZ) rate in 4-, 8-, and 12-day-old mice. At these ages, exposure to a novel environment resulted in minimal changes in CORT secretion. Maternal deprivation increased pups′ CORT secretion in an age-dependent fashion but did not affect their UVZ rate. The aim of experiment 2 was to test the effects of cholordiazepoxide (CDP), an anxyolytic compound, on CORT secretion and UVZ in both normally reared and in maternally deprived 8-day-old mice. CDP administration elevated CORT increases in deprived (DEP) animals. CDP affected UVZ only in nondcprived (NDEP) animals: UVZ ratewas decreased by high CDP doses Overall, these findings demonstrate that the infant mouse shows a period of stress hyp9oresponsiveness similar to the rat and that maternal presence contributes to inhibit adrenocorticalactivity. CDP administration, butnot novelty exposure, increased CORT secretion in 8-day- old normally reared mice suggesting that during the stress hyporesponsive period, the HPA axis is capable of responding only to specific stimuli. Changes in HPA axis activity and UVZ rateresulting from maternal deprivation and/or CDP challenge do not seem to be directly related. ©1994 John Wiley & Sons, Inc.     

Differential signaling by CpG DNA in DCs and B cells: not just TLR9

CpG-containing oligodeoxynucleotides (CpG ODNs) act on Toll-like receptor 9 (TLR9) that is expressed on B cells and plasmacytoid dendritic cells (pDCs) to stimulate the innate immune system, however, different types of CpG ODNs induce distinct responses. Recent papers suggest some CpG ODNs could require a second receptor or cofactor to signal. The different signaling complexes assembled might impact on the affinity with which CpG ODNs signal to TLR9 or activate additional pathways that lead to distinct immune responses.     

Cation channels,cell volume and the death of an erythrocyte

Similar to a variety of nucleated cells, human erythrocytes activate a non-selective cation channel upon osmotic cell shrinkage. Further stimuli of channel activation include oxidative stress, energy depletion and extracellular removal of Cl^–. The channel is permeable to Ca²⁺ and opening of the channel increases cytosolic [Ca²⁺]. Intriguing evidence points to a role of this channel in the elimination of erythrocytes by apoptosis. Ca²⁺ entering through the cation channel stimulates a scramblase, leading to breakdown of cell membrane phosphatidylserine asymmetry, and stimulates Ca²⁺-sensitive K⁺ channels, thus leading to KCl loss and (further) cell shrinkage. The breakdown of phosphatidylserine asymmetry is evidenced by annexin binding, a typical feature of apoptotic cells. The effects of osmotic shock, oxidative stress and energy depletion on annexin binding are mimicked by the Ca²⁺ ionophore ionomycin (1 µM) and blunted in the nominal absence of extracellular Ca²⁺. Nevertheless, the residual annexin binding points to additional mechanisms involved in the triggering of the scramblase. The exposure of phosphatidylserine at the extracellular face of the cell membrane stimulates phagocytes to engulf the apoptotic erythrocytes. Thus, sustained activation of the cation channels eventually leads to clearance of affected erythrocytes from peripheral blood. Susceptibility to annexin binding is enhanced in several genetic disorders affecting erythrocyte function, such as thalassaemia, sickle-cell disease and glucose-6-phosphate dehydrogenase deficiency. The enhanced vulnerability presumably contributes to the shortened life span of the affected erythrocytes. Beyond their role in the limitation of erythrocyte survival, cation channels may contribute to the triggering of apoptosis in nucleated cells exposed to osmotic shock and/or oxidative stress.