Anti-HLA class I antibody-mediated activation of the PI3K/Akt signaling pathway and induction of Bcl-2 and Bcl-xL expression in endothelial cells

Anti-human leukocyte antigen (HLA) antibodies (Ab) have long been implicated in the process of acute and chronic allograft rejection, yet their mechanism(s) of action is not well understood. The aim of this study was to determine whether ligation of HLA class I molecules by anti-HLA Ab on the surface of human endothelial cells (EC) activates the PI3 Kinase (PI3K)/Akt signaling pathway and downstream target proteins of the cell death apparatus. We report that Ab ligation of major histocompatibility complex (MHC) class I molecules on the surface of EC triggers phosphorylation of Akt, PI3K, and recruitment of PI3K and Akt into a signaling unit with focal adhesion kinase. Signaling through class I also stimulated phosphorylation of Bad and upregulated expression of Bcl-2 and Bcl-xL. Pretreatment of EC with the PI3K inhibitor wortmannin blocked class I-mediated expression of Bcl-2, but not Bcl-xL, suggesting a role for the PI3K/Akt signaling pathway in regulation of class I-induced Bcl-2 expression. The intracellular events initiated by class I ligation were influenced by the concentration of the anti-HLA Ab with the lowest tested concentrations of Ab stimulating the highest level of Akt phosphorylation, Bcl-xL and Bcl-2 expression. Consistent with the in vitro experiments, analysis of biopsy samples from heart transplant recipients with evidence of Ab-mediated rejection exhibited increased Bcl-2 expression on the vascular endothelium. These results suggest that exposure of the graft endothelium to low concentrations of anti-HLA Ab may promote cell survival by transducing signals resulting in upregulation of cell survival genes.     

No association between CHRNA7 microsatellite markers and attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder of childhood that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD. First, nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers, and nonsmokers. Second, ADHD is a significant risk factor for early initiation of cigarette smoking in children and maternal cigarette smoking appears to be a risk factor for ADHD. Finally, animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity. The nicotinic system has previously been studied in schizophrenia where the neuronal nicotinic acetylcholine receptor alpha 7 subunit gene (CHRNA7) has been implicated in decreased P50 inhibition and attentional disturbances in patients with schizophrenia and in many of their nonschizophrenic relatives. Three known microsatellite markers (D15S165, D15S1043, and D15S1360) near the nicotinic acetylcholine alpha 7 receptor gene, CHRNA7, were studied in 206 ADHD parent-proband trios of children aged 5-16 with ADHD according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ < 70) were excluded from the study. Markers D15S165 and D15S1360 were in linkage disequilibrium. The extended Transmission Disequilibrium Test analyses demonstrated no evidence that variation at the microsatellite markers D15S1360, D15S1043, and D15S165 influences susceptibility to ADHD. However, it remains possible that the CHRNA7 gene and other nicotinic system genes may be involved in conferring susceptibility to ADHD.     

Mantle Cell Lymphomas Lack Expression of p27kip1, a Cyclin-Dependent Kinase Inhibitor

p27^Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27^Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27^Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27^Kip1 expression in 116 non-Hodgkin’s lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27^Kip1gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin’s lymphoma other than MCL, p27^Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27^Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27^Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27^Kip1gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin’s lymphomas and normal lymphoid tissue, fail to correlate p27^Kip1 expression with the proliferation rate. This peculiar uncoupling of p27^Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.     

Pubertal neuromaturation, stress sensitivity, and psychopathology

Normal adolescent development is often accompanied by transient emotional and behavioral problems. For most individuals with postpubertal-onset adjustment problems, there is a resolution by early adulthood and relative stability through the adult life span. But for a minority, adjustment problems escalate during adolescence and portend the development of serious mental illness in adulthood. In this article, we explore adolescent behavioral changes and neurodevelopmental processes that might contribute to stress sensitivity and vulnerability for the emergence of the mental disorders. Of particular interest is the role that hormonal changes might play in the expression of genetic vulnerabilities for psychopathology. Drawing on recent findings from clinical research and behavioral neuroscience, we describe the ways in which postpubertal hormones might alter brain function and, thereby, behavior. It is concluded that there are both activational and organization effects of hormones on the adolescent brain, and these contribute to developmental discontinuities in behavioral adjustment. Implications for adult psychopathology and preventive intervention are discussed.     

Genital inoculation of male baboons with Neisseria gonorrhoeae.

Eight male baboons inoculated intraurethrally with Neisseria gonorrhoeae failed to shed gonococci or develop serum antibody. Urethral inoculation, preceded by epididymal inoculation, elicited an anamnestic antibody response.     

Eimeria in Fowls: Immunity to Four Species of

Two or three graded infections with oocysts of Eimeria acervulina, E. tenella, E. necatrix and E. maxima produced a resistance to further infection with the immunizing species. The oocyst output after the second infection, in each case, was lower than that after the initial dose indicating the substantial immunizing effect of the initial infection. The species could be placed in a descending order of immunizing activity as follows: E. maxima, E. acervulina, E. tenella and E. necatrix. A solid immunity to the immunizing species in no way prevented the development of an additional infection, here referred to as `cross-infection', with any of the species studied.

Serum precipitins were produced in infections with all four species, the response to infection with E. necatrix being less marked than to the other species. A first challenge of immune fowls with the immunizing species produced some increase in precipitation in agar whereas a second challenge had no such effect; the significance of this lack of response is discussed. Usually, fowls immunized against one species and then infected with an additional one, produced serum precipitins which reacted only with the antigen of the additional species. But E. tenella immunized fowls, when given an additional infection with E. necatrix, produced precipitins that reacted with antigens of both species. The same was also true when E. necatrix immunized fowls were infected with E. tenella.

     

Classical Noonan syndrome is not associated with deletions of 22q11

Deletions of 22qll cause DiGeorge sequence (DGS), velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome, and some isolated conotruncal heart anomalies. Demonstration of a 22qll deletion in a patient with manifestations of DGS and Noonan syndrome (NS) has raised the question of whether NS is another of the chromosome 22 microdeletion syndromes. This prompted us to evaluate a cohort of patients with NS for evidence of 22qll deletions. Five of 6 NS propositi studied in our laboratory with marker N25 (D22S75) did not have a 22qll deletion. A 2-month-old infant with several findings suggestive of NS did have a 22qll deletion, suggesting that a small number of 22qll deletion propositi may present with a NS-like picture. However, most cases of NS must have another cause. © 1995 Wiley-Liss, Inc.     

Ro (SSA) and La (SSB) antibodies

Summary This review traces the historical development of information regarding the Ro (SSA) and La (SSB) autoantibody systems over the past twenty years. Clinical and serologic findings are integrated with fundamental observations in this rapidly expanding area of research. Retrospective analysis of the physicochemical properties of the antigens and the cellular staining characteristics of antibodies to these antigens suggest that SjD and Ro and SSA, as well as SjT and La, SSB, and Ha antigens probably are similar macromolecules. The immunologic identity of Ro with SSA and La with SSB and Ha has been established previously. Antibodies to these antigens are directed against macromolecules containing small RNA nucleotides.Antibodies to the Ro (SSA)-La(SSB) antigen system commonly are detected in the sera of patients with systemic lupus erythematosus and Sjögren's syndrome and appear to be of diagnostic significance. These antibodies occur in up to one quarter of patients with systemic lupus erythematosus (SLE) without the sicca complex, but also in patients with ANA negative SLE who have a prominent photosensitive dermatitis and may have serious renal disease, subacute cutaneous SLE, and in infants and mothers of infants with neonatal SLE. Thus, these antibody systems form a serologic link between many unusual connective tissue diseases and systemic SLE.Antibodies to Ro (SSA)-La(SSB) are associated not only with Sjögren's syndrome occurring alone, but also with Sjögren's syndrome occurring in the setting of other connective tissue diseases including SLE and rheumatoid arthritis. Anemia, leukopenia, and thrombocytopenia, as well as hyperglobulinemia and the presence of rheumatoid factor, cryoglobulins, and antibodies to nuclear antigens are associated significantly with Ro positivity in Sjögren's syndrome patients. There is a striking association of vasculitis in the clinical setting of Sjögren's syndrome with the presence of antibodies to Ro (SSA). In addition to peripheral nerve involvement, unusual central nervous system manifestations as well as myositis occur in these Ro(SSA) positive Sjögren's syndrome patients. Deposition of immunoglobulin and complement within vessel walls of kidney and muscle from Ro positive patients with Sjögren's syndrome suggests a possible role for immune complex deposition in the pathogenesis of the vasculitis.Supported by National Institutes of Health grant 5ROI-AM-25650-03 and Research Career Development Award 5-KO-4-AM-00524-02