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A K Somani

Publications and source records attributed to A K Somani.

11 recordsLinked to original sources
PubMed1999

Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes.

The Wiskott-Aldrich syndrome protein (WASp) has been implicated in modulation of lymphocyte activation and cytoskeletal reorganization. To address the mechanisms whereby WASp subserves such functions, we have examined WASp roles in lymphocyte development and activation using mice carrying a WAS null allele (WAS(-)(/)(-)). Enumeration of hemopoietic cells in these animals revealed total numbers of thymocytes, peripheral B and T lymphocytes, and platelets to be significantly diminished relative to wild-type mice. In the thymus, this abnormality was associated with impaired progression from the CD44(-)CD25(+) to the CD44(-)CD25(-) stage of differentiation. WASp-deficient thymocytes and T cells also exhibited impaired proliferation and interleukin (IL)-2 production in response to T cell antigen receptor (TCR) stimulation, but proliferated normally in response to phorbol ester/ionomycin. This defect in TCR signaling was associated with a reduction in TCR-evoked upregulation of the early activation marker CD69 and in TCR-triggered apoptosis. While induction of TCR-zeta, ZAP70, and total protein tyrosine phosphorylation as well as mitogen-activated protein kinase (MAPK) and stress-activated protein/c-Jun NH(2)-terminal kinase (SAPK/JNK) activation appeared normal in TCR-stimulated WAS(-)(/)(-) cells, TCR-evoked increases in intracellular calcium concentration were decreased in WASp-deficient relative to wild-type cells. WAS(-)(/)(-) lymphocytes also manifested a marked reduction in actin polymerization and both antigen receptor capping and endocytosis after TCR stimulation, whereas WAS(-)(/)(-) neutrophils exhibited reduced phagocytic activity. Together, these results provide evidence of roles for WASp in driving lymphocyte development, as well as in the translation of antigen receptor stimulation to proliferative or apoptotic responses, cytokine production, and cytoskeletal rearrangement. The data also reveal a role for WASp in modulating endocytosis and phagocytosis and, accordingly, suggest that the immune deficit conferred by WASp deficiency reflects the disruption of a broad range of cellular behaviors.

Actins↗
PubMed1999

Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection.

The selection events shaping T cell development in the thymus represent the outcome of TCR-driven intracellular signaling cascades evoked by Ag receptor interaction with cognate ligand. In view of data indicating TCR-evoked thymocyte proliferation to be negatively modulated by the SHP-1 tyrosine phosphatase, a potential role for SHP-1 in regulating selection processes was investigated by analysis of T cell development in H-Y TCR transgenic mice rendered SHP-1 deficient by introduction of the viable motheaten mutation or a dominant negative SHP-1-encoding transgene. Characterization of thymocyte and peripheral T cell populations in H-Y TCR-viable motheaten mice revealed TCR-evoked proliferation as well as the positive and negative selection of H-Y-specific thymocytes to be enhanced in these mice, thus implicating SHP-1 in the negative regulation of each of these processes. T cell selection processes were also augmented in H-Y TCR mice carrying a transgene driving lymphoid-restricted expression of a catalytically inert, dominant-negative form of SHP-1. SHP-1-negative effects on thymocyte TCR signaling were not influenced by co-cross-linking of the CD28 costimulatory and/or CTLA-4 inhibitory receptors and appear, accordingly, to be realized independently of these comodulators. These observations indicate that SHP-1 raises the signaling threshold required for both positive and negative selection and reveal the inhibitory effects of SHP-1 on TCR signaling to be cell autonomous. The demonstrated capacity for SHP-1 to inhibit TCR-evoked proliferation and selection indicate SHP-1 modulatory effects on the magnitude of TCR-generated signal to be a key factor in determining the cellular consequences of TCR-ligand interaction.

Abatacept↗
PubMed1999

The Src-homology domain 2-bearing protein tyrosine phosphatase-1 inhibits antigen receptor-induced apoptosis of activated peripheral T cells.

Restimulation of Ag receptors on peripheral T lymphocytes induces tyrosine phosphorylation-based signaling cascades that evoke Fas ligand expression and induction of Fas-mediated programmed cell death. In view of the role for the Src homology domain 2-bearing protein tyrosine phosphatase-1 (SHP-1) in modulating TCR signaling, we investigated the influence of SHP-1 on TCR-mediated apoptosis by assaying the sensitivity of peripheral T cells from SHP-1-deficient viable motheaten (mev) mice to cell death following TCR restimulation. The results of these studies revealed mev peripheral T cells to be markedly more sensitive than wild-type cells to induction of cell death following TCR stimulation. By contrast, PMA/ionophore and anti-Fas Ab-induced apoptotic responses were no different in mev compared with wild-type activated cells. Enhanced apoptosis of TCR-restimulated mev lymphocytes was associated with marked increases in Fas ligand expression as compared with wild-type cells, but was almost abrogated in both mev and wild-type cells by Fas-Fc treatment. Thus, the increased sensitivity of mev T cells to apoptosis following TCR restimulation appears to reflect a TCR-driven phenomenon mediated through up-regulation of Fas-Fas ligand interaction and induction of the Fas signaling cascade. These findings, together with the hyperproliferative responses of mev peripheral T cells to initial TCR stimulation, indicate that SHP-1 modulation of TCR signaling translates to the inhibition of both T cell proliferation and activation and, as such, is likely to play a pivotal role in regulating the expansion of Ag-stimulated T cells during an immune response.

Animals↗
PubMed1999

Gene therapy and dermatology: more than just skin deep.

BACKGROUND: Recent advances in the molecular characterization of dermatologic disease have substantively augmented the understanding of the pathogenetic processes underlying disorders of the skin. This new knowledge coupled with progress in gene delivery technologies has paved the way for introducing cutaneous gene therapy into the dermatologic therapeutic armamentorium. OBJECTIVE: This review article includes an overview of the current strategies for delivery of gene therapy with an emphasis on the potential role of cutaneous gene delivery in the treatment of skin and systemic diseases. CONCLUSIONS: Accessibility for gene delivery, clinical evaluation, and topical modulation of gene expression render the skin a very attractive tissue for therapeutic gene delivery. However, there are several key hurdles to be overcome before cutaneous gene therapy becomes a viable clinical option. These include difficulties in inducing sustained expression of the desired gene in vivo, the challenge of targeting genes to long-lived stem cells, and the difficulty in achieving specific and uniform transfer to different compartments of the skin. However, these problems are not insurmountable and will likely be resolved in conjunction with ongoing advances in delineating gene expression profiles and other molecular properties of the skin, strategies for stem cell isolation, and improved approaches to regulating gene delivery and expression. These advances should create the framework for translating the enormous potential of cutaneous gene therapy into the clinical arena and, thereby, substantively improving the management of both cutaneous and systemic disease.

Animals↗
PubMed1997

Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase.

Activation of the cellular Src tyrosine kinase depends upon dephosphorylation of the carboxyl-terminal inhibitory tyrosine phosphorylation site. Herein we show that Src isolated from human platelets and Jurkat T cells is preferentially dephosphorylated at its inhibitory phosphotyrosine site by the SHP-1 tyrosine phosphatase. The data also revealed association of Src with SHP-1 in both platelets and lymphocytes and the capacity of Src to phosphorylate SHP-1 and interact with the SHP-1 NH2-terminal SH2 domain in vitro. Analysis of Src activity in thymocytes from SHP-1-deficient motheaten and viable motheaten mice revealed this kinase activity to be substantially lower than that detected in wild-type thymocytes, but to be enhanced by in vitro exposure to SHP-1. Similarly, immunoblotting analysis of thymocyte Src expression before and after selective depletion of active Src protein indicated that the proportion of active relative to inactive Src protein is markedly reduced in motheaten compared with wild-type cells. These observations, together with the finding of reduced Src activity in HEY cells expressing a dominant negative form of SHP-1, provide compelling evidence that SHP-1 functions include the positive regulation of Src activation.

Animals↗
PubMed1995

A diagnostic assay for the Wiskott-Aldrich syndrome and its variant forms.

BACKGROUND: The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease characterized by severe thrombocytopenia, eczema, and impaired immunity. While the diagnosis is usually straightforward, the syndrome may be expressed in an attenuated form, a phenotype which is difficult to distinguish from other types of congenital thrombocytopenia. Although a molecular-based assay for diagnosis of the spectrum of WAS patients has not been available, recent data indicate that WAS is associated with a specific profile of impaired mitogen responsiveness and suggest that detection of this abnormality may provide a diagnostic marker for all forms of the disease. To address this issue, we have studied patients with classical and atypical WAS for their lymphocyte proliferative responses to four T cell mitogenic stimuli and compared their response patterns to those detected in unaffected children. METHODS: Clinical histories and informed consent were obtained from 23 patients with either classical or putative (ie, atypical) WAS, 16 subjects with other disorders, and 12 healthy children. Peripheral blood mononuclear cells (PBMCs) collected from patients and controls were resuspended in culture medium, stimulated with the T cell mitogens phytohemagglutinin (PHA), concanavalin A (Con A), neuraminidase/galactose oxidase (NAGO), or periodate, and cultured for 60 h in 0.2 mL aliquots. Following a 20 h pulse with 3H-thymidine, cultures were harvested and the 3H-thymidine uptake was evaluated by liquid scintillation counting. RESULTS: The most striking observation involved response to periodate. While lymphocytes from all healthy control children proliferated in response to periodate treatment, cells from both classical as well as atypical WAS patients consistently failed to proliferate in response to this mitogen. By contrast, lymphocyte proliferative responses to PHA, Con A, and NAGO were detected in all patients and controls, although responses generally were lower in cells from classical WAS patients compared to other children. In two WAS patients, bone marrow transplantation and clinical improvement were associated with a change from no periodate response (pre-transplant) to periodate responsiveness (post-transplant). In contrast to the WAS patients, cells from patients with other hematologic and primary immune deficiency diseases responded uniformly to all four mitogens, including periodate. CONCLUSIONS: The data presented here indicate that T cells from patients with either classical or attenuated WAS fail to undergo proliferation in response to periodate, an agent that induced extensive T cell mitogenesis of cells from all healthy controls as well as patients with diseases other than WAS. As the WAS patients' cells did proliferate in response to treatment with other T cell mitogens, it appears that periodate induced T cell proliferation is selectively impaired in WAS and that detection of this defect may be of value in the distinction of both classical and attenuated WAS from other thrombocytopenic conditions.

Child↗
PubMed1990

Linkage relationships of the Wiskott-Aldrich syndrome to 10 loci in the pericentromeric region of the human X chromosome.

Twelve families with Wiskott-Aldrich syndrome (WAS) were studied by linkage analysis using 10 polymorphic marker loci from the X-chromosome pericentromeric region. The results confirm close linkage of WAS to the DXS14, DXS7, TIMP, and DXZ1 loci and are consistent with previous data suggesting that WAS maps to the proximal Xp and is flanked by the DXS14 and DXS7 loci. The strongest linkage (Z = 10.19 at theta = 0.00) was found to be between WAS and the hypervariable DXS255 locus, a marker locus already mapped between DXS7 and DXS14 and which was informative for all meioses included in this analysis. Linkage of the WAS to two pericentromeric Xq loci, DXS1 and PGK1, was also established. On the basis of these results, accurate predictive testing should now be feasible in the majority of WAS families.

Chromosome Mapping↗