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Biomedical subjects

William J Grossman

Publications and source records attributed to William J Grossman.

12 recordsLinked to original sources
PubMed2006

Cellular and genetic basis of primary immune deficiencies.

Knowledge of the genetic mutations of primary immune deficiency syndromes has grown significantly over the last 30 years. In this article the authors present an overview of the clinical aspects, laboratory evaluation, and genetic defects of primary immunodeficiencies, with an emphasis on the pathophysiology of the known molecular defects. This article is designed to give the primary pediatrician a general knowledge of this rapidly expanding field.

Humans↗
PubMed2006

Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives.

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease in which the immune system becomes overactive due to its inability to effectively respond to infections and/or shut down the immune response to such infections. The discovery of genetic defects in the secretory pathway of natural killer (NK) cells and cytotoxic T cells in some patients with this disease has raised important questions of the role of cytotoxic cells in the control of infections and in immune regulation. This review will give a brief overview of the clinical presentation and accepted treatment of HLH. Furthermore, it will give an in-depth review into the known genetic defects and current knowledge of the pathophysiology of this disorder, and will highlight recent evidence suggesting that cytotoxic defects in CD4+ T regulatory cells may contribute to the pathogenesis of HLH.

Animals↗
PubMed2005

Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV-8.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of immune dysregulation, characterized by end-organ damage from lymphocytic infiltration and macrophage activation. All known mutations associated with the HLH occur in genes critical in the perforin-granzyme pathway. Herein, we report HLH occurring in 2 female triplet infants who also had associated human herpesvirus type 8 (HHV-8) infections. The subjects had identical novel compound-heterozygous mutations in the Perforin alleles, resulting in undetectable perforin expression and NK-cell cytotoxicity. Both infants also had evidence of infection with HHV-8. These reports are, to our knowledge, the first cases of HLH in triplets and the first reported cases of HHV-8 infection associated with HLH in non-renal transplant and non-HIV-infected subjects.

Female↗
PubMed2005

Granzyme B and the downstream granzymes C and/or F are important for cytotoxic lymphocyte functions.

Although the functions of granzyme A (GzmA) and GzmB are well-defined, a number of orphan granzymes of unknown function are also expressed in cytotoxic lymphocytes. Previously, we showed that a targeted loss-of-function mutation for GzmB was associated with reduced expression of several downstream orphan granzyme genes in the lymphokine-activated killer cell compartment. To determine whether this was caused by the retained phosphoglycerate kinase I gene promoter (PGK-neo) cassette in the GzmB gene, we retargeted the GzmB gene with a LoxP-flanked PGK-neo cassette, then removed the cassette in embryonic stem cells by transiently expressing Cre recombinase. Mice homozygous for the GzmB null mutation containing the PGK-neo cassette (GzmB-/-/+PGK-neo) displayed reduced expression of the closely linked GzmC and F genes in their MLR-derived CTLs and lymphokine-activated killer cells; removal of the PGK-neo cassette (GzmB-/-/DeltaPGK-neo) restored the expression of both genes. Cytotoxic lymphocytes derived from mice with the retained PGK-neo cassette (GzmB-/-/+PGK-neo) had a more severe cytotoxic defect than those deficient for GzmB only (GzmB-/-/DeltaPGK-neo). Similarly, GzmB-/-/+PGK-neo mice displayed a defect in the allogeneic clearance of P815 tumor cells, whereas GzmB-/-/DeltaPGK-neo mice did not. These results suggest that the retained PGK-neo cassette in the GzmB gene causes a knockdown of GzmC and F expression, and also suggest that these granzymes are relevant for the function of cytotoxic lymphocytes in vitro and in vivo.

Animals↗
PubMed2005

Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice.

BACKGROUND: Regulatory T cells have been proposed to play an important role in regulating allergic inflammation. The transcription factor Foxp3 is a master switch gene that controls the development and function of natural and adaptive CD4(+)CD25(+) regulatory T (T(R)) cells. In human subjects loss-of-function Foxp3 mutations trigger lymphoproliferation, autoimmunity, and intense allergic inflammation in a disease termed immune dysregulation polyendocrinopathy enteropathy-X-linked syndrome. OBJECTIVE: We sought to examine the evolution and attributes of allergic inflammation in mice with a targeted loss-of-function mutation in the murine Foxp3 gene that recapitulates a known disease-causing human Foxp3 mutation. METHODS: Foxp3 mutant mice were generated by means of knock-in mutagenesis and were analyzed for histologic, immunologic, and hematologic abnormalities. The role of signal transducer and activator of transcription 6 (Stat6) in disease pathogenesis was analyzed by using Stat6 and Foxp3 double-mutant mice. RESULTS: Foxp3 mutant mice developed an intense multiorgan inflammatory response associated with allergic airway inflammation, a striking hyperimmunoglobulinemia E, eosinophilia, and dysregulated T(H)1 and T(H)2 cytokine production in the absence of overt T(H)2 skewing. Concurrent Stat6 deficiency reversed the hyperimmunoglobulinemia E and eosinophilia and delayed mortality, which is consistent with a pathogenic role for allergic inflammation in Foxp3 deficiency. CONCLUSION: Allergic dysregulation is a common and fundamental consequence of loss of CD4(+)CD25(+) T(R) cells caused by Foxp3 deficiency in different species. Abnormalities affecting T(R) cells might contribute to a variety of allergic diseases.

Animals↗
PubMed2004

Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells.

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the perforin/granzyme pathway as a major mechanism to kill pathogen-containing cells and tumor cells.(1,2) Dysregulation of this pathway results in several human diseases, such as hemophagocytic lymphohistiocytosis. Here we characterize the single-cell expression pattern of granzymes A and B in human lymphocytes using a flow cytometry-based assay. We demonstrate that most circulating CD56(+)8(-) NK cells, and approximately half of circulating CD8(+) T lymphocytes, coexpressed both granzymes A and B. In contrast, few circulating CD4(+) T lymphocytes expressed granzymes A or B. Activation of CD8(+) T lymphocytes with concanavalin A (ConA)/interleukin-2 (IL-2), and activation of CD4(+) T lymphocytes with antibodies to CD3/CD28 or CD3/CD46 (to generate T regulatory [Tr1] cells), induced substantial expression of granzyme B, but not granzyme A. Naive CD4(+)CD45RA(+) cells stimulated with antibodies to CD3/CD46 strongly expressed granzyme B, while CD3/CD28 stimulation was ineffective. Finally, we show that granzyme B-expressing CD4(+) Tr1 cells are capable of killing target cells in a perforin-dependent, but major histocompatibility complex (MHC)/T-cell receptor (TCR)-independent, manner. Our results demonstrate discordant expression of granzymes A and B in human lymphocyte subsets and T regulatory cells, which suggests that different granzymes may play unique roles in immune system responses and regulation.

Animals↗
PubMed2004

Human T regulatory cells can use the perforin pathway to cause autologous target cell death.

Cytotoxic T lymphocytes and natural killer cells use the perforin/granzyme pathway to kill virally infected cells and tumor cells. Mutations in genes important for this pathway are associated with several human diseases. CD4(+) T regulatory (Treg) cells have emerged as important in the control of immunopathological processes. We have previously shown that human adaptive Treg cells preferentially express granzyme B and can kill allogeneic target cells in a perforin-dependent manner. Here, we demonstrate that activated human CD4(+)CD25(+) natural Treg cells express granzyme A but very little granzyme B. Furthermore, both Treg subtypes display perforin-dependent cytotoxicity against autologous target cells, including activated CD4(+) and CD8(+) T cells, CD14(+) monocytes, and both immature and mature dendritic cells. This cytotoxicity is dependent on CD18 adhesive interactions but is independent of Fas/FasL. Our findings suggest that the perforin/granzyme pathway is one of the mechanisms that Treg cells can use to control immune responses.

CD18 Antigens↗
PubMed2003

Sudden unexplained hemolysis occurring in an infant due to presumed Loxosceles envenomation.

We report the case of a 3-week-old infant referred for evaluation of sudden onset jaundice and unexplained hemolysis. After an exhaustive workup, the most likely etiology was found to be envenomation by a brown recluse spider, Loxosceles reclusa. This case underscores the fact that severe loxoscelism may occur in the absence of the classically described necrotic cutaneous lesion, and represents one of the youngest presumed cases of loxoscelism. We present the case to illustrate the importance of considering loxoscelism in the differential diagnosis of sudden massive hemolysis in children, particularly in endemic areas of the midwestern and southern United States.

Anemia, Hemolytic↗
PubMed2003

The orphan granzymes of humans and mice.

The granzyme/perforin pathway is a central pathway for lymphocyte-mediated killing in both the innate and adaptive immune systems. This pathway is important in a variety of host defenses, including viral clearance and tumor cell killing, and its dysregulation results in several human and rodent diseases. To date, the majority of reports in this field have concentrated on the functions of granzymes A and B. Recent reports, however, suggest that the non-A/non-B 'orphan' granzymes found in both humans and mice are potentially significant. Although the functions of these orphan granzymes have yet to be fully established, initial data suggests their importance in both immune and nonimmune cells.

Animals↗
PubMed2003

Isolated CNS relapse following stem cell transplantation for juvenile myelomonocytic leukemia.

A 1-year-old girl with juvenile myelomonocytic leukemia (JMML) underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. A few months after BMT she experienced a bone marrow relapse that did not respond to withdrawal of immunosuppression. To enhance the graft-versus-leukemia (GVL) effect, she underwent peripheral stem cell transplantation (PSCT) from the same donor, using a nonmyeloablative conditioning regimen. She achieved clinical remission and developed chronic graft-versus-host disease (GVHD), which was treated with prednisone and cyclosporine A. One year after PSCT she experienced an isolated central nervous system (CNS) relapse. She was treated with intrathecal Ara-C followed by craniospinal irradiation and achieved a third clinical remission. While extramedullary relapses have been described in JMML, this is the first report of a CNS relapse. Based on this case and others in the literature, the authors suggest that newer therapies are changing the natural history of JMML. By manipulating the GVL effect it is possible to achieve a prolonged bone marrow remission, but only at the expense of unmasking the risk of late extramedullary relapse.

Central Nervous System Neoplasms↗