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J J Bleesing

Publications and source records attributed to J J Bleesing.

8 recordsLinked to original sources
PubMed2001

Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression.

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which genetic defects in proteins that mediate lymphocyte apoptosis, most often Fas, are associated with enlargement of lymph nodes and the spleen and a variety of autoimmune manifestations. Some patients with ALPS have relatives with these same apoptotic defects, however, who are clinically well. This study showed that the circulating levels of interleukin 10 (IL-10) were significantly higher (P <.001) in 21 patients with ALPS than in healthy controls. Moreover, the peripheral blood mononuclear cells (PBMCs) and lymphoid tissues of these patients with ALPS contained significantly higher levels of IL-10 messenger RNA (mRNA; P <.001 and P <.01, respectively). By fractionating PBMC populations, disproportionately high concentrations of IL-10 mRNA were found in the CD4(-)CD8(-) T-cell population, expansion of which is virtually pathognomonic for ALPS. Immunohistochemical staining showed intense IL-10 protein signals in lymph node regions known to contain CD4(-)CD8(-) T cells. Nonetheless, in vitro studies showed no influence of IL-10 on the survival of CD4(-)CD8(-) T cells. Overexpression of IL-10 in patients with inherited apoptotic defects is strongly associated with the overt manifestations of ALPS.

Apoptosis↗
PubMed2001

TcR-alpha/beta(+) CD4(-)CD8(-) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis.

Autoimmune lymphoproliferative syndrome (ALPS), caused by inherited defects in apoptosis secondary to mutations in genes encoding Fas/CD95/APO-1 and Fas ligand (Fasl)/CD95L, is characterized by nonmalignant lymphadenopathy and splenomegaly, increased T cell receptor alpha/beta(+) CD4(-)CD8(-) T cells (alpha/beta(+) double-negative T cells [alpha/beta(+)-DNT cells]), autoimmunity, hypergammaglobulinemia, and cytokine abnormalities. The alpha/beta(+)-DNT cells are immunophenotypically and functionally similar to alpha/beta(+)-DNT cells that accumulate in lpr and gld mice, which bear genetic mutations in Fas and FasL. In these mice, alpha/beta(+)-DNT cells express the B-cell-specific CD45R isoform B220. We show that alpha/beta(+)-DNT cells of ALPS patients, with either Fas or FasL mutations, also express B220. In addition, also similar to LPR/gLD mice, they have an unusual population of B220-positive CD4(+) T cells. B220 expression, together with our finding of characteristic lectin binding profiles, demonstrates that cell surface O-linked glycoproteins have undergone specific modifications, which may have consequences for lymphocyte trafficking, cell-cell interactions, and access to alternative apoptosis pathways.

Autoimmune Diseases↗
PubMed2001

Immunophenotyping.

Immunophenotyping of leukocytes for nonmalignant conditions uses the power of multiparameter flow cytometry to count specific lymphocyte populations and evaluate the presence or absence of particular cell surface markers. Its main clinical indications, and the focus of this chapter, are enumeration of CD4 T-cell counts and activation markers on T cells in human immunodeficiency virus (HIV) infection, immunophenotypic characterization of primary immunodeficiency disorders and immune-mediated diseases, and the study of immune reconstitution following stem cell transplantation (SCT). Immunophenotyping has advanced our understanding of many immunologic disorders, which in turn have stimulated new developments in the field of flow cytometry, such as quantitative flow cytometry and single-platform technology. Semin Hematol 38:100-110. This is a US government work. There are no restrictions on its use.

Animals↗
PubMed2001

Cell function-based flow cytometry.

Flow cytometry is increasingly used to assess the functional status of leukocytes, and practically all aspects of their life (and death) are accessible to flow cytometric study. Together with familiar features of flow cytometry, such as multiparameter immunophenotyping, cell function-based flow cytometry has provided many new insights into the relationships among lymphocyte cell surface features; intracellular processes, such as cytokine production and protein phosphorylation; and the functional status of lymphocytes in a variety of human diseases. Direct visualization and quantification of antigen-specific T cells using major histocompatibility complex (MHC)-peptide tetramer technology, in combination with functional assays, has provided the means to study specific T-cell subsets of interest. Even early in its development, this technology already has offered a better understanding of basic and clinical immunology and has invited reassessment of several long-standing immunologic concepts. Semin Hematol 38:169-178. This is a US government work. There are no restrictions on its use.

Animals↗
PubMed2000

Immune function.

The innate and the adaptive immune systems have evolved to provide a rapid and specific means for protecting hosts against the many microbes experienced over a lifetime. These two immune responses interact cooperatively to enhance the host defense. Defects in either of these two pathways can have devastating consequences, as evidenced [figure: see text] by primary immune deficiencies, many of which are discussed in this issue of the Pediatric Clinics of North America. The immune system has a central role in the pathogenesis of many disorders that involve an inflammatory response, including allergic and autoimmune diseases. New and more effective therapies for these many disorders will develop as the understanding of the immune system and its many secreted mediators continues to increase.

B-Lymphocytes↗
PubMed2000

Autoimmune lymphoproliferative syndrome. A human disorder of abnormal lymphocyte survival.

The importance of Fas in the homeostatic balance between lymphocyte survival and death is underscored by the three main consequences of defective Fas-mediated apoptosis, as experienced by patients with ALPS: (1) abnormal accumulation of lymphocytes results in lymphadenopathy, hepatosplenomegaly, and hypersplenism; (2) failure of removal of potentially autoreactive lymphocytes, a process normally used to eliminate lymphocytes that have escaped negative selection in the thymus and bone marrow (see article by Fleisher and Blessing, p. 1197), is associated with the appearance of autoimmune manifestations; and (3) inappropriate survival of lymphocytes may lead to the development of malignancies. As with other "experiments of nature," the many aspects of ALPS have provided valuable new insights into the immune system and the importance of a proper balance between life and death of lymphocytes. ALPS is an example of how a mouse disease model was applied directly to the identification of the molecular basis and the understanding of a remarkable disease in humans. It is also an example of clinical observations being linked to basic scientific data to unlock the underlying defect(s) causing a disease. Despite the difficulty in fully understanding the complex nature of the clinical course, the immunologic abnormalities, and the genetic aspects of ALPS, the accumulated experience in diagnosis, treatment, and follow-up of patients and relatives has generated a "road map" that can be used as a guide for their care. As examples, the appreciation that manifestations of lymphoproliferation usually subside over time has allowed a "wait-and-see" approach in many patients who might previously have been treated aggressively. The appreciation that these patients are at increased risk for malignancies has mandated the adoption of careful and lifelong follow-up. Future efforts directed at careful clinical follow-up and scientific investigation are required to learn more about the incidence and natural history of ALPS, therapeutic interventions directed at altering the consequences of TNFRSF6 mutations, and the identification of other genetic and environmental factors that may have a role in the pathogenesis of ALPS.

Apoptosis↗