Functional activation of lymphocyte CD44 in peripheral blood is a marker of autoimmune disease activity.

Estess, Pila; DeGrendele, Heather; Pascual, Virginia; Siegelman, Mark H.

doi:10.1172/jci4235

Cited by 93 publications

(77 citation statements)

References 65 publications

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“…Indeed, many autoimmune diseases are characterized by the existence of elevated levels of circulating CD44 ligands (61,62). Regardless of the etiology, this increase in CD44 ligands could result in constant low-level stimulation of NKT cells and lead to immune dysfunction.…”

Section: Discussionmentioning

confidence: 99%

CD44 Differentially Activates Mouse NK T Cells and Conventional T Cells

Larkin

Renukaradhya

Sriram

et al. 2006

The Journal of Immunology

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NK T (NKT) cells are an important component of the innate immune system and recognize the MHC class I-like CD1d molecule. NKT cells possess significant immunoregulatory activity due to their rapid secretion of large quantities of pro- and anti-inflammatory cytokines following CD1d-dependent stimulation. Because the innate immune system is programmed to respond to a multitude of diverse stimuli and must be able to quickly differentiate between pathogenic and endogenous signals, we hypothesized that, apart from stimulation via the TCR (e.g., CD1d-dependent activation), there must be multiple activation pathways that can be triggered through other cell surface receptors on NKT cells. Therefore, we analyzed the ability of CD44, a structurally diverse cell surface receptor expressed on most cells, to stimulate murine NKT cells, compared with conventional T cells. Stimulation of CD44 through Ab cross-linking or binding to its natural ligands hyaluronan and osteopontin induced NKT cells to secrete cytokines, up-regulate activation markers, undergo morphological changes, and resist activation-induced cell death, whereas conventional T cells only exhibited changes in morphology and protection from activation-induced cell death. This CD44-specific stimulation of NKT cells correlated with their ability to bind hyaluronan. Thus, fundamental differences in CD44 function between these lymphocyte subsets suggest an important biological role for CD44 in the innate immune response.

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Section: Discussionmentioning

confidence: 99%

CD44 Differentially Activates Mouse NK T Cells and Conventional T Cells

Larkin

Renukaradhya

Sriram

et al. 2006

The Journal of Immunology

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“…Antigenic stimulation of T cells induces the cell surface expression of the highly active form of CD44 which avidly and with high affinity, binds hyaluronan. CD44 is a marker of activated T cells (10). CD44 is heavily glycosylated.…”

Section: Hyaluronan and Cd44mentioning

confidence: 99%

Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes

Savinov

Strongin

2007

IUBMB Life

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SummaryMembrane type-1 matrix metalloproteinase (MT1-MMP) shedding of the signaling and adhesion CD44 receptor plays a significant role in stimulating cancer cells locomotion. Similarly, and unexpectedly, MT1-MMP-dependent shedding of CD44 plays an equally significant role in regulating the adhesion to the pancreatic vasculature and also in the concomitant transendothelial migration and intra-islet homing of the diabetogenic, cytotoxic, T cells. Inactivation of the T cell MT1-MMP functionality by clinically tested, synthetic inhibitors leads to an extended immobilization of the T killer cells on the pancreatic vasculature and, subsequently, to immunosuppression because of the cessation of the T cell transmigration and homing. Injections of insulin jointly with an MT1-MMP inhibitor stimulated the regeneration of functional, insulin-producing, b-cells in acutely diseased non-obese diabetic (NOD) mice. After insulin injections were suspended and inhibitor injections continued, diabetic NOD mice maintained mild hyperglycemia and did not require further insulin injections for survival. Overall, these data provide a substantive mechanistic rationale for clinical trials of the inhibitors of MT1-MMP in human type 1 diabetes. IUBMB Life, 59: 6-13, 2007

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“…CD4 Ϫ CD8 Ϫ T cells, which are expanded in the autoimmunity-prone MRL/Mp-lpr (MRL-lpr) mice, express increased amounts of CD44 (9). T lymphocytes from patients with SLE and other inflammatory diseases display increased ability to bind to HA-covered membranes (10). Treatment of T cells with an anti-CD3 Ab up-regulates CD44 expression in T cells in vitro and in vivo (11,12), and cross-linking of CD44 enhances signal transduction through the TCR-CD3 complex (13).…”

mentioning

confidence: 99%

Phosphorylated ERM Is Responsible for Increased T Cell Polarization, Adhesion, and Migration in Patients with Systemic Lupus Erythematosus

Harada

Juang

et al. 2007

The Journal of Immunology

161

160

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Systemic lupus erythematosus (SLE) is an autoimmune/inflammatory disease characterized by autoantibody production and abnormal T cells that infiltrate tissues through not well-known mechanisms. We report that SLE T lymphocytes display increased levels of CD44, ezrin, radixin, and moesin (ERM) phosphorylation, stronger actin polymerization, higher polar cap formation, and enhanced adhesion and chemotactic migration compared with T cells from patients with rheumatoid arthritis and normal individuals. Silencing of CD44 by CD44 small interfering RNA in SLE T cells inhibited significantly their ability to adhere and migrate as did treatment with Rho kinase and actin polymerization inhibitors. Forced expression of T567D-ezrin, a phosphorylation-mimic form, enhanced remarkably the adhesion and migration rate of normal T cells. Anti-CD3/TCR autoantibodies present in SLE sera caused increased ERM phosphorylation, adhesion, and migration in normal T cells. pERM and CD44 are highly expressed in T cells infiltrating in the kidneys of patients with lupus nephritis. These data prove that increased ERM phosphorylation represents a key molecular abnormality that guides T cell adhesion and migration in SLE patients.

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Functional activation of lymphocyte CD44 in peripheral blood is a marker of autoimmune disease activity.

Cited by 93 publications

References 65 publications

CD44 Differentially Activates Mouse NK T Cells and Conventional T Cells

CD44 Differentially Activates Mouse NK T Cells and Conventional T Cells

Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes

Phosphorylated ERM Is Responsible for Increased T Cell Polarization, Adhesion, and Migration in Patients with Systemic Lupus Erythematosus

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