High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation

Chiocchetti, Annalisa; Indelicato, Manuela; Bensi, Thea; Mesturini, Riccardo; Giordano, Mara; Sametti, Selina; Castelli, Luca; Bottarel, Flavia; Mazzarino, María Clorinda; Garbarini, L.; Giacopelli, Francesca; Valesini, Guido; Santoro, Claudio; Dianzani, Irma; Ramenghi, Ugo; Dianzani, Umberto

doi:10.1182/blood-2003-05-1748

Cited by 91 publications

(94 citation statements)

References 38 publications

(37 reference statements)

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“…Regardless of the etiology, this increase in CD44 ligands could result in constant low-level stimulation of NKT cells and lead to immune dysfunction. Overexpression of OPN also is a risk factor for the development of autoimmunity and lymphoproliferative disorders (63). Furthermore, experimental administration of GAGs, including HA, chondroitin sulfates (A, B, and C), and heparin, all natural ligands of CD44, induce autoimmune connective tissue disease in normal mice (55,64).…”

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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“…(ALPS III or ALPS due to unknown defect 21,23 36 OPN potentiate in T cells the lymphoproliferation, IFN γ production, and CD 40 expression which stimulates B cell proliferation. 34,35 In sera of ALPS and DALD patients, IL17A and IL17F present increased levels and favor T cell lymphoproliferation. IL-1ß, which supports the production of pro-inflammatory IL-17, presents higher levels in ALPS and DALD patients than in controls.…”

Section: Discussionmentioning

confidence: 99%

Association of severe myoclonic epilepsy of infancy (SMEI) with probable autoimmune lymphoproliferative syndrome-variant

2014

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The paper reported on a case of severe myoclonic epilepsy of infancy (SMEI) associated with a probable autoimmune lymphoproliferative syndrome variant (Dianzani autoimmune lymphoproliferative disease) (DALD). A male patient with typical features of SMEI and a SCN1A gene variant presented in the first year of life with multiple lymph nodes, palpable liver at 2 cm from the costal margin, neutropenia, dysgammaglobulinemia, relative and sometimes absolute lymphocytosis. Subsequently the patient presented with constantly raised IgA in serum and positive antinuclear and thyroid antimicrosomal antibodies. The diagnosis of probable autoimmune lymphoproliferative syndrome was made; arthritis, skin and throat blisters, which appeared subsequently led to the diagnosis of linear IgA disease. On the basis of these unique associations, the Authors hypothesized that autoimmunity may be partly responsible of the severe epileptic symptomatology, perhaps mediated by autoantibodies against sodium channels or by accompanying cytotoxic T-lymphocytes. Corticosteroid treatment ameliorated the epilepsy and laboratory tests. Future studies will be necessary to evaluate the relevance of autoimmunity in SMEI. RiassuntoGli Autori riportano un paziente con epilessia mioclonica severa dell'infanzia (SMEI) ed una variante del gene SCN1A, associata con una probabile sindrome autoimmune linfoproliferativa, (variante malattia autoimmune linfoproliferativa di Dianzani). Un paziente con il quadro clinico tipico della SMEI, presentò nel primo anno di vita multipli linfonodi, margine epatico palpabile a 2 cm dall'arco costale, neutropenia, disgammaglobulinemia, linfocitosi relativa e talvolta assoluta. Successivamente il paziente presentò IgA nel siero costantemente elevate ed anticorpi antinucleo ed antimicrosomi tiroidei positivi. Fu posta diagnosi di probabile variante della sindrome autoimmune linfoproliferativa (DALD); la comparsa di artrite, vescicole cutanee ed in faringe, che apparvero successivamente, portarono alla diagnosi di possibile malattia lineare ad IgA. Sulla base di queste associazioni, segnalate per la prima volta, gli Autori hanno ipotizzato che, oltre alla turba genetica, l'autoimmunità possa essere in parte responsabile della grave sintomatologia epilettica, forse mediata da autoanticorpi contro i canali del sodio o da T-linfociti citotossici. Il trattamento con cortisone migliorò il quadro epilettico, clinico e di laboratorio. Ulteriori studi diranno se è consigliabile ricercare sistematicamente la presenza di autoimmunità in ogni caso di SMEI.

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“…Additionally, we typed the variations in the OPN gene, which have been found to be predisposing factors for ALPS development. 14 The patient carried monoallelic mutations in FAS (926G.A), XIAP (1189delA), and UNC13D (2768C.G), which were not detected in 100 normal donors, and the OPN 1239A.C single-nucleotide polymorphism (SNP), previously associated with ALPS.…”

Section: Patient Presentationmentioning

confidence: 99%

Mutation of FAS, XIAP, and UNC13D Genes in a Patient With a Complex Lymphoproliferative Phenotype

Boggio¹,

Melensi

Dianzani

et al. 2013

Pediatrics

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This article presents a case report for a child presenting with mixed clinical features of autoimmune lymphoproliferative syndrome (ALPS), familial hemophagocytic lymphohistiocytosis (FHL), and X-linked lymphoproliferative (XLP) disease. From 6 months, he exhibited splenomegaly and lymphoadenopathy and from 4 years, he showed recurrent severe autoimmune hemocytopenia and sepsislike bouts of fever, from which he eventually died at the age of 12. Intriguingly, the patient carried mutations in FAS, XIAP, and UNC13D genes, which are involved in ALPS, XLP disease, and FHL, respectively. These mutations were inherited from the mother, who had rheumatoid arthritis but no signs of ALPS. A role for other modifying genes was suggested by the finding that the healthy father exhibited defective Fas function, without mutation of the FAS gene, and had transmitted to the patient an osteopontin (OPN) gene variant previously associated with ALPS. Therefore, several genes might influence the disease outcome in this family. In vitro analyses revealed that the FAS and the XIAP mutations decreased expression of the corresponding proteins, and the UNC13D mutation decreased granule secretion and Munc interaction with Rab27a. These findings suggest that overlap may exist between ALPS, FHL, and XLP disease, in accordance with the notion that FHL and XLP disease are due to defective natural killer (NK)/NK T-cell function, which involves Fas. Therefore, we propose that NK cell defects should be evaluated in patients with ALPS-like characteristics, and hematopoietic stem cell transplantation should be considered in individuals with severe refractory cytopenia and FHL-like manifestations. Pediatrics 2013;132:e1052-e1058 AUTHORS:

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High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation

Cited by 91 publications

References 38 publications

CD44 Differentially Activates Mouse NK T Cells and Conventional T Cells

CD44 Differentially Activates Mouse NK T Cells and Conventional T Cells

Association of severe myoclonic epilepsy of infancy (SMEI) with probable autoimmune lymphoproliferative syndrome-variant

Mutation of FAS, XIAP, and UNC13D Genes in a Patient With a Complex Lymphoproliferative Phenotype

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