RESUMEN
A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22-/- T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22-/- T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22-/- T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22-/- bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.
Asunto(s)
Artritis Experimental/inmunología , Células Dendríticas/inmunología , Antígeno-1 Asociado a Función de Linfocito/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 22/inmunología , Células TH1/inmunología , Animales , Anticuerpos/farmacología , Artritis Experimental/genética , Artritis Experimental/patología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Antígenos CD28/antagonistas & inhibidores , Antígenos CD28/genética , Antígenos CD28/inmunología , Complejo CD3/antagonistas & inhibidores , Complejo CD3/genética , Complejo CD3/inmunología , Proliferación Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Células Dendríticas/patología , Regulación de la Expresión Génica , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/inmunología , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/inmunología , Lipopolisacáridos/farmacología , Antígeno-1 Asociado a Función de Linfocito/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina/farmacología , Fragmentos de Péptidos/farmacología , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 22/deficiencia , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Células TH1/efectos de los fármacos , Células TH1/patologíaRESUMEN
Hepatic clearance of chemotherapy drugs is increased by many antiepilepsy drugs. At our institution, new-onset seizures in children on chemotherapy are treated with gabapentin, a nonhepatic enzyme inducer. The charts of all children given gabapentin for seizures were reviewed. At a median follow-up of 34 months, seizures were controlled in 74% of 50 children given gabapentin monotherapy as initial treatment: 91% of the leukemia group, 57% of the brain tumor group, and 75% of the other tumor group. Seizures were controlled in 49% of 59 children in whom gabapentin was added to other antiepilepsy drugs: 43% of the leukemia group, 53% of the brain tumor group, and 50% of the other tumor group. More than one seizure at presentation, focal neurologic deficits, high-dose methotrexate, brain irradiation, and T2-weighted signal abnormality around the brain tumor cavity predicted uncontrolled seizures. Only 8 children (7%) reported adverse effects, and the drug was discontinued in two. Gabapentin effectively controls seizures in children receiving chemotherapy and is well tolerated.