RESUMEN
BACKGROUND: The term juvenile idiopathic arthritis (JIA) describes a clinically heterogeneous group of arthritides. The onset in all subgroups is before 16 years of age, but each group presents with different clinical signs and symptoms. The cause of the disease is unknown, but both genetic and environmental factors are believed to be involved. Management of the disease has greatly improved in recent years due to advances in pharmacologic treatment options (especially with new biologic agents) and the prognosis for patients is better than ever before. However, none of the available drugs has a curative potential. This review provides an overview on the classification and the clinical symptoms of the defined subgroups of JIA as well as pharmacotherapies for it. CONCLUSIONS: Treatment of children with JIA is challenging and complex. Since lengthy therapy might be necessary, a multidisciplinary pediatric rheumatology team is crucial for optimal treatment. Although a cure is unknown at this time, adequate treatment aims to preserve function of the joints as well as normal childhood development.
Asunto(s)
Artritis Juvenil/clasificación , Adolescente , Antiinflamatorios no Esteroideos/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Niño , Femenino , Humanos , Masculino , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Monocyte-derived macrophage (MPhi) subsets are generated by antagonistic induction pathways. A helper MPhi-type (Mh-MPhi) is induced by interferon gamma (IFN-gamma), whereas a cytotoxic MPhi-type (Mc-MPhi), induced by interleukin-10 (IL-10), is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Compared with MPhi from healthy adults [peripheral blood monocyte-derived macrophages (PBMPhi)], cord blood MPhi (CBMPhi) were found less capable of generating Mh-MPhi. Here we tested the hypothesis that their generation of Mc-MPhi via IL-10 is also impaired. MPhi surface markers were phenotyped. IL-10 protein and mRNA production were detected after stimulation [alphaCD3 monoclonal antibody (mAb)]. CBMPhi or PBMPhi were co-cultured with MPhi-depleted mononuclear cells of adults and CD4-targeting antibodies as models for ADCC were added. In cord blood, we found diminished alphaCD3-induced IL-10 protein and mRNA production (p < 0.05 versus adults). Basal CD16 and HLA-DR expressions on CBMPhi of preterm and full-term neonates were lower (p < 0.05 versus PBMPhi). IL-10 had reduced effects on CD16 up- and HLA-DR down-modulation on CBMPhi (p < 0.05 versus PBMPhi). CD4-directed receptor modulation and deletion were reduced in the presence of CBMPhi (p < 0.05 versus PBMPhi). IL-10 failed to enhance their ADCC capacity, which was in contrast to PBMPhi (p < 0.05). These data suggest that CBMPhi have an impaired cytotoxic capacity via lower sensitivity toward IL-10.
Asunto(s)
Citotoxicidad Inmunológica , Sangre Fetal/inmunología , Interleucina-10/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Anticuerpos Monoclonales/farmacología , Complejo CD3/inmunología , Linfocitos T CD4-Positivos/inmunología , Técnicas de Cocultivo , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Sangre Fetal/citología , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Interleucina-10/metabolismo , Depleción Linfocítica , Mitógenos/farmacología , Embarazo , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismoRESUMEN
The safety of dexamethasone for neonates has been questioned, partly because of its multiple unspecific effects on the immune system. Specific effects of dexamethasone on co-stimulatory and immune suppressive functions of neonatal compared with adult macrophages (MPhi) are not known. We evaluated the effect of dexamethasone on the expression and regulation of MPhi B7 family receptors (B7-1, CD80; B7-2, CD86) and on their ability to co-stimulate T cells. Cord blood macrophages (CBMPhi) and MPhi from healthy adults (PBMPhi) were isolated, and cell surface markers were phenotyped by flow cytometry. In tissue culture, cells were exposed to dexamethasone, interferon-gamma (IFN-gamma), cAMP, or a T cell mitogen (alphaCD3) and examined for their capacity to activate or destroy T cells. CBMPhi were less able to up-regulate CD80 and CD86 than PBMPhi (p < 0.05). Dexamethasone inhibited the up-regulation of CD80, CD86, and HLA-DR on PBMPhi and even more so on CBMPhi (p < 0.05 versus PBMPhi for CD80 and CD86). In the presence of dexamethasone, stimulation with alphaCD3 MAb enhanced cytotoxic functions of PMBMPhi and CB(mu)phi with an increase in deleted T cells, a reduced fraction of enlarged T cells, and an inhibition of T cell CD28 up-regulation, which again were more pronounced with CBMPhi (p < 0.05 versus PBMPhi). In conclusion, neonatal MPhi are exquisitely sensitive to the inhibitory effects of dexamethasone on B7 expression. Although perhaps producing the desired therapeutic effect, dexamethasone may do so in newborns at the expense of a near complete paralysis of MPhi-dependent T cell function.
Asunto(s)
Antígenos CD/biosíntesis , Antígeno B7-1/biosíntesis , Dexametasona/farmacología , Activación de Linfocitos/efectos de los fármacos , Glicoproteínas de Membrana/biosíntesis , Linfocitos T/inmunología , Adulto , Factores de Edad , Antiinflamatorios/farmacología , Antígeno B7-2 , Antígenos CD28/biosíntesis , Complejo CD3/biosíntesis , Técnicas de Cocultivo , AMP Cíclico/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Recién Nacido , Interferón gamma/metabolismo , Leucocitos Mononucleares/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Fenotipo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Juvenile idiopathic arthritis (JIA) is considered to be an autoimmune disease. Various human leukocyte antigen (HLA) associations for different subgroups of this heterogeneous disease have been found. For early-onset pauciarticular arthritis (now oligoarthritic JIA), a strong association with the HLA class II haplotype DQA1*0401/DQB1*0402 (DQ4) has been described. We determined the peptide-binding specificities of this HLA-DQ molecule by screening a synthetic acetylated nonapeptide amide library with one defined and eight random sequence positions. A characteristic binding motif could be deduced. By use of these data, we designed defined specific nonapeptides and identified high-affinity ligands binding to HLA-DQ4. The peptide binding motif of HLA-DQ4 is very similar to the motif of HLA-DQ7, also associated with oligoarthritic JIA. It is, however, different from binding motifs of neutral or protective HLA-DQ molecules. Our results further support the idea of differential peptide presentation in the pathogenesis of oligoarthritic JIA.
Asunto(s)
Artritis Juvenil/inmunología , Antígenos HLA-DQ/inmunología , Péptidos/inmunología , Secuencias de Aminoácidos/inmunología , Secuencia de Aminoácidos , Artritis Juvenil/patología , Línea Celular Transformada , Antígenos HLA-DQ/metabolismo , Humanos , Ligandos , Datos de Secuencia Molecular , Biblioteca de Péptidos , Péptidos/síntesis química , Péptidos/metabolismo , Unión Proteica/inmunologíaRESUMEN
BACKGROUND: Macrophage (MPhi) receptors of the B7 family (CD80, CD86) play a crucial role in T cell activation: the lack of costimulation leads to anergy or apoptosis of reactive T cells. MPhi may differentiate into different subsets, the balance of which defines MPhi-dependent T cell reactions. The aim of this study was to examine neonatal and adult T cell response with respect to the costimulatory MPhi-potential in order to identify molecular predictors for the neonatal immune defense. METHODS: MPhi from peripheral blood (PBMPhi) or cord blood (CBMPhi) were stimulated with interferon-gamma (IFN-gamma), cyclic adenosine monophosphate (cAMP), CD40 ligand (CD40L), or alphaCD3. RESULTS: As compared to PBMPhi, CBMPhi showed a significantly decreased upregulation of CD80 and/or CD86 after stimulation with IFN-gamma, cAMP, CD40L, and alphaCD3. Accordingly, the proliferative T cell response was impaired in the presence of CBMPhi. The fraction of T cells that underwent cell death was higher, and blast formation was significantly lower than that observed in the presence of PBMPhi. CONCLUSIONS: CBMPhi, as compared to PBMPhi, delivered fewer costimulatory but more cytotoxic signals to T cells. These observations suggest that MPhi are one factor explaining the suboptimal immune defense of neonates and their increased susceptibility to infection. Using the costimulatory MPhi-potential as a predictor for immune responses requires a separate reference value system in neonatology.
Asunto(s)
Antígeno B7-1/metabolismo , Sangre Fetal/citología , Citometría de Flujo , Macrófagos/metabolismo , Adulto , Factores de Edad , Antígenos CD/metabolismo , Antígeno B7-2 , Complejo CD3/farmacología , Ligando de CD40/farmacología , AMP Cíclico/farmacología , Humanos , Recién Nacido , Recien Nacido Prematuro , Interferón gamma/farmacología , Macrófagos/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Linfocitos T/metabolismo , Regulación hacia Arriba/inmunologíaRESUMEN
The beta-chains of HLA-DR molecules associated with susceptibility to rheumatoid arthritis (RA) share a common amino acid sequence in their third hypervariable region at position 70-74. This shared epitope could either contribute to preferential binding of a given disease-associated peptide, be involved in disease-induction by molecular mimicry or, by binding to heat shock proteins, influence antigen presentation. It is known that the Escherichia coli M(r)70,000 heat shock protein DnaK can bind peptides from the shared epitope. Using a highly sensitive method, we show that peptides covering the third hypervariable region of associated, but also most of the non-associated HLA-DR alleles, bind to DnaK. Similar binding specificities could be found for the constitutively expressed mammalian M(r)70,000 heat shock protein Hsc73 and the inducible mammalian Hsp72. However, peptides containing the amino acid sequence DERAA, found in HLA-DR alleles and strongly associated with protection from RA, did not bind any HSP70. Thus, our results suggest a possible association of non-binding of HSP70 to HLA-DR molecules or its 70-74 fragments and protection from RA.