RESUMEN
OBJECTIVE: To analyze the composition of known plasmacytosis in systemic lupus erythematosus (SLE) to obtain further insight into the nature of underlying mechanisms. METHODS: Plasmablasts from patients with active SLE, patients with inactive/treated SLE, and healthy controls were characterized by flow cytometry, enzyme-linked immunospot assay, and Transwell migration assays and compared to vaccination-induced plasmablasts. Serum cytokine levels were analyzed by Luminex assay, and histologic analysis of kidney biopsy specimens was performed. RESULTS: Circulating plasmablasts in SLE expressed markers of mucosal immune reactions. IgA, CCR10, and ß7 integrin were expressed by 48%, 40%, and 38% of plasmablasts, respectively, with varying coexpression patterns. Consistent with mucosal homing, some SLE plasmablasts migrated toward the mucosal chemokine CCL28 and secreted polymeric IgA. SLE plasmablasts shared phenotypic characteristics with antigen-specific plasmablasts induced by oral, but not parenteral, vaccinations. Autoreactive antibody-secreting cells of the IgG and IgA isotypes were detectable, but only the emergence of phenotypically mucosal plasmablasts was positively associated with serum interleukin-2 and platelet-derived growth factor BB levels. CONCLUSION: Our data suggest that distinct plasmablast differentiation pathways jointly contribute to peripheral plasmacytosis in SLE, i.e., a cytokine-amplified mucosal "steady-state" plasmablast response, and an autoreactive plasmablast response, representing conventional autoimmunity. Our results indicate an overly activated mucosal immune system in patients with SLE, with both immunologic and clinical implications.
Asunto(s)
Autoanticuerpos/inmunología , Citocinas/inmunología , Riñón/patología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Membrana Mucosa/inmunología , Células Plasmáticas/inmunología , Células Precursoras de Linfocitos B/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Becaplermina , Estudios de Casos y Controles , Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Quimiocinas CC/inmunología , Ensayo de Inmunoadsorción Enzimática , Ensayo de Immunospot Ligado a Enzimas , Femenino , Citometría de Flujo , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Técnicas In Vitro , Cadenas beta de Integrinas/inmunología , Interleucina-2/inmunología , Riñón/inmunología , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/patología , Masculino , Persona de Mediana Edad , Fenotipo , Proteínas Proto-Oncogénicas c-sis/inmunología , Receptores CCR10/inmunología , Adulto JovenRESUMEN
OBJECTIVES: Autoimmune congenital heart block (CHB) is associated with placental transcytosis of maternal autoantibodies directed against Ro/SS-A and La/SS-B. However, only about 2% of children born to mothers with the respective antibodies are affected, indicating that further risk factors exist, which are not yet fully understood. In this study, we investigated whether a maternal type I interferon (IFN) signature represents a risk factor for the development of CHB. METHODS: Blood samples, clinical data and serological parameters from 9 women with CHB pregnancies, 14 pregnant women with antibodies against Ro/SS-A but without a CHB complication and another 30 healthy pregnant women as controls were studied. SIGLEC1 expression was measured by flow cytometry and was correlated to plasma IFN-α levels measured by ELISA, and IFN-γ-induced protein 10 (IP-10) levels measured by Bio-Plex technique. RESULTS: Mothers of affected children had a significantly higher expression of SIGLEC1 (p=0.0034) and IFN-α (p=0.014), but not of IP-10 (p=0.14, all MWU) compared to mothers of unaffected children. SIGLEC1 and IFN-α expression were reduced by hydroxychloroquine and oral glucocorticoids. CONCLUSIONS: High expression of SIGLEC1 in pregnant women with autoantibodies against Ro/SS-A indicates an enhanced risk for CHB development, and these women may benefit especially from IFN-α directed therapy, for example with hydroxychloroquine.