RESUMO
POEMS syndrome is a rare plasma cell disorder characterized by peripheral neuropathy, monoclonal gammopathy, and high levels of serum vascular endothelial growth factor, the pathogenesis of which remains unclear. A unique feature of this syndrome is that the proliferating monoclonal plasma cells are essentially lambda-restricted. Here we determined complete nucleotide sequences of monoclonal immunoglobulin lambda light chain (IGL) variable regions in 11 patients with POEMS syndrome. The V-region of the Ig lambda gene of all 11 patients was restricted to the V lambda 1 subfamily. Searching for homologies with IGL germlines revealed that 2 germlines, IGLV1-44*01 (9/11) and IGLV1-40*01 (2/10), were identified, with an average homology of 91.1%. The IGLJ3*02 gene was used in 11 of 11 re-arrangements with an average homology of 92.2%. These data suggest that the highly restricted use of IGL V lambda 1 germlines plays an important role in the pathogenesis of POEMS syndrome.
Assuntos
Cadeias lambda de Imunoglobulina/genética , Síndrome POEMS/etiologia , Adulto , Idoso , Sequência de Bases , Feminino , Células Germinativas , Humanos , Região Variável de Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade , Homologia de SequênciaRESUMO
Dexamethasone (Dex) is an effective therapeutic agent against multiple myeloma (MM); however, resistance to it often becomes a clinical issue. CD44 is an adhesion molecule that serves as a cell surface receptor for extracellular matrix components, including hyaluronan (HA). HA is an extracellular matrix component that is involved in survival and progression in MM. In the present report, we describe isolation of a CD44-expressing population from a Dex-sensitive MM cell line, RPMI8226, in which the CD44-high population had a significantly higher potential to resist Dex than did the CD44-low population. Furthermore, we demonstrate that CD44 engagement by an anti-CD44 monoclonal antibody (mAb) or HA protects MM cells from Dex-induced growth inhibition. The activity of HA was partially inhibited by blocking its binding to CD44, indicating that CD44 mediates HA activity promoting MM cell survival. CD44 engagement by an anti-CD44 mAb led to phosphorylation and degradation of IkappaB-alpha, thus preventing its Dex-induced up-regulation. Our data suggest that CD44 is not only an important mediator for the survival activity of HA, but it may also contribute to MM cell resistance to Dex.
Assuntos
Dexametasona/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Mieloma Múltiplo/metabolismo , Anticorpos Monoclonais/fisiologia , Linhagem Celular Tumoral , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Humanos , Receptores de Hialuronatos/biossíntese , Receptores de Hialuronatos/imunologia , Ácido Hialurônico/fisiologia , Proteínas I-kappa B/antagonistas & inibidores , Proteínas I-kappa B/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Inibidor de NF-kappaB alfa , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
We herein report a case of aceruloplasminemia in a 27-year-old man who had a 10-year history of diabetes mellitus. The patient developed a convulsion, most likely as a result of hypoglycemia. Unexpectedly, this episode left him in a prolonged state of unconsciousness, which necessitated neurological testing and imaging. Brain MRI showed bilateral hypo-intensities in the basal ganglia and thalamus. Molecular analysis revealed a novel splicing mutation in the ceruloplasmin (CP) gene that would result in the skipping of exon 3 during transcription. This case suggests that diabetes associated with aceruloplasminemia can become manifest in the teens.
