Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Mutación de Línea Germinal , Neoplasias Pulmonares/genética , Neoplasias de Células Escamosas/genética , Adulto , Secuencia de Bases , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Análisis Mutacional de ADN , Activación Enzimática/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Salud de la Familia , Resultado Fatal , Femenino , Humanos , Hibridación in Situ , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Mutación Missense , Neoplasias de Células Escamosas/patología , Neoplasias de Células Escamosas/terapia , Neumonectomía/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Resultado del TratamientoRESUMEN
B cell chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is a clonal expansion of CD5(+)CD19(+) B lymphocytes. Two types of CLLs are being distinguished as carrying either unmutated or somatically mutated immunoglobulins (Igs), which are associated with unfavorable and favorable prognoses, respectively. More than 30% of CLLs can be grouped based on their expression of stereotypic B cell receptors (BCRs), strongly suggesting that distinctive antigens are involved in the development of CLL. Unmutated CLLs, carrying Ig heavy chain variable (IGHV) genes in germline configuration, express low-affinity, poly-, and self-reactive BCRs. However, the antigenic specificity of CLLs with mutated IGHV-genes (M-CLL) remained elusive. In this study, we describe a new subset of M-CLL, expressing stereotypic BCRs highly specific for ß-(1,6)-glucan, a major antigenic determinant of yeasts and filamentous fungi. ß-(1,6)-glucan binding depended on both the stereotypic Ig heavy and light chains, as well as on a distinct amino acid in the IGHV-CDR3. Reversion of IGHV mutations to germline configuration reduced the affinity for ß-(1,6)-glucan, indicating that these BCRs are indeed affinity-selected for their cognate antigen. Moreover, CLL cells expressing these stereotypic receptors proliferate in response to ß-(1,6)-glucan. This study establishes a class of common pathogens as functional ligands for a subset of somatically mutated human B cell lymphomas.