RESUMEN
Most humans harbor both CD177neg and CD177pos neutrophils but 1-10% of people are CD177null, placing them at risk for formation of anti-neutrophil antibodies that can cause transfusion-related acute lung injury and neonatal alloimmune neutropenia. By deep sequencing the CD177 locus, we catalogued CD177 single nucleotide variants and identified a novel stop codon in CD177null individuals arising from a single base substitution in exon 7. This is not a mutation in CD177 itself, rather the CD177null phenotype arises when exon 7 of CD177 is supplied entirely by the CD177 pseudogene (CD177P1), which appears to have resulted from allelic gene conversion. In CD177 expressing individuals the CD177 locus contains both CD177P1 and CD177 sequences. The proportion of CD177hi neutrophils in the blood is a heritable trait. Abundance of CD177hi neutrophils correlates with homozygosity for CD177 reference allele, while heterozygosity for ectopic CD177P1 gene conversion correlates with increased CD177neg neutrophils, in which both CD177P1 partially incorporated allele and paired intact CD177 allele are transcribed. Human neutrophil heterogeneity for CD177 expression arises by ectopic allelic conversion. Resolution of the genetic basis of CD177null phenotype identifies a method for screening for individuals at risk of CD177 isoimmunisation.
Asunto(s)
Isoantígenos/biosíntesis , Neutropenia/inmunología , Neutrófilos/inmunología , Seudogenes/genética , Receptores de Superficie Celular/biosíntesis , Anticuerpos Anticitoplasma de Neutrófilos/biosíntesis , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Transfusión de Sangre Autóloga/efectos adversos , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Regulación de la Expresión Génica , Heterogeneidad Genética , Humanos , Isoantígenos/sangre , Isoantígenos/genética , Isoantígenos/inmunología , Neutropenia/patología , Neutrófilos/metabolismo , Polimorfismo de Nucleótido Simple , Seudogenes/inmunología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Trombocitopenia Neonatal AloinmuneRESUMEN
Gracias al tratamiento con ciclofosfamida la letalidad de las vasculitis asociadas a ANCA ha disminuido considerablemente. Sin embargo, dicho tratamiento se relaciona con efectos adversos agudos y crónicos que contribuyen a la morbimortalidad de estas enfermedades. Por ello, uno de los retos actuales en el manejo de estas patologías consiste en encontrar terapias que sean tan efectivas como la ciclofosfamida pero con un margen de seguridad más favorable. Bajo estas condiciones, el rituximab (RTX), un anticuerpo monoclonal anti-CD20, encabeza la lista de nuevas opciones en el tratamiento de las vasculitis asociadas a ANCA y es el más firme candidato para establecerse como opción terapéutica de primera elección. En este artículo de revisión examinamos la evidencia actual sobre la eficacia y seguridad de RTX como tratamiento para las vasculitis de vasos de pequeño calibre asociadas a ANCA (AU)
Since cyclophosphamide was introduced for the treatment of ANCA-associated vasculitis, the mortality of these diseases has decreased considerably. However, such treatment is related to acute and chronic serious adverse effects, which contribute to the morbidity and mortality of such diseases. Therefore, one of the main challenges in the treatment of such conditions is to find newer and effective therapies with a safer profile. Rituximab (RTX), an anti-CD20 monoclonal antibody stands at the top of new options for the treatment of ANCA-associated vasculitis, and is the strongest candidate to establish itself as a first choice therapeutic agent. Here, we review the rationale of RTX treatment in ANCA-associated small vessel vasculitis, and the current evidence of both its efficacy and toxicity (AU)
Asunto(s)
Humanos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Anticuerpos Anticitoplasma de Neutrófilos/biosíntesis , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Quimioterapia de Inducción , Antígenos CD20/inmunología , Linfocitos B , Linfocitos B/inmunología , Terapia Biológica , Estudios de Cohortes , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Susceptibilidad a Enfermedades , Resistencia a Medicamentos , Granuloma/tratamiento farmacológico , Granuloma/etiología , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Infecciones/etiología , Quimioterapia de Mantención , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Since cyclophosphamide was introduced for the treatment of ANCA-associated vasculitis, the mortality of these diseases has decreased considerably. However, such treatment is related to acute and chronic serious adverse effects, which contribute to the morbidity and mortality of such diseases. Therefore, one of the main challenges in the treatment of such conditions is to find newer and effective therapies with a safer profile. Rituximab (RTX), an anti-CD20 monoclonal antibody stands at the top of new options for the treatment of ANCA-associated vasculitis, and is the strongest candidate to establish itself as a first choice therapeutic agent. Here, we review the rationale of RTX treatment in ANCA-associated small vessel vasculitis, and the current evidence of both its efficacy and toxicity.