RESUMEN
Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.
Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Autoanticuerpos , Síndrome Post Agudo de COVID-19 , QuimiocinasRESUMEN
Efficient humoral responses rely on DNA damage, mutagenesis and error-prone DNA repair. Diversification of B cell receptors through somatic hypermutation and class-switch recombination are initiated by cytidine deamination in DNA mediated by activation-induced cytidine deaminase (AID)1 and by the subsequent excision of the resulting uracils by uracil DNA glycosylase (UNG) and by mismatch repair proteins1-3. Although uracils arising in DNA are accurately repaired1-4, how these pathways are co-opted to generate mutations and double-strand DNA breaks in the context of somatic hypermutation and class-switch recombination is unknown1-3. Here we performed a genome-wide CRISPR-Cas9 knockout screen for genes involved in class-switch recombination and identified FAM72A, a protein that interacts with the nuclear isoform of UNG (UNG2)5 and is overexpressed in several cancers5. We show that the FAM72A-UNG2 interaction controls the levels of UNG2 and that class-switch recombination is defective in Fam72a-/- B cells due to the upregulation of UNG2. Moreover, we show that somatic hypermutation is reduced in Fam72a-/- B cells and that its pattern is skewed upon upregulation of UNG2. Our results are consistent with a model in which FAM72A interacts with UNG2 to control its physiological level by triggering its degradation, regulating the level of uracil excision and thus the balance between error-prone and error-free DNA repair. Our findings have potential implications for tumorigenesis, as reduced levels of UNG2 mediated by overexpression of Fam72a would shift the balance towards mutagenic DNA repair, rendering cells more prone to acquire mutations.
Asunto(s)
Linfocitos B , Reparación de la Incompatibilidad de ADN , Cambio de Clase de Inmunoglobulina , Región de Cambio de la Inmunoglobulina , Mutación , Hipermutación Somática de Inmunoglobulina , Animales , Femenino , Masculino , Ratones , Linfocitos B/metabolismo , Sistemas CRISPR-Cas/genética , Genoma/genética , Cambio de Clase de Inmunoglobulina/genética , Región de Cambio de la Inmunoglobulina/genética , Hipermutación Somática de Inmunoglobulina/genética , Regulación hacia Arriba , Uracilo/metabolismoRESUMEN
OBJECTIVE: The objective of the study was to report our experience in a rare series of treated symptomatic slow-flow vulvar venous malformations (VVMs) using a staged, multidisciplinary approach. STUDY DESIGN: Consecutive patients with symptomatic lesions treated over a 7 year period (2005-2012) were followed up for technical success, resolution of symptoms, aesthetic outcomes, and complications. Direct endovenous sclerotherapy (DEVS) using sodium tetradecyl sulfate (STS) foam was performed in all patients under ultrasound and contrast-enhanced fluoroscopic guidance. Surgical excision and layered primary closure was performed within 24 hours after the last DEVS session. RESULTS: Eleven patients (mean age, 25 years; range, 4-43 years) were treated. Presenting symptoms included pain (n = 11), soft tissue swelling (n = 11), local heaviness (n = 11), dyspareunia (n = 2), and dysmenorrhea (n = 2). Most were isolated lesions (n = 8). There were 2 cases of Klippel-Trénaunay syndrome and 1 case of Maffucci syndrome. The latter required Nd:YAG laser photocoagulation prior to sclerotherapy. On average, approximately 3 DEVS sessions were required prior to surgical excision (range, 1-6). Mean estimated surgical blood loss was 130 mL (range, 20-400 mL). Mean follow-up was 23 months (range, 3-55 months). Elimination of pain and soft tissue redundancy was achieved in all patients with satisfactory aesthetic outcomes. All patients experienced minor pain and swelling after DEVS. Following surgical excision, there was 1 case of hematoma and wound dehiscence requiring surgical evacuation. No other reinterventions, endovascular or surgical, were required. CONCLUSION: VVMs require increased awareness and appropriate preoperative evaluation for proper identification and treatment. A multidisciplinary approach can provide improvement in clinical signs and symptoms with satisfactory cosmesis and minimal complications.
Asunto(s)
Procedimientos Endovasculares , Soluciones Esclerosantes/uso terapéutico , Escleroterapia/métodos , Tetradecil Sulfato de Sodio/uso terapéutico , Malformaciones Vasculares/terapia , Vulva/cirugía , Enfermedades de la Vulva/terapia , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/cirugía , Venas/anomalías , Venas/cirugía , Vulva/irrigación sanguínea , Enfermedades de la Vulva/diagnóstico , Enfermedades de la Vulva/cirugía , Adulto JovenRESUMEN
Infection by SARS-CoV-2 leads to diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse COVID-19 outcomes. Instead, we discovered that antibodies against specific chemokines are omnipresent after COVID-19, associated with favorable disease, and predictive of lack of long COVID symptoms at one year post infection. Anti-chemokine antibodies are present also in HIV-1 infection and autoimmune disorders, but they target different chemokines than those in COVID-19. Monoclonal antibodies derived from COVID- 19 convalescents that bind to the chemokine N-loop impair cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising anti-chemokine antibodies associated with favorable COVID-19 may be beneficial by modulating the inflammatory response and thus bear therapeutic potential. One-Sentence Summary: Naturally arising anti-chemokine antibodies associate with favorable COVID-19 and predict lack of long COVID.
RESUMEN
The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome.