ABSTRACT
Resumen Los autoanticuerpos anticitocinas (ACAA) han sido reportados como causa importante de inmunodeficiencias secundarias. Altos títulos de autoanticuerpos neutralizantes pueden causar susceptibilidad a diferentes enfermedades infecciosas potencialmente mortales. Por ejemplo, se ha informado que autoanticuerpos neutralizantes contra IFNγ se correlacionan con susceptibilidad a infecciones micobacterianas y patógenos fúngicos intracelulares. Autoanticuerpos contra IL-6 se detectaron en pacientes con abscesos subcutáneos y celulitis estafilocócica recurrente; asimismo, pacientes con criptococosis, nocardiosis y proteinosis alveolar pulmonar fueron positivos a autoanticuerpos contra GM-CSF. También se ha establecido una relación entre los autoanticuerpos contra IL-17 e IL-22 y las infecciones crónicas por Candida en mucosas, que se han identificado en pacientes con poliendocrinopatía autoinmune tipo 1 o timoma. Recientemente se han reportado autoanticuerpos contra interferón tipo I durante el inicio de COVID-19 aguda. Estos ACAA se asemejan a defectos genéticos en citocinas o en sus rutas de señalización. Por ello, pueden considerarse fenocopias de inmunodeficiencias primarias. De esta forma, la detección de ACAA podría ser importante en el diagnóstico, particularmente en pacientes con enfermedades de aparición tardía, para decidir los tratamientos apropiados. Esta revisión presenta una descripción general de la comprensión actual de las inmunodeficiencias secundarias asociadas a ACAA.
Abstract Anti-cytokine autoantibodies (ACAA) have been reported to be an important cause of secondary immunodeficiencies. High titers of neutralizing autoantibodies may cause susceptibility to different life-threatening infectious diseases. For example, neutralizing autoantibodies against IFNγ have been reported to be correlated with susceptibility to mycobacterial infections and intracellular fungal pathogens. Autoantibodies against IL-6 were detected in patients with subcutaneous abscesses and recurrent staphylococcal cellulitis; on the other hand, patients with cryptococcosis, nocardiosis, and pulmonary alveolar proteinosis were positive for autoantibodies to GM-CSF. A relationship has also been established between autoantibodies against IL-17 and IL-22 and chronic mucosal Candida infections, which have been identified in patients with APECED or thymoma. Autoantibodies against type-I IFN have been recently reported during the onset of acute COVID-19. These ACAAs resemble genetic defects in cytokines or their signaling pathways. Therefore, they may be considered to be primary immunodeficiencies phenocopies. Consequently, the detection of ACAA could be important in the diagnosis of patients, particularly in the case of late-onset diseases, in order to decide appropriate treatments. This review presents an overview of current understanding of ACAA-associated secondary immunodeficiencies.
ABSTRACT
Objective To explore whether the IL-6/STAT3 signaling pathway regulate the expression of high mobility group proteins1 (HMGB1) in intestinal mucosa of rats with sepsis through the cecum ligation puncture (CLP). Methods One hundred and twenty male SD rats were randomly(random number) divided into three groups: sham operation group (group S, n=40), CLP group(group C, n=40) and anti-IL-6 monoclonal antibody group (group T, n=40). Rats in group S only received the simple laparotomy;Rats in group C and group T were established as a rat model of sepsis using CLP; rats in group T received the intraperitoneal injection of anti-IL-6 monoclonal antibody at 1 h after CLP, while the same volume of sodium lactate ringer's solution was injected to rats in group S and group C. Ten rats in each group were sacrificed at 3, 12, 24 and 48 h, respectively, and intestinal mucosa specimens were collected for pathological examinations by HE staining. The protein expression of HMGB1 and IL-6 were detected by immunohistochemistry, STAT3-protein by Western blot.and the levels of diamine oxidase (DAO) and D lactic acid in plasma by spectrophotometric. Results Rats in group C and group T showed obvious intestinal damage to different degrees, significantly higher intestinal mucosa pathological scores and plasma levels of DAO and D-lactic acid compared with rats in group S (P<0.05). The protein expression of IL-6, HMGBl and p-STAT3 of intestinal mucosa in group C and group T also significantly increased compared with that in group S (P<0.05). The intestinal mucosa pathological score, plasma levels of DAO and D-lactic acid and protein expression of IL-6, HMGBl and STAT3 were decreased in group T compared with those in group C (P<0.05). The intestinal mucosa pathological scores were positively correlated with the protein expression of IL-6 and HMGB1 at 12, 24, and 48 h, respectively. Conclusions IL-6 and HMGBl were involved in the intestinal injury of septic rats. IL-6/STAT3 signaling pathway could up-regulate the expression of HMGB1 in intestinal mucosa of septic rats.
ABSTRACT
Objective:To analyse the biological function of anti-IL-6Rβ(gp130) monoclonal antibody and its regulatory effect on IL-6 signaling.Methods:Biological characteristics of anti-IL-6Rβ(gp130) mAb were assessed by Western blot analysis, capture ELISA and peptide ELISA .The phosphorylation of STAT 3 was tested by Western blot analysis in IL-6-stimulated U266/RA-FLS/RA-PBMC with or without anti-IL-6Rβ(gp130) mAb treatment.Results:3 strains of mouse anti-human gp130 mAb were with high affini-ty and different binding epitopes , the kaff of 10A1 was 2.62E-10.In U266, RA-PBMC and RA-SFMC, IL-6 signaling highly activated STAT3 which could be inhibited by anti-gp130 mAb.Conclusion: Anti-IL-6Rβ( gp130 ) mAb might have different binding epitopes and could affect IL-6 stimulated phosphorylation of STAT3, which provides a preliminary experiment for analyse the correlation of IL-6 signaling and RA .