heavy chain gene
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2021 ◽  
Author(s):  
Felipe Andrade ◽  
Yikai Yu ◽  
Eduardo Gomez-Banuelos ◽  
Jessica Li ◽  
Kevin S. Cashman ◽  
...  

DNase1L3 deficiency is an inborn error of immunity that causes monogenic systemic lupus erythematosus (SLE) in humans. Here, we identified that one third of patients with sporadic SLE have antibodies to DNase1L3. Like DNase1L3 deficiency, we found that patients with anti-DNase1L3 antibodies have features associated with immune pathways activated by immunogenic self-DNA, including elevated antibodies to dsDNA and prominent expression of the interferon and myeloid/neutrophil signatures. Interestingly, 40-80% of anti-DNase1L3 antibodies in SLE serum contain the 9G4 idiotype, which is encoded by the autoreactive heavy-chain gene segment VH4-34. Sequence and functional analysis of four anti-DNase1L3 monoclonal antibodies generated from SLE patients experiencing disease-associated flares showed that these antibodies were derived from self-reactive 9G4+ switched memory B cells. These antibodies are highly enriched in somatic hypermutations, indicating that they originated from antigen-experienced cells, and have neutralizing activity against DNase1L3. Together, the data demonstrate that autoantibodies to DNase1L3 phenocopy pathogenic mechanisms associated with DNase1L3 deficiency. Moreover, the finding that autoreactive B cells bearing the 9G4 idiotype produce dominant serum autoantibodies, including antibodies to DNase1L3, underscores VH4-34+ B cells as sensible therapeutic targets for specific depletion of pathogenic B cells in SLE.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bei Zhang ◽  
Bingyang Bian ◽  
Zhiwei Zhao ◽  
Fang Lin ◽  
Zining Zhu ◽  
...  

Abstract Background Whole-body diffusion-weighted imaging (WB-DWI) is a method for evaluating bone marrow infiltration in multiple myeloma (MM). This study seeks to elucidate the correlation between the apparent diffusion coefficient (ADC) value and some selected clinical parameters. Methods A total of 101 Chinese patients with MM who had undergone WB-DWI from May 2017 to May 2019 were enrolled in this study. The ADC values of the MM lesions and the clinical parameters were quantified at the first (baseline) visit and after four-course induction chemotherapy. Multiple linear regression and logistic analyses were carried out to find the implicit inherent relationships within the patients’ data. Results The paired Wilcoxon test showed that the ADC values at the baseline visit (ADC0) were significantly lower than the values after four-course induction chemotherapy (ADC4 c) (p < 0.001), including different therapeutic responses. The Revised International Staging System (RISS) stage, type of MM, and β2-microglobulin (β2-MG) were predictors of clinically significant increases or decreases in the ADC values (p < 0.05). Multiple linear regression showed that the ADC0 was negatively associated with β2-MG (p < 0.001) and immunoglobulin heavy chain gene rearrangement (p = 0.012), while the RISS Stage III (p = 0.001), type IgG λ (p = 0.005), and albumin were negatively associated with ADC4 c (p = 0.010). The impacts of the therapeutic response were associated with ADC0 and immunoglobulin heavy chain gene rearrangement (p < 0.001). Conclusion The ADC values of WB-DWI may be associated with clinical parameters of MM including the fluorescence in situ hybridization result, and may be useful in the prognosis of patients with MM. Trial Registration: ChiCTR2000029587


2020 ◽  
Vol 22 (4) ◽  
pp. 155-158
Author(s):  
Elham Ghorbani Jazar ◽  
Seyedeh Parisa Chavoshi Tarzjani ◽  
Zahra Sadeghi ◽  
Shekoofe Alaie ◽  
Seyed Abolhassan Shahzadeh Fazeli

Multiple sclerosis (MS) is a chronic disease characterized by degeneration of the central nervous system (CNS). High levels of Neurofilament heavy chain (NEFH) in cerebrospinal fluid (CSF) is associated with MS. 40 MS patients and 40 controls genotyped by polymerase chain reaction (PCR) and Sanger sequencing. Genotypic and allelic distributions were compared between cases and controls. Fisher test was used to estimate the risk of MS associated with genotypes. We showed that NEFH, 1084-244G>A gene polymorphism, has no significant association with the susceptibility or severity of MS in Iranian patients (P = 0.737). Further prospective studies are required for confirmation.


2020 ◽  
Vol 319 (6) ◽  
pp. L1048-L1060
Author(s):  
Amelia Shoemark ◽  
Andreia L. Pinto ◽  
Mitali P. Patel ◽  
Farheen Daudvohra ◽  
Claire Hogg ◽  
...  

Primary ciliary dyskinesia (PCD) is an inherited disorder of the motile cilia. Early accurate diagnosis is important to help prevent lung damage in childhood and to preserve lung function. Confirmation of a diagnosis traditionally relied on assessment of ciliary ultrastructure by transmission electron microscopy (TEM); however, >50 known PCD genes have made the identification of biallelic mutations a viable alternative to confirm diagnosis. TEM and genotyping lack sensitivity, and research to improve accuracy of both is required. TEM can be challenging when a subtle or partial ciliary defect is present or affected cilia structures are difficult to identify due to poor contrast. Here, we demonstrate software to enhance TEM ciliary images and reduce background by averaging ciliary features. This includes an option to classify features into groups based on their appearance, to generate multiple averages when a nonhomogeneous abnormality is present. We validated this software on images taken from subjects with well-characterized PCD caused by variants in the outer dynein arm (ODA) heavy chain gene DNAH5. Examining more difficult to diagnose cases, we detected 1) regionally restricted absence of the ODAs away from the ciliary base, in a subject carrying mutations in DNAH9; 2) loss of the typically poorly contrasted inner dynein arms; and 3) sporadic absence of part of the central pair complex in subjects carrying mutations in HYDIN, including one case with an unverified genetic diagnosis. We show that this easy-to-use software can assist in detailing relationships between genotype and ultrastructural phenotype, improving diagnosis of PCD.


2020 ◽  
Author(s):  
Bei Zhang ◽  
Bingyang Bian ◽  
Zhiwei Zhao ◽  
Fang Lin ◽  
Zining Zhu ◽  
...  

Abstract PURPOSE: Whole-body diffusion-weighted imaging (WB-DWI) is a method for evaluating bone marrow infiltration in multiple myeloma (MM). This study seeks to elucidate the correlation between the apparent diffusion coefficient (ADC) value and some selected clinical parameters. MATERIALS AND METHODS: 101 Chinese patients with MM who had undergone WB-DWI from May 2017 to May 2019 were enrolled in this study. The ADC values of the MM lesions and the clinical parameters were quantified at the first (baseline) visit and after four-course induction chemotherapy. Multiple linear regression and logistic analyses were carried out to find the implicit inherent relationships within the patients’ data.RESULTS: The paired Wilcoxon test showed that the ADC values at the baseline visit (ADC0) were significantly lower than the values after four-course induction chemotherapy (ADC4 c) (p < 0.001), including different therapeutic responses. The Revised International Staging System (RISS) stage, type of MM, and β2-microglobulin (β2-MG) were predictors of clinically significant increases or decreases in the ADC values (p< 0.05). Multiple linear regression showed that the ADC0 was negatively associated with β2-MG (p < 0.001) and immunoglobulin heavy chain gene rearrangement (p = 0.012), while the RISS Stage Ⅲ (p = 0.001), type IgG λ (p = 0.005), and albumin were negatively associated with ADC4 c (p = 0.010). The impacts of the therapeutic response were associated with ADC0 and immunoglobulin heavy chain gene rearrangement (p < 0.001).CONCLUSION: The ADC values of WB-DWI may be associated with clinical parameters of MM including the fluorescence in situ hybridization (FISH) result, and may be useful in the prognosis of patients with MM.TRIAL REGISTRATION: ChiCTR2000029587


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