scholarly journals Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Miriam L. Fichtner ◽  
Casey Vieni ◽  
Rachel L. Redler ◽  
Ljuvica Kolich ◽  
Ruoyi Jiang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Myasthenia Gravis ◽  
Crystal Structures ◽  
Binding Affinity ◽  
Somatic Mutations ◽  
Affinity Maturation ◽  
Antigen Binding ◽  
High Affinity ◽  
Specific Igg4 ◽  
Autoimmune Myasthenia

Pathogenic muscle-specific tyrosine kinase (MuSK)–specific IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The development of these unique autoantibodies is not well understood. We examined MG patient–derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCAs), and monovalent antigen-binding fragments (Fabs) to investigate how affinity maturation contributes to binding and immunopathology. Mature mAbs, UCA mAbs, and mature monovalent Fabs bound to MuSK and demonstrated pathogenic capacity. However, monovalent UCA Fabs bound to MuSK but did not have measurable pathogenic capacity. Affinity of the UCA Fabs for MuSK was 100-fold lower than the subnanomolar affinity of the mature Fabs. Crystal structures of two Fabs revealed how mutations acquired during affinity maturation may contribute to increased MuSK-binding affinity. These findings indicate that the autoantigen drives autoimmunity in MuSK MG through the accumulation of somatic mutations such that monovalent IgG4 Fab-arm–exchanged autoantibodies reach a high-affinity threshold required for pathogenic capacity.

scholarly journals Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

2020 ◽  
Author(s):  
Miriam L. Fichtner ◽  
Casey Vieni ◽  
Rachel L. Redler ◽  
Ljuvica Kolich ◽  
Ruoyi Jiang ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Electrostatic Interactions ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Autoimmune Response ◽  
High Affinity ◽  
Autoimmune Myasthenia ◽  
Self Antigen ◽  
Very High ◽  
Shed Light

AbstractPathogenic IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The origin and development of these unique autoantibodies are not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCA) and monovalent antigen-binding fragments (Fabs) to investigate how antigen-driven affinity maturation contributes to both binding and immunopathology. Mature mAbs, their UCA counterparts and mature monovalent Fabs bound to the autoantigen and retained their pathogenic capacity. However, monovalent UCA Fabs still bound the autoantigen but lost their pathogenic capacity. The mature Fabs were characterized by very high affinity (sub-nanomolar) driven by a rapid on-rate and slow off-rate. However, the UCA affinity was approximately 100-fold less than that of the mature Fabs, which was driven by a rapid off-rate. Crystal structures of two Fabs shed light on how mutations acquired during affinity maturation may contribute to increased MuSK binding affinity. These collective findings indicate that the autoantigen initiates the autoimmune response in MuSK MG and drives autoimmunity through the accumulation of somatic hypermutation such that monovalent IgG4 Fab-arm exchanged MG autoantibodies reach a high affinity threshold required for pathogenic capacity.SummaryIgG4 autoantibodies in autoimmune myasthenia gravis are functionally monovalent, requiring a high affinity threshold featuring fast on/slow off rates, to reach pathogenic capacity. This capacity is dependent on self-antigen initiated and driven maturation, which includes the accumulation of indispensable somatic hypermutations that may alter electrostatic interactions with the antigen.

Muscle-Specific Kinase Autoimmune Myasthenia Gravis: Report of a Pediatric Case and Literature Review

2018 ◽  
Vol 50 (02) ◽  
pp. 116-121
Author(s):  
Hanene Benrhouma ◽  
Hedia Klaa ◽  
Rania Ben Aoun ◽  
Aida Rouissi ◽  
Melika Ben Ahmed ◽  
...  
Keyword(s):  
Literature Review ◽  
Tyrosine Kinase ◽  
Myasthenia Gravis ◽  
Clinical Presentation ◽  
Clinical Course ◽  
Rare Entity ◽  
Pediatric Case ◽  
Axial Muscles ◽  
Autoimmune Myasthenia ◽  
Muscle Specific Kinase

AbstractMyasthenia gravis (MG) with antibodies to the muscle-specific tyrosine kinase (MuSK-MG) receptor is a rare entity. It represents 5 to 8% of all MG patients. Few pediatric cases were reported. Clinical presentation is often atypical. It is characterized by predominant involvement of cranial, bulbar, and axial muscles and early respiratory crises. Myokymia and fasciculation are suggestive of MuSK-MG. The clinical course of patients with MuSK-MG is worse than other types of MG. Responses to standard therapies are variable. We report clinical, neurophysiological, serological, and outcome profile of a Tunisian child with MuSK-MG.

Structural Requirements of the Major Protective Antibody to Haemophilus influenzae Type b

1999 ◽  
Vol 67 (5) ◽  
pp. 2503-2514 ◽  
Author(s):  
Lotte Hougs ◽  
Lars Juul ◽  
Arne Svejgaard ◽  
Torben Barington
Keyword(s):  
Haemophilus Influenzae ◽  
Somatic Mutations ◽  
Affinity Maturation ◽  
Dimensional Structure ◽  
Haemophilus Influenzae Type ◽  
Antigen Binding ◽  
Immunoglobulin Gene ◽  
Type B

ABSTRACT Protective antibodies to the important childhood pathogenHaemophilus influenzae type b (Hib) are directed against the capsular polysaccharide (HibCP). Most of the antibody is encoded by a well-defined set of (“canonical”) immunoglobulin genes, including the Vκ A2 gene, and expresses an idiotypic marker (HibId-1). In comparison to noncanonical antibodies, the canonical antibody is generally of higher avidity, shows higher levels of in vitro bactericidal activity, and is more protective in infant rats. Using site-directed mutagenesis, we here characterize canonical HibCP antibodies expressed as antigen-binding fragments (Fabs) in Escherichia coli, define amino acids involved in antigen binding and idiotype expression, and propose a three-dimensional structure for the variable domains. We found that canonical Fabs, unlike a noncanonical Fab, bound effectively to HibCP in the absence of somatic mutations. Nevertheless, pronounced mutation-based affinity maturation was demonstrated in vivo. An almost perfect correlation was found between unmutated gene segments that mediated binding in vitro and those encoding canonical HibCP antibodies in vivo. Thus, the Vκ A2a gene could be replaced by the A2c gene but not by the highly homologous sister gene, A18b, corresponding to the demonstrated usage of A2c but not of A18b in vivo. Similarly, only Jκ1 and Jκ3, which predominate in the response in vivo, were able to facilitate binding in vitro. These findings suggest that the restricted immunoglobulin gene usage in HibCP antibodies reflects strict structural demands ensuring relatively high affinity prior to somatic mutations—requirements met by only a limited spectrum of immunoglobulin gene combinations.

Role of antibody heavy and light chain interface residues in affinity maturation of binding to HIV envelope glycoprotein

2019 ◽  
Vol 4 (4) ◽  
pp. 737-746 ◽  
Author(s):  
Alberto Cisneros ◽  
Rachel Stecker Nargi ◽  
Erica Hammaker Parrish ◽  
Christian Marie Haliburton ◽  
Jens Meiler ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Heavy Chain ◽  
Light Chain ◽  
Envelope Glycoprotein ◽  
Affinity Maturation ◽  
Antigen Binding ◽  
Glycoprotein P ◽  
Contact Residues ◽  
Hiv Envelope

Optimization of the heavy chain/light chain interface could serve as an important tool for maximizing antibody/antigen binding affinity without altering antigen contact residues.

scholarly journals The repertoire of somatic antibody mutants accumulating in the memory compartment after primary immunization is restricted through affinity maturation and mirrors that expressed in the secondary response.

1990 ◽  
Vol 172 (6) ◽  
pp. 1681-1689 ◽  
Author(s):  
U Weiss ◽  
K Rajewsky
Keyword(s):  
B Cells ◽  
Genomic Dna ◽  
Gamma Globulin ◽  
Affinity Maturation ◽  
Secondary Response ◽  
Antigen Binding ◽  
Memory Cells ◽  
Primary Immunization ◽  
High Affinity ◽  
Vh Gene

The anti-(4-hydroxy-3-nitro-phenyl)acetyl (NP) response is dominated by lambda 1 chain-bearing antibodies expressing the VH gene V186.2 in combination with the D element DFL16.1. lambda 1-positive B cells were isolated from the spleens of mice immunized with NP-chicken gamma globulin 6 wk earlier. Rearranged V186.2 genes were amplified from the genomic DNA of these cells and sequenced. In cases where the rearrangement was typical for secondary anti-NP antibodies, the VHDJH sequences were generally heavily mutated. The frequency and the nature of the nucleotide exchanges mirrored those of secondary response antibodies. V186.2 genes with other rearrangements and V186.2-related genes isolated concomitantly were essentially unmutated. These results demonstrate: (a) that somatic antibody mutants are largely restricted to a small compartment of peripheral B cells, namely, that of memory cells; (b) that the memory compartment is strongly selected for high affinity precursors and largely purged from antigen-binding loss mutants; and (c) that the repertoire of binding specificities expressed in the secondary response is established in its final form before secondary immunization.

404: MuSK (muscle specific tyrosine kinase) seropositive and seronegative autoimmune myasthenia gravis in Australasia

2007 ◽  
Vol 14 (10) ◽  
pp. 1015
Author(s):  
Matthew J. Thurtell ◽  
Jayamala Parmar ◽  
Garth A. Nicholson ◽  
Stephen W. Reddel
Keyword(s):  
Tyrosine Kinase ◽  
Myasthenia Gravis ◽  
Autoimmune Myasthenia

The Role of the Initiator System in the Synthesis of Acidic Multifunctional Nanoparticles Designed for Molecular Imprinting of Proteins

2020 ◽  
Vol 65 (1) ◽  
pp. 28-41
Author(s):  
Marwa Aly Ahmed ◽  
Júlia Erdőssy ◽  
Viola Horváth
Keyword(s):  
Acrylic Acid ◽  
Binding Affinity ◽  
Molecular Imprinting ◽  
Low Temperatures ◽  
Ammonium Persulfate ◽  
Sodium Bisulfite ◽  
Multifunctional Nanoparticles ◽  
High Affinity ◽  
Initiator System

Multifunctional nanoparticles have been shown earlier to bind certain proteins with high affinity and the binding affinity could be enhanced by molecular imprinting of the target protein. In this work different initiator systems were used and compared during the synthesis of poly (N-isopropylacrylamide-co-acrylic acid-co-N-tert-butylacrylamide) nanoparticles with respect to their future applicability in molecular imprinting of lysozyme. The decomposition of ammonium persulfate initiator was initiated either thermally at 60 °C or by using redox activators, namely tetramethylethylenediamine or sodium bisulfite at low temperatures. Morphology differences in the resulting nanoparticles have been revealed using scanning electron microscopy and dynamic light scattering. During polymerization the conversion of each monomer was followed in time. Striking differences were demonstrated in the incorporation rate of acrylic acid between the tetramethylethylenediamine catalyzed initiation and the other systems. This led to a completely different nanoparticle microstructure the consequence of which was the distinctly lower lysozyme binding affinity. On the contrary, the use of sodium bisulfite activation resulted in similar nanoparticle structural homogeneity and protein binding affinity as the thermal initiation.

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