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.

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 Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies.

1976 ◽  
Vol 144 (3) ◽  
pp. 739-753 ◽  
Author(s):  
J M Lindstrom ◽  
A G Engel ◽  
M E Seybold ◽  
V A Lennon ◽  
E H Lambert
Keyword(s):  
Myasthenia Gravis ◽  
Nerve Stimulation ◽  
Neuromuscular Transmission ◽  
Postsynaptic Membrane ◽  
Passive Transfer ◽  
Autoimmune Response ◽  
End Plate ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune

Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.

scholarly journals Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation

2013 ◽  
Vol 211 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Radhika Goenka ◽  
Andrew H. Matthews ◽  
Bochao Zhang ◽  
Patrick J. O’Neill ◽  
Jean L. Scholz ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Local Source ◽  
High Affinity ◽  
Cell Clones ◽  
B Lymphocyte Stimulator ◽  
Efficient Selection

We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21–mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell–derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.

scholarly journals Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs.

1975 ◽  
Vol 141 (6) ◽  
pp. 1365-1375 ◽  
Author(s):  
V A Lennon ◽  
J M Lindstrom ◽  
M E Seybold
Keyword(s):  
Myasthenia Gravis ◽  
Guinea Pigs ◽  
Autoimmune Response ◽  
Mammalian Skeletal Muscle ◽  
Electrophorus Electricus ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Electric Organs ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune ◽  
Experimental Disease

Immunization of animals with acetylcholine receptor (AChR) protein from the electric organs of Electrophorus electricus and Torpedo californica induces an autoimmune response to the AChR of mammalian skeletal muscle. Rats and guinea pigs develop experimental autoimmune myasthenia gravis (EAMG) after a single inoculation with small quantities of AChR and adjuvant. The indicence and severity of disease appears to depend on the dose of AChR and stability of the emulsion. EAMG is strikingly similar to myasthenia gravis (MG) of man in its clinical picture and its electrophysiological abnormalities. The presence of antibodies to syngeneic rat muscle AChR in the serum of rats with EAMG documents the existence of autoimmunity in the experimental disease. A common immunopathogenesis is suggested for both EAMG and mg.

scholarly journals Somatic Hypermutation Shapes the Antibody Repertoire of Memory B Cells in Humans

2001 ◽  
Vol 194 (3) ◽  
pp. 375-378 ◽  
Author(s):  
Eric Meffre ◽  
Nadia Catalan ◽  
Françoise Seltz ◽  
Alain Fischer ◽  
Michel C. Nussenzweig ◽  
...  
Keyword(s):  
B Cells ◽  
Significant Contribution ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Antibody Repertoire ◽  
Lambda Light Chain ◽  
High Affinity ◽  
Activation Induced Cytidine Deaminase

High-affinity antibodies produced by memory B cells differ from antibodies produced in naive B cells in two respects. First, many of these antibodies show somatic hypermutation, and second, the repertoire of antibodies expressed in memory responses is highly selected. To determine whether somatic hypermutation is responsible for the shift in the antibody repertoire during affinity maturation, we analyzed the immunoglobulin lambda light chain (Igλ) repertoire expressed by naive and antigen-selected memory B cells in humans. We found that the Igλ repertoire differs between naive and memory B cells and that this shift in the repertoire does not occur in the absence of somatic hypermutation in patients lacking activation-induced cytidine deaminase (AID). Our work suggests that somatic hypermutation makes a significant contribution to shaping the antigen-selected antibody repertoire in humans.

scholarly journals Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci

2004 ◽  
Vol 5 (5) ◽  
pp. 398-404 ◽  
Author(s):  
M Giraud ◽  
G Beaurain ◽  
B Eymard ◽  
C Tranchant ◽  
P Gajdos ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Genetic Control ◽  
The Self ◽  
Autoimmune Myasthenia ◽  
Self Antigen

scholarly journals Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis.

1976 ◽  
Vol 144 (3) ◽  
pp. 726-738 ◽  
Author(s):  
J M Lindstrom ◽  
B L Einarson ◽  
V A Lennon ◽  
M E Seybold
Keyword(s):  
Myasthenia Gravis ◽  
Acetylcholine Receptor ◽  
Neuromuscular Transmission ◽  
Clinical Signs ◽  
Autoimmune Response ◽  
Receptor Complexes ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Autoimmune Myasthenia ◽  
Alpha Bungarotoxin ◽  
Experimental Autoimmune

Immunization of Lewis rats with acetylcholine receptor (AChR) purified from either Electrophorus electricus electric organ or syngeneic rat muscle induced experimental autoimmune myasthenia gravis (EAMG). This was demonstrated by clinical signs of weakness and by electromyographic evidence of imparied neuromuscular transmission. The amount of rat AChR required to induce an autoimmune response was comparable to the amount of eel AChR required. In vitro complexing of rat AChrR with antibody reduced its immunogenicity. Autoantibody to muscle AChR was present in serum and complexed with AChR in muscle. Antibody was not bound to the ACh binding site of AChR, since antibody-AChR complexes extracted from muscle could still bind 125I-alpha-bungarotoxin. The amount of AChR extracted from muscle of rats with EAMG was diminished. The amount of AChR and antibody-AChR complexes in muscle was measured at intervals after immunization with eel AChR. The amount of AChR decreased in rats with acute EAMG, then transiently increased to more than normal amounts during remission, and finally decreased to only about 20% of normal in rats with chronic EAMG. At least half of the AChR remaining in animals with chronic EAMG was complexed with antibody. Thus, both a decrease in amount of AChR and the formation of antibody-AChR complexes contribute to impairment of neuromuscular transmission in rats with EAMG. The possible mechanisms involved in the changes in AChR content are discussed.

Effects of Heparin Oligosaccharides with High Affinity for Antithrombin III in Experimental Venous Thrombosis

1982 ◽  
Vol 47 (03) ◽  
pp. 244-248 ◽  
Author(s):  
D P Thomas ◽  
Rosemary E Merton ◽  
T W Barrowcliffe ◽  
L Thunberg ◽  
U Lindahl
Keyword(s):  
Antithrombin Iii ◽  
Specific Activity ◽  
High Specific Activity ◽  
Factor Xa ◽  
Blood Levels ◽  
Thrombin Time ◽  
High Affinity ◽  
Very High

SummaryThe in vitro and in vivo characteristics of two oligosaccharide heparin fragments have been compared to those of unfractionated mucosal heparin. A decasaccharide fragment had essentially no activity by APTT or calcium thrombin time assays in vitro, but possessed very high specific activity by anti-Factor Xa assays. When injected into rabbits at doses of up to 80 ¼g/kg, this fragment was relatively ineffective in impairing stasis thrombosis despite producing high blood levels by anti-Xa assays. A 16-18 monosaccharide fragment had even higher specific activity (almost 2000 iu/mg) by chromogenic substrate anti-Xa assay, with minimal activity by APTT. When injected in vivo, this fragment gave low blood levels by APTT, very high anti-Xa levels, and was more effective in preventing thrombosis than the decasaccharide fragment. However, in comparison with unfractionated heparin, the 16-18 monosaccharide fragment was only partially effective in preventing thrombosis, despite producing much higher blood levels by anti-Xa assays.It is concluded that the high-affinity binding of a heparin fragment to antithrombin III does not by itself impair venous thrombogenesis, and that the anti-Factor Xa activity of heparin is only a partial expression of its therapeutic potential.

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