Crystal Structure of a Human Autoimmune Complex between IgM Rheumatoid Factor RF61 and IgG1 Fc Reveals a Novel Epitope and Evidence for Affinity Maturation

Duquerroy, S.; Stura, E.A.; Bressanelli, Stéphane; Fabiane, Stella M.; Vaney, M.C.; Beale, D.; Hamon, M.; Casali, Paolo; Rey, F.A.; Sutton, Brian J.; Taussig, Michael J.

doi:10.1016/j.jmb.2007.02.085

Cited by 62 publications

(56 citation statements)

References 36 publications

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“…These interpretations and conclusions are confirmed in other X-ray structures obtained for human IgG-Fc alone (Harris, et al, 1997;Saphire, et al, 2002;Matsumiya et al, 2007) and in complex with Staphylococcal protein A (SpA) (Deisenhofer, 1981), Streptococcal protein G (SpG) (Sauer-Eriksson et al, 1995), rheumatoid factor (RF) (Duquerroy et al, 2007;Sohi et al, 1996;Corper, et al, 1997) and human FcγRIIIb (Sondermann et al, 2000;. The internal mobility of the lower hinge and hinge proximal regions of the CH2 domains ("softness of structure) may result in the generation of an equilibrium of high order conformers that may differentially bind unique ligands, e.g.…”

Section: Quaternary Structure Of Igg-fc: the Protein Moietysupporting

confidence: 62%

“…the neonatal Fc receptor (FcRn), RF, SpA, SpG (Woof and Burton, 2004;Nezlin and Ghetie, 2004;Jefferis, 2009;Deisenhofer, 1981;SauerEriksson et al, 1995;West, et al, 2000;Matsumiya et al, 2007;Duquerroy et al, 2007;Sohi et al, 1996;Corper, et al, 1997), Figure 2. Due to the symmetry of the IgG-Fc these interaction sites are at ~180 o to each other and each is accessible to bind macromolecular ligands to form multimeric complexes.…”

Section: Quaternary Structure Of Igg-fc: the Protein Moietymentioning

confidence: 99%

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The antibody paradigm: present and future development as a scaffold for biopharmaceutical drugs

Jefferis

2009

Biotechnology and Genetic Engineering Reviews

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Early studies of the humoral immune response revealed an apparent paradox: an infinite diversity of antibody specificities encoded within a finite genome. In consequence antibodies became a focus of interest for biochemists and geneticists. It resulted in the elucidation of the basic structural unit, the immunoglobulin (Ig) domain, comprised of ~ 100 amino acid residues that generate the characteristic "immunoglobulin (Ig) fold". The Ig fold has an anti-parallel ß-pleated sheet (barrel) structure that affords structural stability whilst the ß-bends allow for essentially infinite structural variation and functional diversity. This versatility is reflected in the Ig domain being the most widely utilised structural unit within the proteome. Human antibodies are comprised of multiple Ig domains and their structural diversity may be enhanced through the attachment of oligosaccharides. This review summarizes our current understanding of the immunoglobulin structure/function relationships and the application of protein and oligosaccharide engineering to further develop the Ig domain as a scaffold for the generation of new and novel antibody based therapeutics.Biotechnology and Genetic Engineering Reviews -Vol. 26, 1-42 (2009) Early studies of the humoral immune response revealed an apparent paradox: an infinite diversity of antibody specificities encoded within a finite genome. In consequence antibodies became a focus of interest for biochemists and geneticists. It resulted in the elucidation of the basic structural unit, the immunoglobulin (Ig) domain, comprised of 100 amino acid residues that generate the characteristic "immunoglobulin (Ig) fold". The Ig fold has an anti-parallel 13-pleated sheet (barrel) structure that affords structural stability whilst the 13-bends allow for essentially infinite structural variation and functional diversity. This versatility is reflected in the Ig domain being the most widely utilised structural unit within the proteome. Human antibodies are comprised of multiple Ig domains and their structural diversity may be enhanced through the attachment of oligosaccharides. This review summarizes our current understanding of the immunoglobulin structure/function relationships and the application of protein and oligosaccharide engineering to further develop the Ig domain as a scaffold for the generation of new and novel antibody based therapeutics. Early studies of the humoral immune response revealed an apparent paradox: an infinite diversity of antibody specificities encoded within a finite genome. In consequence antibodies became a focus of interest for biochemists and geneticists. It resulted in the elucidation of the basic structural unit, the immunoglobulin (Ig) domain, comprised of 100 amino acid residues that generate the characteristic "immunoglobulin (Ig) fold". The Ig fold has an anti-parallel 13-pleated sheet (barrel) structure that affords structural stability whilst the 13-bends allow for essentially infinite structural variation and functional diversity. This versat...

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Section: Quaternary Structure Of Igg-fc: the Protein Moietysupporting

confidence: 62%

Section: Quaternary Structure Of Igg-fc: the Protein Moietymentioning

confidence: 99%

The antibody paradigm: present and future development as a scaffold for biopharmaceutical drugs

Jefferis

2009

Biotechnology and Genetic Engineering Reviews

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“…Although interaction sites on human IgGs for FcgRs are primarily situated in their lower hinge region, residues in the Cg2 domain are also involved in the interaction (43). RF is known to interact with epitopes located at the Cg2/Cg3 interface, but variations in the antigenic specificity have been reported, not only for monoclonal cryoglobulinemia-associated IgM RF but also for polyclonal RF or IgM RF clones from RA patients (44)(45)(46)(47). The proximity or potential overlap between binding sites for RF and for FcgRs suggests that some RF clones could hinder FcgR engagement by the IgG they bind and thereby inhibit cytokine induction via this pathway (48).…”

Section: Discussionmentioning

confidence: 99%

IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

Anquetil

Clavel

Offer

et al. 2015

The Journal of Immunology

108

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Rheumatoid factors (RF) and the disease-specific anti–citrullinated protein autoantibodies (ACPA) coexist in the joints of rheumatoid arthritis (RA) patients where they probably contribute to synovitis. We investigated the influence of IgM and IgA RF on the FcR- and complement-dependent effects of ACPA immune complexes (ACPA-IC). When stimulated by ACPA-IC formed in the presence of IgM RF or IgA RF fractions purified from RA serum pools, M-CSF–generated macrophages skewed their cytokine response toward inflammation, with increases in the TNF-α/IL-10 ratio and in IL-6 and IL-8 secretion, and decreases in the IL-1Ra/IL-1β ratio. In the IgM RF-mediated amplification of the inflammatory response of macrophages, the participation of an IgM receptor was excluded, notably by showing that they did not express any established receptor for IgM. Rather, this amplification depended on the IgM RF-mediated recruitment of more IgG into the ACPA-IC. However, the macrophages expressed FcαRI and blocking its interaction with IgA inhibited the IgA RF-mediated amplification of TNF-α secretion induced by ACPA-IC, showing its major implication in the effects of RF of the IgA class. LPS further amplified the TNF-α response of macrophages to RF-containing ACPA-IC. Lastly, the presence of IgM or IgA RF increased the capacity of ACPA-IC to activate the complement cascade. Therefore, specifically using autoantibodies from RA patients, the strong FcR-mediated or complement-dependent pathogenic potential of IC including both ACPA and IgM or IgA RF was established. Simultaneous FcR triggering by these RF-containing ACPA-IC and TLR4 ligation possibly makes a major contribution to RA synovitis.

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“…It is stated that these injuries are caused by immune deposits accumulated in vasa nervorum as the disease progresses. Patients with rheumatoid arthritis may have mononeuropathies and polineuropathies as peripheral nervous system involvements (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Isolated Superior Gluteal Nerve Mononeuropathy in Patient with Rheumatoid Arthritis

Ural¹,

Alptekin²,

Balci³

2017

JAREM

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Isolated mononeuritis multiplex may be rarely seen in patients with rheumatoid arthritis. Superior gluteal nerve palsies may result especially from iatrogenic causes, such as total hip arthroplasty operations. Patients complain of burning pain spreading to the lateral side of the thigh region. As our patient had bilateral hip dysplasia and rheumatoid arthritis at the same time, thorough examination was conducted with abdominal magnetic resonance imaging (MRI)'s, multiple electroneuromyography (ENMG) and laboratory studies. Malign illnesses such as aneurysms and tumoral lesions were eliminated. As the patient was diagnosed as mononeuritis multiplex due to Rheumatoid Arthritis, she began to use gabapentin 800 mg three times a day and alpha-lipoic acid 600 mg once a day for 6 months. In addition, she had a physical therapy cure with conventional Transcutaneous Electrical Nerve Stimulation (TENS), continuous Ultrasound (US), hot pack, strengthening and relaxation exercises for the lumbosacral region lasting for three weeks. Most of her complaints subsided after the treatment. Isolated superior gluteal nerve mononeuropathy due to rheumatoid arthritis is a rare presentation and should be thoroughly evaluated and followed for appropriate cures.

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Crystal Structure of a Human Autoimmune Complex between IgM Rheumatoid Factor RF61 and IgG1 Fc Reveals a Novel Epitope and Evidence for Affinity Maturation

Cited by 62 publications

References 36 publications

The antibody paradigm: present and future development as a scaffold for biopharmaceutical drugs

The antibody paradigm: present and future development as a scaffold for biopharmaceutical drugs

IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

Isolated Superior Gluteal Nerve Mononeuropathy in Patient with Rheumatoid Arthritis

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