A Human Immunoglobulin λ Locus Is Similarly Well Expressed in Mice and Humans

Попов, А. В.; Zou, Xiangang; Jian, Xian; Nicholson, I.; Brüggemann, Marianne

doi:10.1084/jem.189.10.1611

Cited by 44 publications

(23 citation statements)

References 51 publications

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“…False positive signals resulting from remaining serum IGN311 (IgG1/κ) were eliminated by an ELISA detection system specific for the human λ chain. In humans, the ratio of antibodies containing κ or λ light chains is 60:40 [21] therefore the chance for the existence of a specific Ab3 clone expressing a λ light chain or λ light chain is roughly equal. As can be seen in Figure 5, patient 1 developed a significant λ chain related anti-id (anti-MMA383) reactivity.…”

Section: Ab3 Inductionmentioning

confidence: 99%

Induction of Human Anti-Human Antibody Responses (Ab2) after Application of a Humanized Lewis Y Carbohydrate Specific Antibody (Ab1): Connection of Prolonged Disease Stabilization with Ab3 Induction?

Nechansky¹,

Stranner²,

Scheiber³

et al. 2012

JCT

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Purpose: Detailed analysis of a patient with epithelial Lewis Y (LeY) positive cancer who received twice 50 mg of the humanized Lewis Y carbohydrate specific mAb IGN311 and developed a clinically significant human anti-human antibody (HAHA) response (Ab2). Results: Clinical stabilization of the disease was assigned to in this patient. The HAHA response consisted mainly of IgG1 and was found to be directed against the IGN311 binding site. Consistent with the induction of the HAHA response, CDC activity against Lewis Y positive target cells was completely abolished at day 8 and could not be restored by the second 50 mg infusion indicating complete neutralization of applied IGN311. The ADCC reactivity was also significantly reduced and anti-anti idiotype-specific antibodies (Ab3) were detectable at day 65. Conclusions: Induction of Ab3 antibodies should be considered as an additional factor influencing the efficacy of humanized antibodies. In this context, the potential threat of induced HAHA responses against therapeutic mAbs might have to be reconsidered because they might actually have also beneficial immunological long-term effects leading to an active immunization component induced by therapeutic antibodies.

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Section: Ab3 Inductionmentioning

confidence: 99%

Induction of Human Anti-Human Antibody Responses (Ab2) after Application of a Humanized Lewis Y Carbohydrate Specific Antibody (Ab1): Connection of Prolonged Disease Stabilization with Ab3 Induction?

Nechansky¹,

Stranner²,

Scheiber³

et al. 2012

JCT

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“…The human Igl locus on an ∼410-kb YAC was obtained by recombination assembly of a Vl YAC with 3 Cl containing cosmids (23). Rearrangement and expression was verified in transgenic mice derived from ES cells containing one copy of a complete human Igl YAC (24). This Igl YAC was shortened by the generation of a cYAC removing ∼100 kb of the region 59 of Vl3-27.…”

Section: Construction Of Modified Human Ig Loci On Yeast Artificial Cmentioning

confidence: 99%

High-Affinity IgG Antibodies Develop Naturally in Ig-Knockout Rats Carrying Germline Human IgH/Igκ/Igλ Loci Bearing the Rat CH Region

Osborn

Avis

et al. 2013

The Journal of Immunology

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Mice transgenic for human Ig loci are an invaluable resource for the production of human Abs. However, such mice often do not yield human mAbs as effectively as conventional mice yield mouse mAbs. Suboptimal efficacy in delivery of human Abs might reflect imperfect interaction between the human membrane IgH chains and the mouse cellular signaling machinery. To obviate this problem, in this study we generated a humanized rat strain (OmniRat) carrying a chimeric human/rat IgH locus (comprising 22 human VHs, all human D and JH segments in natural configuration linked to the rat CH locus) together with fully human IgL loci (12 Vκs linked to Jκ-Cκ and 16 Vλs linked to Jλ-Cλ). The endogenous Ig loci were silenced using designer zinc finger nucleases. Breeding to homozygosity resulted in a novel transgenic rat line exclusively producing chimeric Abs with human idiotypes. B cell recovery was indistinguishable from wild-type animals, and human V(D)J transcripts were highly diverse. Following immunization, the OmniRat strain performed as efficiently as did normal rats in yielding high-affinity serum IgG. mAbs, comprising fully human variable regions with subnanomolar Ag affinity and carrying extensive somatic mutations, are readily obtainable, similarly to conventional mAbs from normal rats.

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“…We used mice in which endogenous H-and L-chain genes were inactivated and instead were engineered to express human Igs (44). The Ig transgenes somatically recombine and mutate upon immunization to encode a functional human repertoire (44,51). Here, we have determined the consequences of confronting B cells expressing human surface Igs with protein L in vivo.…”

mentioning

confidence: 99%

Specific In Vivo Deletion of B-Cell Subpopulations Expressing Human Immunoglobulins by the B-Cell Superantigen Protein L

et al. 2004

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Some pathogens have evolved to produce proteins, called B-cell superantigens, that can interact with human immunoglobulin variable regions, independently of the combining site, and activate B lymphocytes that express the target immunoglobulins. However, the in vivo consequences of these interactions on human B-cell numbers and function are largely unknown. Using transgenic mice expressing fully human immunoglobulins, we studied the consequences of in vivo exposure of protein L of Peptostreptococcus magnus with human immunoglobulins. In the mature pool of B cells, protein L exposure resulted in a specific reduction of splenic marginal-zone B cells and peritoneal B-1 cells. Splenic B cells exhibited a skewed light-chain repertoire consistent with the capacity of protein L to bind specific kappa gene products. Remarkably, these two B-cell subsets are implicated in innate B-cell immunity, allowing rapid clearance of pathogens. Thus, the present study reveals a novel mechanism that may be used by some infectious agents to subvert a first line of the host's immune defense.Throughout evolution, the continuous interactions between the mammalian host and infectious agents have produced an array of innate and adaptive immune effectors able to combat insults by pathogens (30). Reciprocally, infectious agents have developed efficient countermeasures to persist in the infected host (63). These pathogens have developed mechanisms to mutate, exchange genetic materials, multiply rapidly, vary their phenotype, and occupy diverse ecological niches (61). One intriguing feature of some infectious agents is to produce proteins able to interact specifically with the immunoglobulin (Ig) heavy (H)-or light (L)-chain variable regions, independently of the conventional binding site. They are referred to as "B-cell superantigens" (SAgs) and include protein A of Staphylococcus aureus (SpA) (22,29,52,57), gp120 of human immunodeficiency virus type 1 (HIV-1) (3, 20, 32, 33, 43, 50), staphylococcal enterotoxins A and D (7, 45), and protein L of Peptostreptococcus magnus (12, 13).Although conventional antigens stimulate a small proportion of B cells, the B lymphocytes responsive to SAgs can be orders of magnitude higher. Because the B-cell SAg interacts primarily with the V H or V L portion of the Ig molecule, it can, in principle, trigger all B cells bearing the appropriate V H or V L , regardless of the other J H , D, J L , and pairing with V H or V L segments (58, 68). Since there are a limited number of V genes, this property results in stimulation of a large proportion of the repertoire. For example, the bacterial cell wall protein SpA has sites that interact with the Fab of many IgM, IgA, IgG, and IgE, and this interaction is restricted to the V H 3 gene family, leading to activation of ca. 40% of human polyclonal IgMs (58,68).The function of these proteins is unclear, but their ability to bind conserved portions of Igs suggests that they help the bacteria to evade the host's immune system. Through direct interaction with host Igs, they ...

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A Human Immunoglobulin λ Locus Is Similarly Well Expressed in Mice and Humans

Cited by 44 publications

References 51 publications

Induction of Human Anti-Human Antibody Responses (Ab2) after Application of a Humanized Lewis Y Carbohydrate Specific Antibody (Ab1): Connection of Prolonged Disease Stabilization with Ab3 Induction?

Induction of Human Anti-Human Antibody Responses (Ab2) after Application of a Humanized Lewis Y Carbohydrate Specific Antibody (Ab1): Connection of Prolonged Disease Stabilization with Ab3 Induction?

High-Affinity IgG Antibodies Develop Naturally in Ig-Knockout Rats Carrying Germline Human IgH/Igκ/Igλ Loci Bearing the Rat CH Region

Specific In Vivo Deletion of B-Cell Subpopulations Expressing Human Immunoglobulins by the B-Cell Superantigen Protein L

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