Errors in data interpretation from genetic variation of human analytes

Howie, Heather L.; Delaney, Meghan; Wang, Xiaohong; Er, Lay See; Kapp, Linda M.; Lebedev, Jenna N.; Zimring, James C.

doi:10.1172/jci.insight.94532

Cited by 7 publications

(8 citation statements)

References 22 publications

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“…Future studies will shed light on the effector functions of the various IgG allotypes and the potential implications in susceptibility to infectious diseases or translation to antibody-based therapeutics. Interestingly, reactivity of monoclonal or polyclonal anti-IgG antibodies with all IgG allotypes indicated that some monoclonal antibodies, either subclass- or isotype-specific do not recognize all allotypic variants, a phenomenon described as ‘serological blind spots’ [100,101]. In addition, subclass-specific polyclonal anti-IgG were found to react with isoallotypic variants of another subclass, which could lead to misinterpretation of IgG subclass responses and can be of great importance, not only for scientific interpretations of immune responses, but also for critical diagnostic conclusion that leads to life-and-death decisions for patients [100].…”

Section: Igg Allotypesmentioning

confidence: 99%

The Ligands for Human IgG and Their Effector Functions

2019

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Activation of the humoral immune system is initiated when antibodies recognize an antigen and trigger effector functions through the interaction with Fc engaging molecules. The most abundant immunoglobulin isotype in serum is Immunoglobulin G (IgG), which is involved in many humoral immune responses, strongly interacting with effector molecules. The IgG subclass, allotype, and glycosylation pattern, among other factors, determine the interaction strength of the IgG-Fc domain with these Fc engaging molecules, and thereby the potential strength of their effector potential. The molecules responsible for the effector phase include the classical IgG-Fc receptors (FcγR), the neonatal Fc-receptor (FcRn), the Tripartite motif-containing protein 21 (TRIM21), the first component of the classical complement cascade (C1), and possibly, the Fc-receptor-like receptors (FcRL4/5). Here we provide an overview of the interactions of IgG with effector molecules and discuss how natural variation on the antibody and effector molecule side shapes the biological activities of antibodies. The increasing knowledge on the Fc-mediated effector functions of antibodies drives the development of better therapeutic antibodies for cancer immunotherapy or treatment of autoimmune diseases.

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Section: Igg Allotypesmentioning

confidence: 99%

The Ligands for Human IgG and Their Effector Functions

2019

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“…There are clear benefits in the use of monoclonal AHG including issues of production, reagent consistency, and avoiding the manipulation of animals. However, as pointed out previously (and in the current report), the risk of using monoclonal AHG is nonreactivity with genetic IgG variants found in particular patient populations . A “virtual polyclonal” reagent can be generated by blending monoclonals with specificity against different epitopes.…”

Section: Resultsmentioning

confidence: 99%

Characterization and refinement of monoclonal anti‐human globulins that lack reactivity with human IgG4

et al. 2020

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“…In contrast, the commonly available monoclonal anti-IgG3 (clone HP6050) has a blind spot for IgG3-04 20. To the best of our knowledge, no data have been published that would allow a determination of the exact frequency of IgG3-04 heterogeneity or homogeneity in human populations.…”

Section: Discussionmentioning

confidence: 99%

“…However, once one takes into account the 29 known variants, the available polyclonal antisera cross react with inappropriate variants in incorrect subclasses 20. Conversely, monoclonal reagents are more specific; however, available anti-IgG3 reagents have a blind-spot for the IgG3-04 variant, creating a diagnostic problem in the characterisation of any individual whose genome encodes IgG3-04 20…”

Section: Introductionmentioning

confidence: 99%

Identification of IgG3-specific epitope that remedies problem in diagnostic IgG subclass determination due to human genetic variation

et al. 2018

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There are four subtypes of human IgG with different effector functions. Quantifying the relative amount of each IgG subtype is important for laboratory diagnosis in multiple settings. However, in an evolving landscape of the appreciation of human variability and the need for precision/personalised laboratory diagnosis, it has also been shown that there are numerous natural variants of IgG subtypes, with at least 29 having been described. It has recently been reported that commercially available polyclonal antisera to IgG3 cross react with variants of other IgG subtypes, while available monoclonal anti-IgG3 have a blind-spot for the IgG3-04 variant. Herein, we report that IgG3-04 contains an epitope in common with all known IgG3 variants and absent in other subtypes. A novel monoclonal anti-IgG3 is described that is specific to IgG3 but without any blind-spots for known IgG3 variants, providing a remedy to the problem of genetic variability of IgG3.

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Errors in data interpretation from genetic variation of human analytes

Cited by 7 publications

References 22 publications

The Ligands for Human IgG and Their Effector Functions

The Ligands for Human IgG and Their Effector Functions

Characterization and refinement of monoclonal anti‐human globulins that lack reactivity with human IgG4

Identification of IgG3-specific epitope that remedies problem in diagnostic IgG subclass determination due to human genetic variation

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