Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation

Zelm, Menno C. van; Bartol, Sophinus J. W.; Driessen, Gertjan J.; Mascart, Françoise; Reisli, İsmail; Franco, José Luis; Wolska-Kuśnierz, Beata; Kanegane, Hirokazu; Boon, Louis; Dongen, Jacques J. M. van; Burg, Mirjam van der

doi:10.1016/j.jaci.2013.11.015

Cited by 69 publications

(47 citation statements)

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“…2,25–29 Siglecs expressed on more or less restricted sets of immune cells are often involved in immune inhibition, with many carrying immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on their short cytoplasmic tails. 2 Exemplary are Siglec-8 on allergic inflammatory cells (eosinophils, mast cells and basophils) and Siglec-9 on neutrophils, monocytes, dendritic cells and natural killer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Each has three extracellular Ig-like domains (the outermost carrying the primary sialic acid binding domain) and ITIM sequences on their cytoplasmic tails. 30 Ligation of each siglec on the surfaces of immune cells on which they are carried results in immune inhibition, including apoptosis. Siglec-8 and Siglec-9 likely encounter multivalent target sialoglycan ligands on tissues, leading to their ligation and initiation of their inhibitory program.…”

Section: Discussionmentioning

confidence: 99%

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Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells

Jia

Fernandes

et al. 2015

Journal of Allergy and Clinical Immunology

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Background Balanced activation and inhibition of the immune system ensures pathogen clearance while avoiding hyperinflammation. Siglecs, sialic acid binding proteins found on subsets of immune cells, often inhibit inflammation: Siglec-8 on eosinophils and Siglec-9 on neutrophils engage sialoglycan ligands on airways to diminish ongoing inflammation. The identities of human siglec ligands and their expression during inflammation are largely unknown. Objective The histological distribution, expression and molecular characteristics of siglec ligands were explored in healthy and inflamed human upper airways and in a cellular model of airway inflammation. Methods Normal and chronically inflamed upper airway tissues were stained for siglec ligands. The ligands were extracted from normal and inflamed tissues and from human Calu-3 cells for quantitative analysis by siglec blotting and isolation by siglec capture. Results Siglec-8 ligands were expressed on a subpopulation of submucosal gland cells of human inferior turbinate, whereas Siglec-9 ligands were expressed more broadly (submucosal glands, epithelium, connective tissue); both were significantly upregulated in chronic rhinosinusitis patients. Human airway (Calu-3) cells expressed Siglec-9 ligands on mucin 5B under inflammatory control via the NF-κB pathway, and mucin 5B carried sialoglycan ligands of Siglec-9 on human upper airway tissue. Conclusion Inflammation results in upregulation of immune inhibitory Siglec-8 and Siglec-9 sialoglycan ligands on human airways. Siglec-9 ligands were upregulated via the NF-κB pathway resulting in their enhanced expression on mucin 5B. Siglec sialoglycan ligand expression in inflamed cells and tissues may contribute to the control of airway inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells

Jia

Fernandes

et al. 2015

Journal of Allergy and Clinical Immunology

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“…The most notorious is CD40L that will bind to CD40 on the B cell and drives B cell proliferation, antibody affinity maturation and Ig class switch recombination (CSR) through activation of NF-B [172]. Consequently, genetic defects in CD40 or CD40L result in an Ig class switch defect in humans with complete absence of IgG, impaired affinity maturation and absence of germinal center structures [173,174].…”

Section: T-b Cell Signalingmentioning

confidence: 99%

The activation of the adaptive immune system: Cross-talk between antigen-presenting cells, T cells and B cells

2014

Self Cite

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“…The extent of hypermutation has also been used to infer the likely activation pathway of a repertoire, with the assumption being that a T‐dependent response would always produce B cells carrying more highly mutated Ig genes than a T‐independent response. There is some evidence for this since patients with CD40L deficiency, whose B cells are unable to receive traditional T cell help, have fewer mutations in their class switched repertoire than controls 25. Therefore, a study of the human immune response to Dengue infection, which showed a hypomutated repertoire, lead to a model of Dengue immune response involving the T‐independent repertoire as well as the T‐dependent response 26…”

Section: Generation Of B Cell Diversitymentioning

confidence: 99%

Immunoglobulin gene analysis as a tool for investigating human immune responses

Dunn-Walters

Townsend

Sinclair

et al. 2018

Immunological Reviews

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SummaryThe human immunoglobulin repertoire is a hugely diverse set of sequences that are formed by processes of gene rearrangement, heavy and light chain gene assortment, class switching and somatic hypermutation. Early B cell development produces diverse IgM and IgD B cell receptors on the B cell surface, resulting in a repertoire that can bind many foreign antigens but which has had self‐reactive B cells removed. Later antigen‐dependent development processes adjust the antigen affinity of the receptor by somatic hypermutation. The effector mechanism of the antibody is also adjusted, by switching the class of the antibody from IgM to one of seven other classes depending on the required function. There are many instances in human biology where positive and negative selection forces can act to shape the immunoglobulin repertoire and therefore repertoire analysis can provide useful information on infection control, vaccination efficacy, autoimmune diseases, and cancer. It can also be used to identify antigen‐specific sequences that may be of use in therapeutics. The juxtaposition of lymphocyte development and numerical evaluation of immune repertoires has resulted in the growth of a new sub‐speciality in immunology where immunologists and computer scientists/physicists collaborate to assess immune repertoires and develop models of immune action.

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Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation

Cited by 69 publications

References 50 publications

Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells

Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells

The activation of the adaptive immune system: Cross-talk between antigen-presenting cells, T cells and B cells

Immunoglobulin gene analysis as a tool for investigating human immune responses

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