CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans - PubMed (original) (raw)
CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans
S Weller et al. Proc Natl Acad Sci U S A. 2001.
Abstract
Somatically mutated IgM(+)-only and IgM(+)IgD(+)CD27(+) B lymphocytes comprise approximately 25% of the human peripheral B cell pool. These cells phenotypically resemble class-switched B cells and have therefore been classified as postgerminal center memory B cells. X-linked hyper IgM patients have a genetic defect characterized by a mutation of the CD40L gene. These patients, who do not express a functional CD40 ligand, cannot switch Ig isotypes and do not form germinal centers and memory B cells. We report here that an IgM(+)IgD(+)CD27(+) B cell subset with somatically mutated Ig receptors is generated in these patients, implying that these cells expand and diversify their Ig receptors in the absence of classical cognate T-B collaboration. The presence of this sole subset in the absence of IgM(+)-only and switched CD27(+) memory B cells suggests that it belongs to a separate diversification pathway.
Figures
Figure 1
Location of CD40L mutations in XHIM patients. The schematic representation of the cDNA sequence and of the domains of the CD40L molecule is according to Seyama et al. (17). IC, intracellular tail; TM, transmembrane domain; ECU, extracellular unique region; TNFH, tumor necrosis factor-homology domain. For each exon and domain, the starting nucleotide or amino acid residue number is indicated. Nonsense mutations are shown above the scheme, insertions (ins) and deletions (del) below.
Figure 2
Fluorescence analysis and sorting of IgD+CD27+ peripheral blood B cells of XHIM patients and a control adult donor. (A) Anti-IgD/anti-CD27 two-color staining of CD19+ B cells enriched by magnetic cell sorting (MACS) was performed as described in Materials and Methods. The gates selected for sorting of the IgD+CD27+ B cell population are indicated. The IgD−CD27+ population present in XHIM patients corresponds to a residual T cell contamination (see B and Materials and Methods). The sorted fractions were used for sequence analysis of rearranged VH3–23 gene segments. (B) Anti-IgD/anti-CD27/anti-CD19 three-color staining performed on peripheral blood mononuclear cells confirmed the absence of IgD−CD27+ memory B cells in XHIM patients. Three-color analysis shows CD27 and IgD expression on CD19+-gated cells. The data are representative of all XHIM patients studied.
Figure 3
Distribution of mutations in rearranged VH3–23 gene segments from control donors and XHIM patients. Each histogram represents the percentage of VH3–23 sequences displaying the number of mutations in a given range. Because of his remarkable mutation profile, patient C.Q. was represented separately from the other XHIM patients. (Patient Z.A., for whom mutation frequency was close to background level, was not included in this analysis.) The number of V sequences analyzed in each group is: control children, n = 33; control adults,n = 37; XHIM patients, n = 125; patient C.Q., n = 28.
Figure 4
Proposed scheme of human B cell development leading to Ig gene hypermutation. Pathway I corresponds to T-dependent responses occurring in GCs. Pathway II could correspond to T-independent responses, which may include nonconventional help from natural killer or T cells. The splenic marginal zone (MZ) or equivalent sites in Peyer's patches or lymph nodes could be the site of B cell activation. Ig gene hypermutation takes place in both pathways.
Similar articles
- Absence of IgD-CD27(+) memory B cell population in X-linked hyper-IgM syndrome.
Agematsu K, Nagumo H, Shinozaki K, Hokibara S, Yasui K, Terada K, Kawamura N, Toba T, Nonoyama S, Ochs HD, Komiyama A. Agematsu K, et al. J Clin Invest. 1998 Aug 15;102(4):853-60. doi: 10.1172/JCI3409. J Clin Invest. 1998. PMID: 9710455 Free PMC article. - Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-linked immunodeficiency with hyper-IgM.
Saiki O, Tanaka T, Wada Y, Uda H, Inoue A, Katada Y, Izeki M, Iwata M, Nunoi H, Matsuda I, et al. Saiki O, et al. J Clin Invest. 1995 Feb;95(2):510-4. doi: 10.1172/JCI117692. J Clin Invest. 1995. PMID: 7532185 Free PMC article. - IgG subclass switch capacity is low in switched and in IgM-only, but high in IgD+IgM+, post-germinal center (CD27+) human B cells.
Werner-Favre C, Bovia F, Schneider P, Holler N, Barnet M, Kindler V, Tschopp J, Zubler RH. Werner-Favre C, et al. Eur J Immunol. 2001 Jan;31(1):243-9. doi: 10.1002/1521-4141(200101)31:1<243::AID-IMMU243>3.0.CO;2-0. Eur J Immunol. 2001. PMID: 11265640 - Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features.
Lougaris V, Badolato R, Ferrari S, Plebani A. Lougaris V, et al. Immunol Rev. 2005 Feb;203:48-66. doi: 10.1111/j.0105-2896.2005.00229.x. Immunol Rev. 2005. PMID: 15661021 Review. - Defects of class-switch recombination.
Notarangelo LD, Lanzi G, Peron S, Durandy A. Notarangelo LD, et al. J Allergy Clin Immunol. 2006 Apr;117(4):855-64. doi: 10.1016/j.jaci.2006.01.043. J Allergy Clin Immunol. 2006. PMID: 16630945 Review.
Cited by
- Composition of the CD27+ Memory-B-Cell Compartment Delineates Immunoglobulin Deficiency Endotypes.
Starich O, Rieck JM, Tarter WJ, Hochheimer CJ, Knight V, Abbott JK. Starich O, et al. Res Sq [Preprint]. 2024 Jan 9:rs.3.rs-3838482. doi: 10.21203/rs.3.rs-3838482/v1. Res Sq. 2024. PMID: 38260264 Free PMC article. Preprint. - Oral mucosa immunity: ultimate strategy to stop spreading of pandemic viruses.
Jang H, Matsuoka M, Freire M. Jang H, et al. Front Immunol. 2023 Oct 19;14:1220610. doi: 10.3389/fimmu.2023.1220610. eCollection 2023. Front Immunol. 2023. PMID: 37928529 Free PMC article. Review. - Mechanism and regulation of secondary immunoglobulin diversification.
Bello A, Hirth G, Voigt S, Tepper S, Jungnickel B. Bello A, et al. Cell Cycle. 2023 Sep;22(18):2070-2087. doi: 10.1080/15384101.2023.2275397. Epub 2023 Nov 23. Cell Cycle. 2023. PMID: 37909747 Review. - NF-kB's contribution to B cell fate decisions.
Guldenpfennig C, Teixeiro E, Daniels M. Guldenpfennig C, et al. Front Immunol. 2023 Jul 18;14:1214095. doi: 10.3389/fimmu.2023.1214095. eCollection 2023. Front Immunol. 2023. PMID: 37533858 Free PMC article. Review. - Antibody diversity in IVIG: Therapeutic opportunities for novel immunotherapeutic drugs.
von Gunten S, Schneider C, Imamovic L, Gorochov G. von Gunten S, et al. Front Immunol. 2023 Mar 28;14:1166821. doi: 10.3389/fimmu.2023.1166821. eCollection 2023. Front Immunol. 2023. PMID: 37063852 Free PMC article. Review.
References
- Maurer D, Holter W, Majdic O, Fischer G F, Knapp W. Eur J Immunol. 1990;20:2679–2684. - PubMed
- van Es J H, Meyling F H, Logtenberg T. Eur J Immunol. 1992;22:2761–2774. - PubMed
- Klein U, Kuppers R, Rajewsky K. Blood. 1997;89:1288–1298. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials