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Defective B-cell memory in patients with Down syndrome

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1 Defective B-cell memory in patients with Down syndrome
Ruud H.J. Verstegen, MD, Gertjan J. Driessen, MD, Sophinus J.W. Bartol, BSc, Carel J.M. van Noesel, MD, PhD, Louis Boon, PhD, Mirjam van der Burg, PhD, Jacques J.M. van Dongen, MD, PhD, Esther de Vries, MD, PhD, Menno C. van Zelm, PhD  Journal of Allergy and Clinical Immunology  Volume 134, Issue 6, Pages e9 (December 2014) DOI: /j.jaci Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Composition of the blood B-cell compartment in children with Down syndrome. A, Model for B-cell maturation. B, Absolute numbers of B-cell subsets. C, Frequencies of CD21lowCD38− B cells. D, BAFF serum levels. Panels B through D include patients with Down syndrome (P1, P4-P8, and P11-P17). Statistical analysis was done with the Mann-Whitney test: *P < .05, **P < .01, ***P < .001, and ****P < ns, Not significant. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Germinal center composition and plasma cell maturation. A, Tonsil sections of a representative patient with Down syndrome. B and C, Frequencies of CD38+IgD− germinal center B cells (Fig 2, B) and CD38hi plasma cells (Fig 2, C). D, Gene expression levels in naive B cells after 6 days of stimulation expressed as the fold difference from uncultured naive cells. Statistical analysis was done with the Mann-Whitney test. H&E, Hematoxylin and eosin; PD-1, programmed cell death 1. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Abnormal immunophenotypes of memory B-cell subsets of patients with Down syndrome. Expression levels of CD80 (L307.4; A), CD95 (DX2; B), and TACI (goat polyclonal; C) on naive mature, natural effector, CD27+IgA+, and CD27+IgG+ memory B cells. Data are shown from 4 patients with Down syndrome (P7, P13, P16, and P17) and 4 healthy control subjects. MFI, Median fluorescence intensity. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Replication history and SHM. A and B, In vivo replication history (Fig 4, A) and frequencies of mutated IGKV3-20 alleles (Fig 4, B) in B-cell subsets (patients P1, P4-6, P8, P11-12, and P14-15). C and D, SHM frequencies in rearranged IGHV genes (Fig 4, C) and selection for replacement mutations in CDR (red) and FR regions (blue; Fig 4, D).14,15 Each subset includes 18 to 52 sequences from 4 to 6 subjects. Statistical analysis in Fig 4, A-C, was done with the Mann-Whitney test. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E1 Flow cytometric gating strategy to determine the described B-cell subsets in a representative control subject (A) and a patient with Down syndrome (B). Gates were electronically defined on cells that did not express specific markers (ie, CD19− lymphocytes for IgD, IgD+ B cells for IgG and IgA, and CD27+ B cells for CD38 and CD24). For each analysis, more than 5,000 to 10,000 CD19+ events were acquired for control subjects and approximately 50% of patients, and greater than 1000 events were acquired in patients with low B-cell counts. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E2 IGHV mutation frequencies of distinct IgA and IgG subclass transcripts. A, Distribution of IgA and IgG subclass use in IGH transcripts. The total number of analyzed sequences is indicated in the center of each plot. No significant differences were seen in the relative use of IGHM-proximal IgG1, IgG3, and IgA1 versus IGHM-distal IgG2, IgG4, and IgA2 constant regions. B and C, The frequency of mutated nucleotides in IGHV genes are shown for the 2 IgA subclasses (Fig E2, B) and IgG subclasses (Fig E2, C). Each dot represents a transcript from a healthy control subject (light gray) or a patient with Down syndrome (dark gray), with red lines indicating the median value for each category. The total number of analyzed transcripts is shown in brackets. Twenty-seven to 45 sequences from 4 patients (P1 and P9-11) and 18 to 52 sequences from 4 control subjects were obtained for IgA and IgG transcripts. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E3 Selection against IGHV4-34 use and long IGH-CDR3 in natural effector, IgA, and IgG memory B cells. A, IGH-CDR3 size distributions. All individual sizes of healthy control subjects (light gray) and patients with Down syndrome (dark gray) are indicated as dots, with black lines representing median values. The dashed line represents the median value for centroblasts (n = 67). Differences between healthy control subjects and patients with Down syndrome were statistically analyzed with the Student t test. *P < .05. B-D, IGHV4 gene use in natural effector (Fig E3, B), IgA (Fig E3, C), and IgG (Fig E3, D) memory B cells of patients with Down syndrome. IGHV4 gene use is displayed as frequency within the total IGHV4 subgroup, and in each plot the patients are depicted together with the corresponding subset and with naive mature B cells from healthy control subjects. The arrows highlight IGHV4-34 gene use. The total numbers of analyzed transcripts are shown in brackets. Fig E3, A-D, include 23 to 28 sequences from 4 patients (P1, P8, P11, and P12) and 10 to 18 sequences from 6 control subjects for natural effector B cells and 27 to 45 sequences from 4 patients (P1 and P9-11) and 18 to 52 sequences from 4 control subjects for IgA and IgG transcripts. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E4 Distribution of replacement mutations in rearranged IGHV genes in memory B-cell subsets. Distribution of replacement mutations in rearranged IGHV genes is determined for natural effector B cells (A), IgA+ memory B cells (B), and IgG+ memory B cells (C) from control subjects (left) and patients with Down syndrome (right). Each bar represents the frequency of replacement mutations at each amino acid position starting from 20 (first codon after the primer sequence) to 104 (last codon of the FR3 region). The total numbers of analyzed transcripts are shown in brackets. Panels A through C include 23 to 28 sequences from 4 patients (P1, P8, P11, and P12) and 10 to 18 sequences from 6 control subjects for natural effector B cells and 27 to 45 sequences from 4 patients (P1 and P9-11) and 18 to 52 sequences from 4 control subjects for IgA and IgG transcripts. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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