Timo Lindemann’s research while affiliated with Universität zu Lübeck and other places

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Publications (4)


Fig. 2 IgE and IgG1 sequences and clonotypes. cDNA from naive mice and allergic mice challenged o.g. 13 times with EG/EYP was analyzed by NGS. Individual clonotypes within the IgG1 and IgE IgH-repertoires were defined by unique VDJ-rearrangements. a Number of sequences and clonotypes in BM and mLN, as indicated. Colored bars represent the mean. b Ratios of IgG1 to IgE sequences and ratios of IgG1 to IgE clonotypes, as indicated. c Number and percentages of hypermutated and unmutated IgE and IgG1 clonotypes. Representative data from two samples from BM and mLN each are shown. d Clone size distribution of unmutated IgE clonotypes. Representative data from mLN and BM of one mouse are shown, as indicated. e Upper panel: clone size distribution of all mutated IgE clonotypes. Lower panel: Clone size distribution of mutated IgE clonotypes with a clone size of 10 or less. f Mean copy numbers. Each symbol represents the average copy numbers of mutated IgG1 clonotypes (muIgG1), mutated IgE clonotypes (muIgE), unmutated IgG1 clonotypes (umIgG1) and unmutated IgE clonotypes (umIgE) from the mLN or BM of one mouse, as indicated. g Number of high copy number clones, defined as clones with copy numbers greater than the average umIgE or umIgG1 copy number, respectively. a/b: samples from 5 allergic mice and 2 naive mice from one experiment were analyzed. One BM sample was excluded due to insufficient cDNA quality (mLN: n = 7, BM: n = 6). c-f samples from mLN of 5 allergic mice from one experiment and pooled samples from BM of 7 allergic mice from two experiments are shown (mLN: n = 5, BM: n = 7). No sample was excluded from the analysis. Total number of mice: 7. Statistics a-c: Mann Whitney's nonparametric test for comparisons within the BM or mLN; Wilcoxon nonparametric matched paired test for comparisons between BM and mLN. Data presented as mean ± SEM. Statistics d-g: pairwise t-test. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001.
Fig. 5 BCR crosslinking induced calcium flux. Single-cell suspensions from spleen were stained for IgM and IgD. After incubation with CalbryteTM 520 AM, separate samples were treated with various concentrations of polyclonal anti-IgM, or anti-Ig-kappa F(ab′) 2, as indicated. Calcium flux was measured by flow cytometry (LSRII, BD, using a Flow Jo 10.7.1 software). a Representative histogram plots for IgMhigh/IgDlow naive B cells and IgMhigh/IgDlow marginal zone B cells, as indicated. b Statistical analysis of calcium flux after incubation with increasing concentrations of polyclonal anti-IgM F(ab′)2, for IgMhigh/IgDlow naive B cells, IgMhigh/IgDlow marginal zone B cells and IgMneg/IgDneg cells. Each symbol represents one cell culture well (n = 5 for all conditions). Representative data from one of three independent experiments, median and range are indicated. No sample was excluded from the analysis. Statistics: Friedmann-Test was calculated using R. ***p ≤ 0.001.
Fig. 7 IL-21 reduces the IgE to IgG1 ratio for class-switched cells. Naive B cells were cultured together with CD40L / BAFF-transfected feeder cells and IL-4. At day 0 and day 1, various concentrations of IL-21 were added. The frequencies of IgE+ and IgG1+ cells were analyzed by flow cytometry at day 4. Dead cells, debris, doublets and feeder cells were excluded by Life/Dead stain and forward/sideward scatter and B cells were identified by CD19 expression. a Representative FACS plots of CD19+ B cells, stimulated with IL-21 in concentrations of 0, 10 or 20 ng/ml, as indicated. b Statistical analysis of the percentages of IgE+ and IgG1+ B cells, and the ratios between IgE:IgG1+ cells. Representative data from one of two independent experiments are shown. No sample was excluded from the analysis. Data presented as mean ± SEM. Statistics: Each symbol represents data from a culture of cells from one mouse (n = 5 for all conditions). Unpaired parametric t-test *p ≤ 0.05; **p ≤ 0.01; ****p ≤ 0.0001.
IgE clonotypes.
B-cell receptor physical properties affect relative IgG1 and IgE responses in mouse egg allergy
  • Article
  • Full-text available

September 2022

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161 Reads

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9 Citations

Mucosal Immunology

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Rudolf A. Manz

Mutated and unmutated IgE and IgG play different and partly opposing roles in allergy development, but the mechanisms controlling their relative production are incompletely understood. Here, we analyzed the IgE-response in murine food allergy. Deep sequencing of the complementary-determining region (CDR) repertoires indicated that an ongoing unmutated extrafollicular IgE response coexists with a germinal center response, even after long-lasting allergen challenges. Despite overall IgG1-dominance, a significant proportion of clonotypes contained several-fold more IgE than IgG1. Clonotypes with differential bias to either IgE or IgG1 showed distinct hypermutation and clonal expansion. Hypermutation rates were associated with different physiochemical binding properties of individual B-cell receptors (BCR). Increasing BCR signaling strength inhibited class switching from IgG1 to IgE in vitro, preferentially constraining IgE formation. These data indicate that antigen-binding properties of individual BCRs determine differential IgE hypermutation and IgE versus IgG1 production on the level of single B-cell clones.

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IL-2-Agonist-Induced IFN-γ Exacerbates Systemic Anaphylaxis in Food Allergen-Sensitized Mice

December 2020

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102 Reads

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11 Citations

Food allergies are common, costly and potentially life-threatening disorders. They are driven by Th2, but inhibited by Th1 reactions. There is also evidence indicating that IL-2 agonist treatment inhibits allergic sensitization through expansion of regulatory T cells. Here, we tested the impact of an IL-2 agonist in a novel model for food allergy to hen´s egg in mice sensitized without artificial adjuvants. Prophylactic IL-2 agonist treatment expanded Treg populations and inhibited allergen-specific sensitization. However, IL-2 agonist treatment of already sensitized mice increased mast cell responses and allergic anaphylaxis upon allergen re-challenge. These effects depended on allergen-specific IgE and were mediated through IFN-γ, as shown by IgE transfer and blockade of IFN-γ with monoclonal antibodies. These results suggest that although shifting the allergic reaction toward a Treg/Th1 response inhibits allergic sensitization, the prototypic Th1 cytokine IFN-γ promotes mast cell activation and allergen-induced anaphylaxis in individuals that are already IgE-sensitized. Hence, while a Th1 response can prevent the development of food allergy, IFN-γ has the ability to exacerbate already established food allergy.


IgG Fc N-Glycosylation Translates MHCII Haplotype into Autoimmune Skin Disease

July 2020

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117 Reads

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13 Citations

Journal of Investigative Dermatology

The major histocompatibility complex (MHC)-haplotype represents the most prevalent genetic risk factor for the development of autoimmune diseases. However, the mechanisms by which MHC-associated genetic susceptibility translates into autoimmune disease are not fully understood. Epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease driven by autoantibodies to type VII collagen (COL7). Here, we investigated autoantigen-specific plasma cells, CD4+ T cells and IgG Fc-glycosylation in murine EBA in congenic mouse strains with the disease-permitting H2s or -non-permitting H2b MHCII haplotypes. Mice with an H2s haplotype showed increased numbers of autoreactive CD4+ T cells and elevated IL-21- and IFN-γ-production, associated with a higher frequency of IgG autoantibodies with an agalactosylated, proinflammatory N-glycan moiety. Mechanistically, we show that the altered antibody glycosylation leads to increased ROS release from neutrophils, the main driver of autoimmune inflammation in this model. These results indicate that MHCII-associated susceptibility to autoimmune diseases acuminates in a proinflammatory IgG Fc N-glycosylation pattern and provide a mechanistic link to increased ROS release by neutrophils.


Bone Marrow Plasma Cells Modulate Local Myeloid-Lineage Differentiation via IL-10

May 2019

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261 Reads

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30 Citations

Bone marrow plasma cells have been reported to represent a major source of IL-10; however, the impact of plasma cell derived IL-10 in that tissue remains poorly understood. We confirm in this study that even in the absence of acute immune reactions, mature plasma cells represent the dominant IL-10+ cell population in the bone marrow, and identify myeloid-lineage cells as a main local target for plasma cell derived IL-10. Using Vert-X IL-10 transcriptional reporter mice, we found that more than 50% of all IL-10+ cells in bone marrow were CD138+ plasma cells, while other IL-10+ B lineage cells were nearly absent in this organ. Accordingly, IL-10 was found in the supernatants of short-term cultures of FACS-sorted bone marrow plasma cells, confirming IL-10 secretion from these cells. IL-10+ bone marrow plasma cells showed a B220−/CD19−/MHCII low phenotype suggesting that these cells represent a mature differentiation stage. Approximately 5% of bone marrow leucocytes expressed the IL-10 receptor (IL-10R), most of them being CD115+/Ly6C+/CD11c− monocytes. Compared to littermate controls, young B lineage specific IL-10 KO mice showed increased numbers of CD115+ cells but normal populations of other myeloid cell types in bone marrow. However, at 7 months of age B lineage specific IL-10 KO mice exhibited increased populations of CD115+ myeloid and CD11c+ dendritic cells (DCs), and showed reduced F4/80 expression in this tissue; hence, indicating that bone marrow plasma cells modulate the differentiation of local myeloid lineage cells via IL-10, and that this effect increases with age. The effects of B cell/plasma cell derived IL-10 on the differentiation of CD115+, CD11c+, and F4/80+ myeloid cells were confirmed in co-culture experiments. Together, these data support the idea that IL-10 production is not limited to early plasma cell stages in peripheral tissues but is also an important feature of mature plasma cells in the bone marrow. Moreover, we provide evidence that already under homeostatic conditions in the absence of acute immune reactions, bone marrow plasma cells represent a non-redundant source for IL-10 that modulates local myeloid lineage differentiation. This is particularly relevant in older individuals.

Citations (4)


... Concurrently, decreased IFN-γ levels weaken regulatory mechanisms that typically suppress the Th2 response and limit IgE production. This imbalance perpetuates the inflammatory cascade, exacerbating AD symptoms [22]. Reduction in IgE levels and alteration of the Th1/Th2 balance explain the improvement in skin symptoms and reduction in itching behavior. ...

Reference:

Evaluating the Adjuvant Therapeutic Effects of Probiotic Strains Lactococcus cremoris and Lacticaseibacillus paracasei on Canine Atopic Dermatitis and Their Impact on the Gut and Skin Microbiome
B-cell receptor physical properties affect relative IgG1 and IgE responses in mouse egg allergy

Mucosal Immunology

... Contrastingly, Th1 reaction and the prototypic cytokine interferon (IFN)-γ could counterbalance Th2 responses, thus reducing the generation of IL-4 and IgE and ultimately inhibiting allergic sensitization. 13 Regulating Th1/Th2 balance exerts certain roles in mitigating allergic inflammatory responses in ovalbumin-elicited AR mice. 14 From the aforementioned research, we can learn the paramount significance of the Th1/Th2 balance in AR. ...

IL-2-Agonist-Induced IFN-γ Exacerbates Systemic Anaphylaxis in Food Allergen-Sensitized Mice

... Fc-galactosylation levels are highly variable (40-60%), with decreased levels being found in inflammatory diseases such as various infectious, cardiovascular, and autoimmune diseases as well as cancer. [8][9][10][11][12] In contrast, increased Fc-galactosylation has been shown to characterize IgG after vaccination 13,14 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. [2][3][4] Elevated Fc-galactosylation promotes IgG ...

IgG Fc N-Glycosylation Translates MHCII Haplotype into Autoimmune Skin Disease
  • Citing Article
  • July 2020

Journal of Investigative Dermatology

... This underscores the potential of bmDCs to interpret and induce hematopoietic bias in response to immune stimuli. Considering the inherent challenges associated with G-CSF administration, such as the need for repeated injections and symptoms like bone pain, nausea, headache, and fatigue [70], the administration of in Long-lived plasma cells, identified as CD19 − /B220 − / MCH II lo CD138 + in mouse bone marrow, represent a substantial local source of IL-10 under steady-state conditions [97,98]. IL-10 assumes a pivotal role in regulating the proliferation and differentiation of myeloid cells, DCs, and macrophages within the bone marrow, operating in a nonredundant capacity [98,99]. ...

Bone Marrow Plasma Cells Modulate Local Myeloid-Lineage Differentiation via IL-10