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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

Many thanks to all the amazing people contributing to this project, especially my PI @boztugk.bsky.social, @sevgikostelbal.bsky.social and the other wonderful members of our lab, our many collaborators, the treating clinicians and finally the patients and their relatives for enabling this study!

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

In summary, the absence of LTBR signaling results in a miscommunication between stromal and immune cells that is required for the function & formation of SLOs. Without this, the lymphocytes lack the environment required for the GC reaction, resulting in B cell defects. 9/10

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

…by combining donor derived stromal cells, PBMCs and monocyte derived DCs. After 12 days of culture in this system, also the patient derived B cells were able to differentiate into memory B cells and plasma blasts. 8/10

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

LTBR is not expressed on B and T cells, but on stromal cells. We were curious if the patients had a GC defect following the defect in the SLOs, or if the cell interaction and GC reaction itself is also affected. To test this, we developed a novel ex vivo co-culturing system… 7/10

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

Accordingly, we detected only marginal numbers of memory B cells and class switched B cells in the patients, explaining the hypogammaglobulinemia. 6/10

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

The secondary lymphoid organs (SLOs) are essential for the initiation of the adaptive immunity by providing the microenvironment required for Germinal Center (GC) formation, resulting in the differentiation of B cells into antibody secreting plasma cells and memory B cells. 5/10

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

Additionally, we identified Howell-Jolly bodies in the patients' blood smears - DNA remnants in erythrocytes usually removed by a functional spleen. Their presence indicates spleen dysfunction. The spleen, like the lymph nodes, is one of the secondary lymphoid organs. 4/10

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

Although no disease-causing mutations in LTBR have been described before, the gene has been well studied in KO mice, which show aberrant secondary lymphoid organs (SLOs). Like these previously described KO mice, our patients presented with a complete absence of lymph nodes. 3/10

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

We found biallelic LOF mutations in LTBR underlying a novel inborn error of immunity in patients from two unrelated families, presenting with recurrent infections and hypogammaglobulinemia. The mutation results in a complete absence of the expression of the receptor. 2/10

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Bernhard Ransmayr @bernhard-ransmayr.bsky.social · 25/11/2024

Happy to announce the publication of our paper in Science Immunology. Here we describe the first patients with biallelic disease causing mutations in the LTBR gene encoding for the lymphotoxin beta receptor. 1/10 www.science.org/doi/10.1126/...

science.org

LTβR deficiency causes lymph node aplasia and impaired B cell differentiation

Loss-of-function mutations in LTBR result in a stromal defect, leading to dysfunctional secondary lymphoid organs and combined immunodeficiency in humans.

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Reposted by Bernhard Ransmayr

Hannah Isles @hannah-isles.bsky.social · 23/11/2024

New in #ScienceImmunology: Research from @boztugk.bsky.social and team identifies an inborn error of #immunity caused by human LTβR deficiency, resulting in defective stromal cell signaling and impaired humoral immune responses. Read more: www.science.org/doi/10.1126/...

science.org

LTβR deficiency causes lymph node aplasia and impaired B cell differentiation

Loss-of-function mutations in LTBR result in a stromal defect, leading to dysfunctional secondary lymphoid organs and combined immunodeficiency in humans.

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Reposted by Bernhard Ransmayr

St. Anna Children's Cancer Research Institute (CCRI) @stanna-ccri.bsky.social · 25/11/2024

💡 Newly found genetic defect! In their study published in Science Immunology, @boztugk.bsky.social and @bernhard-ransmayr.bsky.social describe how LTBR-mutations disrupt secondary lymphoid organs, causing severe Immune Deficiencies (IEI). 🔗 tinyurl.com/57mmv5v7

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