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

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

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

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

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

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