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Human memory B cells (MBCs) are generated and diversified in secondary lymphoid tissues throughout the organism. A paired immunoglobulin (Ig)-gene repertoire analysis of peripheral blood (PB) and splenic MBCs from infant, adult, and elderly humans revealed that throughout life, circulating MBCs are comprehensively archived in the spleen. Archive MBC clones are systematically preserved and uncoupled from class-switching. Clonality in the spleen increases steadily, but boosts at midlife, thereby outcompeting small clones. The splenic marginal zone (sMZ) represents a primed MBC compartment, generated from a stochastic exchange within the archive memory pool. This is supported by functional assays, showing that PB and splenic CD21+ MBCs acquire transient CD21high expression upon NOTCH2-stimulation. Our study provides insight that the human MBC system in PB and spleen is composed of three interwoven compartments: the dynamic relationship of circulating, archive, and its subset of primed (sMZ) memory changes with age, thereby contributing to immune aging., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Kibler et al.)

Recently developed molecular prognostic tests in patients with early Binet stage chronic lymphocytic leukemia (B-CLL) are costly and often require a high level of technologic expertise. Recent data give evidence for the prognostic relevance of the percentage of smudge cells in B-CLL. In our study we analysed the prognostic potential of this novel marker in a cohort of 100 CLL patients. The percentage of smudge cells ranged from 0% to 70% (median 21%). Patients with 20% smudge cells. Multivariate Cox regression analysis identified percentages of smudge cells, stage according to Binet and CD38 expression as independent prognostic markers. The percentage of smudge cells was significantly lower in CD38+, ZAP-70+ and unmutated IgVH patients. Combined analysis of smudge cell percentages with CD38 expression provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. Comparing gene expression profiles in a subset of 12 patients we identified eight differentially expressed genes in groups with high vs. low percentage of smudge cells suggesting a role of these differentially expressed genes, especially for Tribbles homolog 2 (Trib2), in the disease progression of high risk CLL patients. In conclusion, our data confirm previous studies showing that the simple and inexpensive microscopic detection of smudge cells on blood smears prepared for routine diagnostic purposes is a novel independent factor predicting overall survival in CLL., (Copyright 2010 Elsevier Ltd. All rights reserved.)

CD49d plays a critical role in leucocyte trafficking, activation and survival, and facilitates interactions between leucocytes and stromal cells. Recent data give evidence for the prognostic relevance of CD49d protein expression in B-CLL. In our study we analyzed both the expression of CD49d protein and mRNA in a cohort of 101 CLL patients. The percentage of leukemic B-cells expressing CD49d determined by flow cytometry ranged from 0 to 100%. 37 patients with high CD49d protein expression >or=45% (according to ROC analysis) had a significantly shorter treatment-free survival (TFS) and overall survival (OS) than 64 patients with low CD49d expression (median TFS: 116 versus 43 months, p=0.015; median OS: not reached in both groups, p=0.018). CD49d protein expression was strongly associated with CD38 status (p=0.0001) and ZAP-70 status (p=0.03) but not with IGVH mutation. In multivariate analysis high CD49d expression was a significantly independent prognostic factor (HR 3.0; p=0.005). According to the strong correlation of CD49d protein expression with CD49d mRNA expression (r=0.39; p<0.0001) we could confirm the results on mRNA level with worse prognosis for patients with high mRNA level. Collectively, our data confirm the prognostic significance supporting the idea to use CD49d as target molecules for therapeutic approaches in B-CLL.

Chronic lymphocytic leukemia (CLL) is characterized by a number of T-cell abnormalities, which may play a causative role in disease progression and immune dysfunction. Recently, expression levels of CD38 in T cells have been suggested as a novel adverse prognostic factor in male CLL patients. In the current study, CD38 expression on CLL T cells was examined by flow cytometry in 126 patients with B-CLL and correlated with clinical parameters and established molecular risk factors. In line with previous results we observed a positive correlation of CD38 expression on leukemic B and non-leukemic T cells with clinical stage. CD38 expression on B-CLL cells, cytogenetic aberrations and mutations of IgVH genes were found to significantly influence treatment-free survival. By contrast, CD38 expression on T cells was not significantly associated with an adverse clinical outcome.