Chronic lymphocytic leukemia with clinical debut as neurological involvement: a rare phenomenon and the need for better predictive markers

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. The frequency of symptomatic central nervous system (CNS) involvement is unknown but thought to be a rare phenomenon. Currently there are no known risk factors for CNS involvement. CASE PRESENTATION: We describe a clinically staged low-risk CLL case that presented with symptomatic CNS involvement and progressed rapidly to death. Evaluation of the surface adhesion molecules identified a markedly altered expression pattern of the integrin, CD49d, and the tetraspanin, CD82, in the index case when compared to similar low-risk CLL cases. We found that the early Rai clinical stage CLL patients showed linear correlation for the co-expression of CD82 and CD49d. In contrast, this unique index case with CNS involvement, which has the same Rai clinical stage, had a significantly lower expression of CD82 and higher expression of CD49d. CONCLUSIONS: These data suggest that the expression profile of CD49d and CD82 may represent potential biomarkers for patients with increased propensity of CNS involvement. Moreover, this study illustrates the critical need for a better mechanistic understanding of how specific adhesion proteins regulate the interactions between CLL cells and various tissue sites

Pentraxins and IgA share a binding hot-spot on FcαRI

The pentraxins, C-reactive protein (CRP), and serum amyloid P component (SAP) have previously been shown to function as innate opsonins through interactions with Fcγ receptors. The molecular details of these interactions were elucidated by the crystal structure of SAP in complex with FcγRIIA. More recently, pentraxins were shown to bind and activate FcαRI (CD89), the receptor for IgA. Here, we used mutations of the receptor based on a docking model to further examine pentraxin recognition by FcαRI. The solution binding of pentraxins to six FcαRI alanine cluster mutants revealed that mutations Y35A and R82A, on the C-and F-strands of the D1 domain, respectively, markedly reduced receptor binding to CRP and SAP. These residues are in the IgA-binding site of the receptor, and thus, significantly affected receptor binding to IgA. The shared pentraxin and IgA-binding site on FcαRI is further supported by the results of a solution binding competition assay. In addition to the IgA-binding site, pentraxins appear to interact with a broader region of the receptor as the mutation in the C′-strand (R48A/E49A) enhanced pentraxin binding. Unlike Fcγ receptors, the H129A/I130A and R178A mutations on the BC-and FG-loops of D2 domain, respectively, had little effect on FcαRI binding to the pentraxins. In conclusion, our data suggest that the pentraxins recognize a similar site on FcαRI as IgA

Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus

Activation of β-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory storage processes and long-term potentiation in downstream targets of BLA efferents, including the hippocampus. Here, we show that this activation also increases hippocampal levels of activity-regulated cytoskeletal protein (Arc), an immediate-early gene (also termed Arg 3.1) implicated in hippocampal synaptic plasticity and memory consolidation processes. Infusions of the β-adrenoreceptor agonist, clenbuterol, into the BLA immediately after training on an inhibitory avoidance task enhanced memory tested 48 h later. The same dose of clenbuterol significantly increased Arc protein levels in the dorsal hippocampus. Additionally, posttraining intra-BLA infusions of a memory-impairing dose of lidocaine significantly reduced Arc protein levels in the dorsal hippocampus. Increases in Arc protein levels were not accompanied by increases in Arc mRNA, suggesting that amygdala modulation of Arc protein and synaptic plasticity in efferent brain regions occurs at a posttranscriptional level. Finally, infusions of Arc antisense oligodeoxynucleotides into the dorsal hippocampus impaired performance of an inhibitory avoidance task, indicating that the changes in Arc protein expression are related to the observed changes in memory performance

Evaluation Of CLL Adhesion Molecule Expression As a Diagnostic Tool For Disease Progression

Abstract Introduction Chronic lymphocytic leukemia (CLL) is a chronic B cell lymphoproliferative disorder characterized by small mature neoplastic lymphocytes, which primarily involve blood, bone marrow, and/or lymph nodes. Complex cellular and molecular interactions between CLL cells and the bone marrow or lymph node have been shown to affect CLL proliferation, survival and confer drug resistance that may be responsible for residual disease after conventional therapy. The standard methods used to assess CLL patient survival and treatment requirements involve the Rai and Binet staging systems. Pathologic markers such as CD38 expression by flow cytometric analysis, immunoglobulin heavy chain variable region (IgVH) mutation status, and conventional cytogenetics also demonstrate loose association with overall patient survival. However, these systems cannot identify stable or progressive forms of the disease in individual patients, especially in the early stages of CLL. Objective The objective of this study is to evaluate the expression profile of specific adhesion molecules that may regulate critical interactions between CLL cells and the bone marrow as potential dynamic biomarkers that correlate with CLL disease progression and response to chemotherapy. We evaluate the co-surface-expression of the molecular scaffold protein, CD82, with its interacting integrin partner, alpha 4 on CLL cells. We correlate the expression of these adhesion molecules with the patient’s clinical stage, lymphocyte doubling time (LDT), IgVH mutation status, conventional cytogenetics and the expression level of CD38 antigen on CLL cells. Methods A single-institution study prospectively enrolled CLL patients diagnosed and followed up at a university-based cancer center. Peripheral blood samples were obtained from consented patients at the time of their follow up appointments. Peripheral blood mononuclear cells were isolated from the whole blood using a ficoll density gradient and CLL cells were isolated by magnetic bead negative selection. Using flow cytometry, CLL cells were analyzed for alpha 4 and CD82 surface expression and the median fluorescence intensity values were correlated with the patient’s clinical staging parameters (Ann Arbor system, Rai stage classification) and LDT. A non-parametric measure (Spearman’s rho) was used to assess the correlation between variables. The correlation analyses were stratified by indolent cases versus aggressive disease cases and, also by the IgVH mutation status and the presence of CD38 overexpression and cytogenetics at the time of diagnosis. An unpaired t-test was used to compare differences in the CD82 and alpha 4 expression among groups. Results At the time of abstract submission, a total of 18 patients were enrolled in the pilot study. Nine patients had indolent disease and had not received treatment for CLL, whereas nine patients had received treatment for CLL at the time of enrollment. CD82 and alpha 4 expression data were not obtained for three patients on active treatment due to severe lymphopenia. CD82 and alpha 4 data were obtained for all of the indolent cases. IgVH mutation status and CD38 expression data at diagnosis were evaluated when available. A statistically significant correlation (P&lt; 0.05) was observed for the co-expression of CD82 and alpha 4 in all of the cases. When analyzed by subgroups, the co-expression of CD82 and alpha 4 remained statistically significant in the indolent disease group and there was a similar trend in the aggressive disease group that did not reach statistical significance. In the aggressive disease group, CD82 expression negatively correlated (P&lt;0.05) with lower absolute lymphocyte counts and a lower platelet counts at the time of enrollment in the study. In addition, we observed a trend of negative correlation between the CD82 expression and LDT in the indolent disease group. For those patients with CD38 overexpression a trend to a higher expression of CD82 and alpha 4 was found. Conclusion In this initial data set, we observed trends of correlation of CD82 and alpha 4 integrin expression with platelet count, absolute lymphocyte count, LDT and CD38 overexpression. In future work, we will continue to recruit more patients to enhance the statistic power of the study. Furthermore, we will evaluate the expression level changes of CD82 and alpha 4 during treatment and their role in response to chemotherapy and CLL metabolic activity. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Neutrophil and monocyte kinetics play critical roles in mouse peritoneal adhesion formation

Key Points Upon injury, the mesothelium recruits neutrophils to the peritoneal space, which contributes to adhesion formation. Neutrophil recruitment and macrophage-depletion kinetics in adhesions differ from the normal innate response.</jats:p