Lymphoid aggregates in the bone marrow biopsies of patients with myelodysplastic syndromes – A potential prognostic marker?

BackgroundLymphoid aggregates (LA) are occasionally seen in bone marrow biopsies (BMB) of myelodysplastic syndromes (MDS) patients. Our aim was to evaluate their incidence and association with prognosis.MethodsWe compared BMB reports of MDS patients treated at the Tel Aviv Sourasky Medical Center (2011-2018), and controls (2015-2017, normal BMB), and examined the charts of the MDS patients (LA+ and LA-). Categorical, normally and non-normally distributed continuous variables were compared using Fisher’s exact, independent t and Mann-Whitney tests respectively. Adjusted [age, gender, lymphocytes, white blood cells (WBC) and diabetes mellitus (DM)] Cox proportional hazard model examined survival at 12 and 24 months.ResultsMDS patients (N=140) were older than controls (N=38; 74.1 vs 69.2 years, p=0.005); 34 MDS (24.3%) and 5 controls (13.2%) had LA+ (P=0.141). CD20/CD3 staining suggested LA polyclonality. MDS/LA+ (vs MDS/LA-) patients were younger, with a trend (not statistically significant) towards poor prognostic parameters: lower Hb, WBC, and platelets, higher LDH, BM cellularity, and IPSS-R score. The incidence of cardiovascular disease was similar, but MDS/LA+ had twice the incidence of DM (38.2% vs 19.0%, p=0.022). Similar trend for cancer (26.5% vs 14.3%, p=0.102). Twelve-month survival: 24/34 (70.6%) MDS/LA+; 88/106 (83.0%) MDS/LA- (p=0.140). This trend, seen in Kaplan-Meier curves, disappeared at 24 months. The hazard ratio for LA was 2.283 (p=0.055) for 12 months.ConclusionThese preliminary data suggest LA are relatively common (24%) in MDS BMB, and might indicate poor prognosis. This may reflect involvement of the immune system in MDS. Future studies will examine larger groups, to clarify the incidence, significance and the pathophysiology

Endurance exercise diverts the balance between Th17 cells and regulatory T cells.

Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon) on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes, Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs). While interleukin (IL)-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF) β levels were significantly elevated. Treg levels in sedentary controls' decreased in vitro after incubation with athletes' post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies. Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma

The Clinical Significance of Circulating Lymphocytes Morphology in Diffuse Large B-Cell Lymphoma As Determined by a Novel, Highly Sensitive Microscopy

Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable treatment in relapsed/refractory diffuse large B-cell lymphomas (DLBCL) patients. Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to insufficient data regarding their morphology and low sensitivity. The morphological evolution of CAR Ts along their production process, and in patients, was established by Full-Field Morphology (FFM), a novel digital microscopy approach that provides highly sensitive PBS analysis. At day 8 of production, 42.7 ± 10.8% of the CAR T transduced cells exhibited activated morphology compared with 9.3 ± 3.8% in untransduced cells. Moreover, engagement of transduced CAR Ts with target cells resulted in further morphological transformation into activated morphology (83 ± 5.6% of the cells). In patients, the average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. A high number of activated morphology CAR Ts at day 14 was associated with prolonged cytokine release storm. Overall, CAR Ts exhibited heterogeneous morphology, with the activated morphology attributed predominantly to transduced cells following engagement with target cells. Post-transfusion CAR T detection was associated with increased complete responses. FFM CAR T surveillance in PBS may serve as a simple inexpensive method to provide clinically relevant insights into this treatment modality

Endurance exercise induced changes in cytokine levels.

<p>Shown are changes in serum levels of cortisol, IL-6, IL-10 and TGFβ (ELISA) in response to endurance exercise. Pre = pre- exercise, Post = post- exercise, Recovery = 10 days post-exercise. * = statistically significant differences (p<0.05).</p

Exercise-induced changes in white blood cell and CD4+ lymphocytes.

<p>Shown are peripheral blood counts of white blood cells and differential counts of neutrophils, lymphocytes Coulter LH 750 Analyzer (Beckman Coulter) and percentage of CD4+, CD4+CD25+, FoxP3+Treg and Th17 lymphocytes (Flow cytometer) as measured 4 days before endurance exercise (pre-race), at the end of exercise (post-exercise) and 10 days after the competition (recovery). NS = not statistically significant.</p

Sustained decrease in Tregs and FOXP3 levels in response to endurance exercise.

<p>Percent change in of CD4+CD25+FoxP3+ (Tregs), from the total CD4+ lymphocytes (<b>A</b>) and mean fluorescence intensity (MFI) of FOXP3 within the Tregs (<b>B</b>) in response to endurance exercise, as analyzed by flow cytometry. (<b>C</b>) Representative Tregs levels, as detected by flow cytometry. Pre = pre- exercise, Post = post- exercise, Recovery = 10 days post-exercise. ** = statistically significant differences (p<0.01).</p

A model of homeostatic balance between Tregs and Th17 under endurance exercise.

<p>Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.</p

Post-race serum can induce a decrease in Tregs levels <i>in vitro</i>.

<p>Shown are changes in controls' PBMNC that were incubated for 4 hours with athletes' pre-race (pre) and post-race (post) serum. Athletes post-race serum induced a significant decrease in controls Tregs levels (mean percent of Tregs 3±1.93% and 1.9±1.6% in pre- and post-race serum, respectively; p = 0.009 Student <i>t</i> test).</p