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We reviewed eight cases that were diagnosed before 1995 with B-prolymphocytic leukaemia (B-PLL) harbouring t(11;14)(q13;q32) and/or cyclin D1 staining. Thirteen B-PLL patients without t(11;14) were selected as controls. Peripheral blood, bone marrow and histological sections were re-examined without cytogenetic information. Final diagnosis was made using morphology, cytogenetics, immunophenotype and immunohistochemistry. Clinical characteristics were similar for both groups except for younger age, male predominance and extranodal involvement in cases with t(11;14). CD5 was more frequently positive in the t(11;14)+ group (80%) than in the t(11;14)− group (31%). Surface membrane immunoglobulin was strongly expressed by all t(11;14)+ cases, but only 45% of t(11;14)− cases. Histopathological and cytological review of cases with t(11;14) showed an infiltrate with a mixture of cells, some resembling prolymphocytes and others with mantle cell lymphoma (MCL) morphology. Blood films of cases with t(11;14) showed features suggestive of B-PLL in three, and in others, a mixture of cells resembling MCL and nucleolated ones; none corresponded to the blastoid form of MCL. We suggest that ‘B-PLL’ with t(11;14) may represent a splenomegalic form of MCL evolving with leukaemia. These cases illustrate the importance of tissue diagnosis with cyclin D1 staining and fluorescence in situ hybridization analysis in B-cell leukaemia with prolymphocytic features. [ABSTRACT FROM AUTHOR]

Because of its B-cell depleting effect, rituximab has entered clinical trials in several autoimmune conditions. This study assesses the efficacy and safety of rituximab in 57 adults with chronic immune thrombocytopenic purpura (ITP). All patients had platelet counts <30 × 109/l, all had received two or more previous ITP treatments and 31 had undergone splenectomy. Patients received rituximab 375 mg/m2 weekly for 4 weeks. Thirty-one patients (54%) responded, achieving a platelet count >50 × 109/l: 18 achieved a complete response (CR: platelet count >150 × 109/l) and 13 a partial response (PR: platelet count 50–150 × 109/l). Twenty-nine responses occurred within 8 weeks of the first infusion. Sixteen of 18 CR patients (28% overall), including eight who had failed splenectomy, continued in CR after a median of 72·5 weeks; 15 of 16 are >1 year from the first infusion. Only two of 13 maintained a PR. Thirty-three patients experienced grade 1–2 adverse events and one a grade 3 event, but they all completed treatment. Circulating B cells fell to <0·03 × 109/l. No changes in immunoglobulin levels or infectious complications were seen. In summary, rituximab was well tolerated with no immediate complications and induced a lasting, substantial response in 32% of adults with chronic ITP. [ABSTRACT FROM AUTHOR]

The frequency and prognostic relevance of translocations t(11;14) and t(4;14), the most common translocations involving the immunoglobulin heavy chain (IgH) gene in multiple myeloma (MM), were investigated in 128 patients treated with intensive chemotherapy and autologous stem cell transplant. Myeloma cells were identified by cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (cIg-FISH) for detection of translocations t(11;14) and t(4;14). Overall, t(11;14) was detected in 16 of 125 (12·8%) and t(4;14) in 15 of 120 (12·5%) patients. Progression-free and overall survivals were similar for patients with or without t(11;14). However, patients with t(4;14) had significantly shorter progression-free (median 9·9 months vs. 25·8 months; P = 0·0003) and overall survivals (median 18·3 months vs. 48·1 months; P < 0·0001) than patients without t(4;14). The t(4;14) was associated with IgA and t(11;14) with light chain MM. There was no association between the t(11;14) or t(4;14) and other biological parameters including age, gender, haemoglobin, β-2 microglobulin, C-reactive protein, calcium, creatinine, albumin, or the percentage of bone marrow plasma cells. Multivariate analysis identified t(4;14) as the only adverse prognostic factor for both progression-free survival and overall survival. Our results indicate that the t(4;14) detected by cIg-FISH is associated with a poor prognosis in MM patients receiving intensive chemotherapy and autotransplant. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) of inflammatory cytokine genes were examined in 84 adult Japanese patients with chronic immune thrombocytopenic purpura (ITP) and 56 race-matched healthy controls. The SNPs examined were within the genes encoding tumour necrosis factor (TNF)- α (−238 G/A and −308 G/A), TNF- β (+252 G/A), and interleukin (IL)-1 β (−511 C/T and +3953 T/C). Of these SNPs, the frequency of the TNF- β (+252) G/G phenotype was significantly higher in ITP patients than in healthy controls (21% vs. 7%, P = 0·04, odds ratio = 3·6, 95% confidence interval 1·1–11·1), while no significant association was detected for the other SNPs. The distribution of the TNF- β (+252) phenotype was not associated with human leucocyte antigen class II alleles or the therapeutic response in ITP patients. The frequency of circulating anti-glycoprotein IIb/IIIa antibody-producing B cells was significantly higher in ITP patients with the TNF- β (+252) G/G phenotype than in those with the G/A or A/A phenotype (11·9 ± 4·9 vs. 6·8 ± 4·9 and 3·7 ± 2·8 per 105 peripheral blood mononuclear cells; P = 0·02 and P < 0·001, respectively). These findings suggest that the SNP located at TNF- β (+252) contributes to susceptibility to chronic ITP by controlling the autoreactive B-cell responses to platelet membrane glycoproteins. [ABSTRACT FROM AUTHOR]

We have investigated whether intracellular signal transduction molecules can be used as immunohistological markers of normal and neoplastic human leucocytes in routine tissue sections. We obtained selective labelling of white cells for eight such molecules (the ‘linker’ molecules SLP-76 and BLNK, the Src family kinases Lyn, Fyn, Syk and Hck, and the phospholipases PLC- γ1 and PLC- γ2). Antibodies to SLP-76 and PLC- γ1 selectively labelled T cells, and antibodies to BLNK, Lyn, Fyn, Syk and PLC- γ2 labelled B cells (although Fyn immunostaining was restricted to mantle zone B cells). Antibodies to the Syk and Hck kinases labelled probable thymocyte precursors at the periphery of the thymic cortex. In addition to lymphoid cells, several other leucocyte types were immunostained (e.g. SLP-76, Lyn, Syk and Hck were found in megakaryocytes, myeloid cells and/or macrophages, and PLC- γ2 was detected in arterial endothelium). SLP-76 and PLC- γ1 were found in most T-cell lymphomas studied, and some B-cell lymphomas were also positive for PLC- γ1 (e.g. diffuse large cell and Burkitt's lymphoma). The five B cell-associated markers were found in most B-cell non-Hodgkin's lymphomas, although some diffuse large B-cell lymphomas were negative (e.g. for Lyn) and anti-Fyn tended not to stain small B-cell neoplasms. The observation that a range of leucocyte signalling molecules can be detected in routine biopsies offers new possibilities for studying normal and neoplastic human white cells in diagnostic tissue samples. [ABSTRACT FROM AUTHOR]

Intravenous (IV) anti-D and IV immunoglobulin (IVIG) slow the Fc γ receptor (Fc γR)-mediated destruction of antibody-coated platelets in patients with immune thrombocytopenic purpura (ITP). This pilot study explored the mechanism of these immunoglobulin preparations by measuring interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1), IL-6 and tumour necrosis factor  α (TNF α), before and after infusion and by assessing the effect of Fc γRIIa and Fc γRIIIa polymorphisms on both cytokine and haematologic responses to anti-D. Following IVIG, only IL-10 was increased at 2 h and MCP-1 on day 7 ( P < 0·05). In contrast, 2 h after anti-D infusion, plasma levels of all four cytokines were increased ( P < 0·01); five of six patients with the highest MCP-1, IL-6 and TNF α levels had chills. Higher IL-10 levels correlated with platelet increases at 24 h and haemoglobin decreases at day 7 ( P < 0·025). Patients with the Fc γRIIa-131HH genotype had significantly higher MCP-1, IL-6 and TNF α levels. Patients with the Fc γRIIIa-158VF genotype had higher platelet increments at day 7 ( P < 0·05). Soluble CD16 (sCD16) was increased 2 h after IV anti-D; day 7 levels correlated with day 7 haemoglobin decreases ( P < 0·01). In conclusion, the relationship of Fc γRIIa and Fc γRIIIa polymorphisms with both cytokine levels and platelet increments implicated these receptors in responses to anti-D and supported different mechanisms of Fc γR interaction to those seen with IVIG. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) shares immunophenotypic and karyotypic features with chronic lymphocytic leukaemia. The latter comprises two distinct entities with prognosis dependent upon immunoglobulin heavy chain (IgH) gene mutational status and the presence of 11q deletion. We evaluated the relevance of IgH gene mutational status, IgV gene family usage and presence of 11q deletion in a series of 42 histologically reviewed classical MCL cases to determine the prognostic impact. VH3 was the most common VH family, with VH3-21 being the most frequent individual VH gene. Approximately 30% of the cases had a IgH somatic mutation rate higher than 2%, but was only higher than 4% in <10% of cases. Half of the cases had deletion of chromosome 11q21-telomere (11q21->ter), with two minimal deleted regions, at 11q22.2 and 11q23.2. There was no association between 11q loss and IgH gene somatic mutation rate; the use of VH3-21 gene could be associated with a better prognosis. [ABSTRACT FROM AUTHOR]

Systemic AL amyloidosis (AL) is a disorder in which light chains form fibrillar deposits, leading to organ dysfunction and death. Rarely, AL has been associated with non-Hodgkin's lymphoma (NHL), although this association has not been well characterized. We report a series of six patients with AL associated with NHL, primarily lymphoplasmacytic lymphoma. Organ involvement was variable, with frequent bulky lymphadenopathy and visceral cavity deposits, but no cardiac involvement. Positron emission tomography scans were negative. Bone marrow and lymph node biopsies showed a mixed population of CD20+ lymphoid and CD138+ plasma cells. Serum free light chains were elevated, and correlated with response to therapy. Immunoglobulin light chain variable region (Ig VL) germline gene use was typical for AL, reflecting previously observed correlations between germline gene use and organ tropism. Five patients received rituximab-based therapies with two responses. Two patients underwent autologous stem cell transplantation with one complete haematological response. Four patients survive at 10–132 months from diagnosis. AL with NHL has distinctive clinical features but employs the same Ig VL gene repertoire as AL with clonal plasma cell dyscrasias. Serial serum free light chain levels are useful for tracking response to therapy. Treatments aimed at both lymphoid and plasma cell components appear warranted. [ABSTRACT FROM AUTHOR]

Alloantibody tests demonstrate immunological causes of insufficient increments in random platelet transfusions. The value of a positive or negative test result in predicting the outcome of human leucocyte antigen (HLA)-matched transfusions in patients refractory to leucodepleted random platelet transfusions has not been assessed. We retrospectively evaluated the outcome of the first HLA-matched platelet transfusion in 72 patients with haematological diseases in two ways: first, the strategy according to which the patient was selected for HLA-matched platelet transfusions was analysed. The strategies were: (i) results of alloantibody tests were not available, (ii) a positive alloantibody test, (iii) a negative alloantibody test. Secondly, the outcome of the first HLA-matched transfusion was investigated relative to the results of alloantibody tests, irrespective of the decision strategy. No significant association was found between the decision strategy and the outcome of the first HLA-matched platelet transfusion. Positive alloantibody tests, however, predicted a better outcome of the first HLA-matched platelet transfusion ( P = 0·04 and P = 0·03 after 1 and 16 h respectively). In patients refractory to random platelet transfusions, positive alloantibody tests predicted a better outcome of HLA-matched platelet transfusions. Patients with negative alloantibody tests, however, may benefit from HLA-matched platelet transfusions. [ABSTRACT FROM AUTHOR]

The article discusses the relationship between antibody specificities and efficacy of rituximab in patients with primary immune thrombocytopenia (ITP). The authors discovered that patients with anti-GPIIb/IIIa autoantibodies responded more to rituximab therapy. Autoantibody specificity was found before rituximab therapy using modified monoclonal antibody immobilization of platelet antigen assay.

Antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction ( ITI). Our knowledge about ITI in haemophilia A and B was, historically, derived from small cohort studies and retrospective national and international ITI registries. Practice is now further influenced by prospective cohort data, and the results of a single prospective randomized international ITI trial. However, due to the low incidence of inhibitors in haemophilia B, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of factor IX inhibitors. The lack of an effective strategy is particularly problematic given the morbidity associated with the unique occurrence of allergic and anaphylactic reactions that often herald factor IX antibody development and preclude effective eradication. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; review the current consensus practice recommendations for ITI; and summarize the emerging body of immunological science relating to antibody formation and tolerance. It will conclude by suggesting how our knowledge might inform the future investigative priorities impacting the therapeutic and preventative tolerance strategies of tomorrow. [ABSTRACT FROM AUTHOR]

Acquired haemophilia A is an auto-immune disease caused by an inhibitory antibody to factor VIII. Patients with an acquired factor VIII inhibitor are at risk of life- and limb-threatening bleeding until the inhibitor has been eradicated. Management relies on rapid and accurate diagnosis, control of bleeding episodes, investigation for a precipitating cause and eradication of the inhibitor by immunosuppression. Patients should always be managed jointly with a specialist centre even if they present without overt bleeding. Despite an extensive literature, few controlled data are available and management guidelines are predominantly based on case reports, retrospective cohorts and expert opinion. This paper reviews the current literature on incidence, pathogenesis, diagnosis, haemostatic therapy and inhibitor eradication strategies. Potential future developments are discussed. [ABSTRACT FROM AUTHOR]

In conclusion, anti-IFC antibodies are capable of inducing an acute extravascular haemolytic transfusion reaction and IFC-compatible blood should be strongly considered for elective blood transfusion in patients with CHAPLE syndrome. CHAPLE syndrome is an extremely rare autosomal recessive condition hallmarked by a complete loss of the CD55 protein, hyperactivation of complement, angiopathic thrombosis and protein-losing enteropathy based on primary lymphangiectasia.[1] The mechanism behind this syndrome is believed to reside in the fact that CD55, also known as the decay accelerating factor, mitigates complement activation and thus modulates the immune response.[[1]] Importantly, the CD55 protein harbours the entire Cromer blood group system and patients with CHAPLE syndrome characteristically produce antibodies against these antigens when exposed to red blood cells (RBCs) from CD55 SP + sp individuals.[[3], [5]] The clinical characteristics of these antibodies have not been well documented and are thus largely unclear. It is possible that anti-IFC antibodies vary between patients in their potential of causing a haemolytic transfusion reaction. [Extracted from the article]

The clinical influence of preformed nonspecific anti-HLA antibodies on single-unit umbilical cord blood transplantation in patients with haematological malignancies For over 30 years, umbilical cord blood transplantation (UCBT) has been an option available to patients who require allogeneic haematopoietic stem cell transplantation (allo-HSCT) but for whom a human leukocyte antigen (HLA)-matched sibling or unrelated donor is unavailable.1 Anti-HLA antibodies (AHAs) are antibodies that target class I and II HLA antigens and are mostly produced in response to foreign antigens during pregnancy, blood transfusion, or solid organ transplantation. Among the 392 patients, seventy-three patients (18.6%) were positive for AHAs and were considered the AHA-positive group, and the remaining 319 patients were considered the AHA-negative group. [Extracted from the article]

Vaccine-induced immune thrombocytopenia and thrombosis: The decline in anti-platelet factor 4 antibodies is assay-dependent The platelet-activating antibodies in the PIPA have disappeared by 12 weeks post vaccination in most patients,6 although we had at least one patient out of six who had a positive PIPA assay after 14 weeks. Keywords: ELISA; platelet activation; thrombocytopenia; thrombosis; vaccines EN ELISA platelet activation thrombocytopenia thrombosis vaccines 428 430 3 05/10/22 20220515 NES 220515 NICE guidance on the management of vaccine-induced immune thrombocytopenia and thrombosis (VITT) has recently been published.1 This includes recommendations on which laboratory assays should be performed at diagnosis and during recovery, as well as recommendations on anticoagulation and other therapeutic strategies. [Extracted from the article]

Summary: Treatment of relapsed/resistant acute myeloid leukaemia (AML) remains a significant area of unmet patient need, the outlook for most patients remaining extremely poor. A promising approach is to augment the anti‐tumour immune response in these patients; most cancers do not activate immune effector cells because they express immunosuppressive ligands. We have previously shown that CD200 (an immunosuppressive ligand) is overexpressed in AML and confers an inferior overall survival compared to CD200low/neg patients. Here we show that a fully human anti‐CD200 antibody (TTI‐CD200) can block the interaction of CD200 with its receptor and restore AML immune responses in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The article discusses research on the prevalence of immunoglobulin (Ig) paraproteinemia in diffuse large B cell lymphoma (DLBCL) populations and its prognostic influence. Topics covered include baseline characteristics and their associations with Ig paraprotein in patients, survival analysis regarding the association of Ig paraprotein with both progression-free survival (PFS) and overall survival (OS), and the association between survival and type of Ig paraprotein.

Summary: Autoantibodies to thrombopoietin (TPO, also termed THPO) or the TPO receptor (cMpl, also termed MPL) could play a pathological role in immune thrombocytopenia (ITP). In this study, we tested for autoantibodies against TPO, cMpl, or the TPO/cMpl complex in ITP and other thrombocytopenic disorders. Using an inhibition step with excess TPO in fluid‐phase to improve binding specificity, the prevalence of anti‐TPO autoantibodies was: active ITP: 9/32 (28%); remission ITP: 0/14 (0%); non‐immune thrombocytopenias: 1/10 (10%); and healthy controls: 1/11 (9%). Similarly, using an inhibition step with excess cMpl, the prevalence of specific anti‐cMpl autoantibodies was: active ITP: 7/32 (22%); remission ITP: 1/14 (7%); non‐immune thrombocytopenias: 3/10 (30%); and healthy controls: 0/11 (0%). Two active ITP patients had autoantibodies against the TPO/cMpl complex, but not against TPO or cMpl alone. Anti‐TPO or anti‐cMpl autoantibodies were found in 44% of ITP patients, and in 40% of patients with other thrombocytopenic disorders. These autoantibodies did not correlate with ITP disease severity or number of ITP treatments received; however, in this cohort, 3 patients failed to respond to TPO receptor agonist medications, and of those, 2 had anti‐TPO autoantibodies. This suggests that anti‐TPO and anti‐cMpl autoantibodies are associated with thrombocytopenia, and may be clinically relevant in a subset of ITP patients. [ABSTRACT FROM AUTHOR]

Summary: Immune dysfunction attributed to hypogammaglobulinaemia is common in chronic lymphocytic leukaemia (CLL) and infection is a major contributor to morbidity and mortality. A higher incidence of multiple immunoglobulin and immunoglobulin G (IgG) subclass deficiency was associated with more advanced disease (P < 0·001 and P < 0·001, respectively) in a cohort of 147 CLL patients. Multiple immunoglobulin and IgG subclass deficiency were significantly associated with shorter treatment‐free survival (TFS) (P < 0·001 and P = 0·006, respectively). The association between disease stage and immune dysfunction demonstrated by these data suggest aspects of immune deficiency correlate with disease severity and may be associated with shorter TFS in CLL. [ABSTRACT FROM AUTHOR]

Haemolytic disease of the fetus and newborn (HDFN) is a severe disease in which fetal red blood cells (RBC) are destroyed by maternal anti-RBC IgG alloantibodies. HDFN is most often caused by anti-D but may also occur due to anti-K, -c- or -E. We recently found N-linked glycosylation of anti-D to be skewed towards low fucosylation, thereby increasing the affinity to IgG-Fc receptor IIIa and IIIb, which correlated with HDFN disease severity. Here, we analysed 230 pregnant women with anti-c, -E or -K alloantibodies from a prospective screening cohort and investigated the type of Fc-tail glycosylation of these antibodies in relation to the trigger of immunisation and pregnancy outcome. Anti-c, -E and -K show - independent of the event that had led to immunisation - a different kind of Fc-glycosylation compared to that of the total IgG fraction, but with less pronounced differences compared to anti-D. High Fc-galactosylation and sialylation of anti-c correlated with HDFN disease severity, while low anti-K Fc-fucosylation correlated with severe fetal anaemia. IgG-Fc glycosylation of anti-RBC antibodies is shaped depending on the antigen. These features influence their clinical potency and may therefore be used to predict severity and identify those needing treatment. [ABSTRACT FROM AUTHOR]

Brentuximab vedotin ( BV) significantly improved progression-free survival in a phase 3 study in patients with relapsed or refractory Hodgkin lymphoma ( RR- HL) post-autologous-haematopoietic stem cell transplant (auto-HSCT); we report the impact of BV on quality of life ( QOL) from this trial. The European Quality of Life five dimensions questionnaire was administered at the beginning of each cycle, end of treatment, and every 3 months during follow-up; index value scores were calculated using the time trade-off ( TTO) method for UK-weighted value sets. Questionnaire adherence during the trial was 87·5% ( N = 329). In an intent-to-treat analysis, compared with placebo, TTO scores in the BV arm did not exceed the minimally important difference ( MID) of 0·08 except at month 15 (−0·084; 95% confidence interval, −0·143 to −0·025). On-treatment index scores were similar between arms and did not reach the MID at any time point; mixed-effect modelling showed that BV treatment effect was not significant ( P = 0·2127). BV-associated peripheral neuropathy did not meaningfully impact QOL. Utility scores for patients who progressed declined compared with those who did not; TTO scores between these patients exceeded the MID beginning at month 15. In conclusion, QOL decreased modestly with BV consolidation treatment in patients with RR- HL at high risk of relapse after auto- HSCT. [ABSTRACT FROM AUTHOR]

Calculations of blood group antigen immunogenicity have been based on antigen and antibody frequencies in transfused populations, with the assumption of a single red blood cell ( RBC) unit exposure per patient. Given that patients are usually transfused >1 RBC unit, antigen exposures will be greater than assumed, resulting in inaccurate immunogenicity calculations. As such, the goal of this study was to modify the calculation to correct for RBC exposures. To further improve accuracy, we used an empirically-derived immunogenicity for the reference antigen, K, in calculations of absolute immunogencity and eliminated anamnestic and pre-existing antibodies (i.e., antibodies induced outside the study site) from the calculation. Alloantibody numbers for the top 12 specificities and mean RBCs ( MRBC) transfused per patient were obtained from the records of a hospital transfusion service. A revised immunogenicity calculation, incorporating a correction for MRBC, was developed. This correction resulted in up to a 4-fold increase in the immunogenicity of relatively high frequency antigens, with smaller increases for lower frequency antigens, yielding the following revised immunogenicity ranking: K>Jka>Lua>E>P1>c>M>Leb>C>Lea>Fya>S. Use of an empirical value for K immunogenicity resulted in a 1·9-fold increase in absolute immunogenicities for all antigens. In summary, the calculation of blood group antigen immunogenicity has been further refined. [ABSTRACT FROM AUTHOR]

Historically, an increase in the percentage and number of circulating prolymphocytes in chronic lymphocytic leukaemia ( CLL) has been associated with strong expression of surface immunoglobulin, trisomy 12 and a poor outcome. This study re-examines the biological and clinical significance of increased peripheral blood prolymphocytes in 508 patients at entry into the randomized UK Leukaemia Research Fund CLL4 trial. It also investigates the associations between increased prolymphocytes and a comprehensive array of biomarkers. 270 patients (53%) had <5% prolymphocytes, 167 (33%) had 5-9%, 60 (12%) had 10-14% and 11 (2%) had ≥15% prolymphocytes. We show that a higher proportion of prolymphocytes (≥10%) was independently associated with NOTCH1 mutations ( P = 0·006), absence of 13q deletion ( P = 0·001), high CD38 expression ( P = 0·02) and unmutated IGHV genes ( P = 0·01). Deaths due to Richter syndrome were significantly more common amongst patients who had ≥10% vs <10% prolymphocytes (13% vs 2%) respectively ( P < 0·0001). ≥10% prolymphocytes was also associated with a shorter progression-free survival (Hazard ratio [ HR] 1·50 [95% confidence interval [ CI]: 1·16-1·93], P = 0·002) and overall survival ( HR 1·99 [95% CI: 1·53-2·59], P < 0·0001). Our data support the routine examination of blood films in CLL and suggest that a finding of an increased proportion of prolymphocytes may be a trigger for further evaluation of clinical and laboratory features of progressive disease. [ABSTRACT FROM AUTHOR]

Keywords: human platelet antigens; fetal and neonatal alloimmune thrombocytopenia; HPA-5b EN human platelet antigens fetal and neonatal alloimmune thrombocytopenia HPA-5b 485 486 2 11/18/21 20211115 NES 211115 Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by maternal IgG antibodies produced against incompatible human platelet antigens (HPA) on fetal platelets. This was probably because many hospital laboratories can detect HPA-1a antibodies using commercial platelet antibody detection kits and, therefore, reference laboratories like Sanquin receive fewer HPA-1a cases and more difficult FNAIT cases for testing. HPA antibodies were detected in maternal sera from 262 (14%) cases: 161 (61%) HPA-1a antibodies and 60 (23%) HPA-5b antibodies. [Extracted from the article]

Multiple myeloma ( MM) is characterized by the enhanced production of the same monoclonal immunoglobulin (M-Ig or M protein). Techniques such as serum protein electrophoresis and nephelometry are routinely used to quantify levels of this protein in the serum of MM patients. However, these methods are not without their shortcomings and problems accurately quantifying M proteins remain. Precise quantification of the types and levels of M-Ig present is critical to monitoring patient response to therapy. In this study, we investigated the ability of the HevyLite ( HLC) immunoassay to correlate with clinical status based on levels of involved and uninvolved antibodies. In our cohort of MM patients, we observed that significantly higher ratios and greater differences of involved HLC levels compared to uninvolved HLC levels correlated with a worse clinical status. Similarly, higher absolute levels of involved HLC antibodies and lower levels of uninvolved HLC antibodies also correlated with a worse clinical status and a shorter progression-free survival. These findings suggest that the HLC assay is a useful and a promising tool for determining the clinical status and survival time for patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

High-throughput sequencing ( HTS) is considered a technical revolution that has improved our knowledge of lymphoid and autoimmune diseases, changing our approach to leukaemia both at diagnosis and during follow-up. As part of an immunoglobulin/T cell receptor-based minimal residual disease ( MRD) assessment of acute lymphoblastic leukaemia patients, we assessed the performance and feasibility of the replacement of the first steps of the approach based on DNA isolation and Sanger sequencing, using a HTS protocol combined with bioinformatics analysis and visualization using the Vidjil software. We prospectively analysed the diagnostic and relapse samples of 34 paediatric patients, thus identifying 125 leukaemic clones with recombinations on multiple loci ( TRG, TRD, IGH and IGK), including Dd2/Dd3 and Intron/ KDE rearrangements. Sequencing failures were halved (14% vs. 34%, P = 0.0007), enabling more patients to be monitored. Furthermore, more markers per patient could be monitored, reducing the probability of false negative MRD results. The whole analysis, from sample receipt to clinical validation, was shorter than our current diagnostic protocol, with equal resources. V(D)J recombination was successfully assigned by the software, even for unusual recombinations. This study emphasizes the progress that HTS with adapted bioinformatics tools can bring to the diagnosis of leukaemia patients. [ABSTRACT FROM AUTHOR]

Immunoglobulin light chain ( AL) amyloidosis, the most common of the systemic amyloidosis, is characterized by the deposition of amyloid fibrils that derive from the aggregation of misfolded monoclonal immunoglobulin light chains. Amyloid fibrils disrupt tissue architecture and the pre-fibril oligomers are directly toxic to myocardiac cells, causing cardiac dysfunction. The lethal consequences of AL amyloidosis are due to the toxic product and not due to the malignant behaviour of the plasma cell clone; however, the characteristics of this clone are associated with long-term prognosis. Early and accurate diagnosis is the key to effective management, but is challenging. Modern chemotherapy options (including autologous transplantation, bortezomib, lenalidomide) have improved the outcomes of patients at low or intermediate risk, but the prognosis of patients with severe cardiac dysfunction is still poor. Therapies targeting amyloid deposits and the amyloidogenic process are under investigation and offer promise for better future treatments. [ABSTRACT FROM AUTHOR]

The article offers information on a study concerning induction of human leucocyte antigen (HLA)-B restricted T cells possessing cytotoxic and suppressive functions against haematopoietic progenitor cells from a patient with severe aplastic anaemia. Topics discussed include treatment of acquired aplastic anaemia (AA) with antithymocyte globulin and ciclosporin (CsA), bone marrow (BM) hypoplasia and pancytopenia, and immune pressure of autoreactive cytotoxic T lymphocytes.

The article discusses findings of a study on use of heavy/light chain (HCL) ratio for the assessment of minimal residual disease in myeloma patients achieving complete response. It states that a study of HLC ratio, and its comparison with free light chain (FLC) ratio, for the evaluation of minimal residual disease (MRD) and early detection of relapse, and mentions that Abnormal HLC ratios at presentation have been associated with shorter overall survival in multiple myeloma.

The article discusses the anti-CD20 antibodies rituximab and obinutuzumab and their differential regulation pattern in mantle cell lymphoma. Topics include information on Mantle cell lymphoma (MCL), the higher reduction in cell viability of every MCL cell line of Obinutuzumab as compared to rituximab, and the need for more combination experiments to show potential additive effects in MCL therapy.

Red blood cell ( RBC) antibodies can persist for decades or decrease quickly to undetectable levels. Antibody persistence has not been systematically studied. Women whose children are treated with intrauterine transfusions ( IUT) for haemolytic disease of the fetus ( HDFN) often produce additional antibodies, which can be evoked by the intrauterine transfusion or by fetomaternal haemorrhage during the procedure. Factors associated with persistence of both the antibodies responsible for HDFN and additional antibodies were studied in 260 women whose children were treated with IUT between 1988 and 2008. They possessed 499 (205 anti-D and 294 non-D) antibodies after the last IUT. After a median follow-up of 8·7 years, all 260 antibodies primarily responsible for HDFN had persisted. Additional antibodies directed against antigens of the children persisted in 70·6%, and in 32·3% if they were not child-specific ( P < 0·001). Antibodies induced by irradiated IUT persisted in only 7·1%. Multivariate analyses showed that non- HDFN antibody persistence was dependent on the antibody titre and specificity. In conclusion, persistence of antibodies mainly depends on antibody strength and specificity. Difference between fetal or non-fetal immunogens suggests maintenance of antigenic stimulation possibly by long-term fetomaternal chimerism. [ABSTRACT FROM AUTHOR]

The article discusses the role of immunoglobulin ratio in identification of monoclonal gammopathy of patients that are at high risk of progression to multiple myeloma. Topics discussed include risk factors of monoclonal gammopathy, the increase in monoclonal immunoglobulin during progression risk to multiple myeloma, and the analysis of heavy/light chain (HLC) pairs in cohort of monoclonal gammopathy patients.

Amiodarone has been implicated as a cause of thrombocytopenia but the responsible mechanism is unknown. We performed studies in three patients to characterize the pathogenesis of this complication. No amiodarone-dependent, platelet-reactive antibodies were identified using conventional serological techniques. However, water-insoluble amiodarone solubilized in methanol and diluted to 1·0 mg/ml in aqueous buffer reproducibly promoted binding of Ig G antibodies in patient serum to platelets. Solid phase assays identified drug-dependent antibodies specific for platelet glycoproteins ( GP)Ia/ IIa (integrin α2β1) in each patient and a second antibody specific for GPIIb/ IIIa (α IIbβ3 integrin) in one patient. When studied by ion mobility analysis and transmission electron microscopy, the serologically active amiodarone preparation, a milky suspension, was found to consist of particles 2-30 nm in diameter, typical of a coacervate, a state characteristic of amiodarone in aqueous medium. The findings provide evidence that thrombocytopenia in the three patients studied was caused by drug-dependent antibodies specific for platelet glycoproteins GPIa/ IIa and/or GPIIb/ IIIa. We postulate that, in vivo, amiodarone may become incorporated into occult lipophilic domains in platelet glycoproteins, producing structural modifications that are immunogenic in some individuals, and that the resulting antibodies can cause platelet destruction in a person taking this drug. [ABSTRACT FROM AUTHOR]

Patients with immune thrombocytopenia ( ITP) paradoxically have an increased risk of thrombosis. The presence of antiphospholipid antibodies ( aPL) has been observed in a substantial proportion of ITP patients, but its clinical significance remains to be established. This study retrospectively investigated the prevalence and clinical significance of aPL in ITP patients and assessed the risk factors for thrombosis. One hundred and sixty-five subjects with ITP were included in the study and followed for a mean period of 63·4 months. Sixty-nine (41·6%) patients were positive for aPL at diagnosis, and their clinical characteristics and course of ITP were not different from those of aPL-negative patients. Twenty-one (12·7%) patients developed a thrombotic event during follow-up and the cumulative incidence rate ratio of aPL-positive to aPL-negative patients for thromboembolism was 3·15 [95% confidence interval ( CI) 1·21-8·17] after adjusting for confounding factors. Lupus anticoagulant and hypertension were identified by Cox regression analysis as independent risk factors for thrombosis [hazard ratio ( HR) 4·1, 95% CI 1·4-11·9, P = 0·009 and HR 5·6, 95% CI 1·9-15·8, P = 0·001, respectively]. Our results showed that a substantial proportion of ITP patients were aPL-positive, and that lupus anticoagulant and hypertension were independent risk factors for thrombosis. Detection of aPL can provide useful information for identifying patients at high-risk for developing thrombosis. [ABSTRACT FROM AUTHOR]

The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma ( MM), as defined by the current International Myeloma Working Group ( IMWG) criteria, in patients with immunoglobulin light chain amyloidosis ( AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0·27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0·005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL. [ABSTRACT FROM AUTHOR]

This study, conducted for the UK Blood Transfusion Services ( UKBTS), evaluated the clinical safety of red cells filtered through a CE-marked prion removal filter (P-Capt™). Patients requiring blood transfusion for elective procedures in nine UK hospitals were entered into a non-randomized open trial to assess development of red cell antibodies to standard red cell ( RCC) or prion-filtered red cell concentrates ( PF- RCC) at eight weeks and six months post-transfusion. Patients who received at least 1 unit of PF- RCC were compared with a control cohort given RCC only. About 917 PF- RCC and 1336 RCC units were transfused into 299 and 291 patients respectively. Twenty-six new red cell antibodies were detected post-transfusion in 10 patients in each arm, an overall alloimmunization rate of 4·4%. Neither the treatment arm [odds ratio ( OR) 0·93, 95% confidence interval ( CI) 0·3, 2·5] nor number of units transfused ( OR 0·95, 95% CI 0·8, 1·1) had a significant effect on the proportion of patients who developed new alloantibodies. No pan-reactive antibodies or antibodies specifically against PF- RCC were detected. There was no difference in transfusion reactions between arms, and no novel transfusion-related adverse events clearly attributable to PF- RCC were seen. These data suggest that prion filtration of red cells does not reduce overall transfusion safety. This finding requires confirmation in large populations of transfused patients. [ABSTRACT FROM AUTHOR]

Summary To evaluate the role of intravenous immunoglobulin (IVIg) in platelet apoptosis in paediatric immune thrombocytopenia, we investigated the platelets of 20 paediatric patients with acute immune thrombocytopenia (ITP), before and after IVIg treatment. Healthy children with platelet counts in the normal range and children with thrombocytopenia due to chemotherapy were enrolled as controls. All ITP patients presented with platelet counts <20 × 109/l and bleeding symptoms. Markers of apoptosis, including activated caspase-3, -8 and -9, phosphatidylserine (PS) exposure, mitochondrial inner membrane potential (ΔΨm), as well as platelet-derived microparticle formation, were analysed by flow cytometry. After IVIg treatment, platelet counts increased to >20 × 109/l in all patients. ITP patients had significantly increased proportions of platelets with activated caspase-3, -8 and -9, with PS exposure, and with decreased ΔΨm, and demonstrated increased microparticle formation. Except for ΔΨm, these markers for apoptosis were reduced by IVIg treatment. Platelets of children with thrombocytopenia after chemotherapy also demonstrated increased microparticle formation and decreased ΔΨm, but no activation of caspases 3, 8 and 9 or PS exposure. In conclusion, in acute paediatric ITP, enhanced platelet apoptosis is seen at diagnosis that normalizes after IVIg treatment. [ABSTRACT FROM AUTHOR]

Summary Monogenic hereditary diseases, such as haemophilia A and B, are ideal targets for gene therapeutic approaches. While these diseases can be treated with protein therapeutics, such as factor VIII (FVIII) or IX (FIX), the notion that permanent transfer of the genes encoding these factors can cure haemophilia is very attractive. An underlying problem with a gene therapy approach, however, is the patient's immune response to the therapeutic protein (as well as to the transmission vector), leading to the formation of inhibitory antibodies. Even more daunting is reversing an existing immune response in patients with pre-existing inhibitors. In this review, we will describe the laboratory and clinical progress, and the challenges met thus far, in achieving the goal of gene therapy efficacy, with a focus on the goal of tolerance induction. [ABSTRACT FROM AUTHOR]

Summary In a study conducted on 114 patients undergoing unrelated donor haematopoietic stem cell transplantation (HSCT) for thalassaemia, we observed that the lack of activating killer immunoglobulin-like receptors (KIRs) on donor natural killer (NK) cells significantly increased the risk of graft-versus-host disease (GvHD) [hazard risk (HR) 4·2, 95% confidence interval (CI) 1·7-10·1, P = 0·002] and transplantation-related mortality (HR 4·7, 95% CI 1·6-14·2, P = 0·01). The risk of GvHD furthermore increased when recipients heterozygous for HLA-C KIR ligand groups (C1/C2) were transplanted from donors completely lacking activating KIRs (HR 6·1, 95% CI 1·9-19·2, P = 0·002). We also found that the risk of rejection was highest when the recipient was homozygous for the C2 HLA-KIR ligand group and the donor carried two or more activating KIRs (HR 6·8, 95% CI 1·9-24·4, P = 0·005). By interpolating the number of donor activating KIRs with recipient HLA-C KIR ligands, we created an algorithm capable of stratifying patients according to the immunogenetic risk of complications following unrelated HSCT. In clinical practice, this predictive tool could serve as an important supplement to clinical judgement and decision-making. [ABSTRACT FROM AUTHOR]

Summary The long-term antibody responses to re-immunization in recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) have not been well studied. We prospectively and longitudinally evaluated the antibody responses to eight vaccine antigens (diphtheria, tetanus, pertussis, measles, mumps, rubella, hepatitis B, and poliovirus) and assessed the factors associated with negative titres in 210 allo-HSCT recipients at St. Jude Children's Research Hospital. Antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95·7%), rubella (92·3%), poliovirus (97·9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25·0%), measles (66·7%), mumps (61·5%), hepatitis B (72·9%), and diphtheria in tetanus-diphtheria (Td) recipients (48·6%) were less favourable, with either only transient antibody responses or persistently negative titres. Factors associated with vaccine failure were older age at immunization; lower CD3, CD4 or CD19 counts; higher IgM concentrations; positive recipient cytomegalovirus serology; negative titres before immunization; acute or chronic graft- versus-host disease; and radiation during preconditioning. These response patterns and clinical factors can be used to formulate re-immunization and monitoring strategies. Patients at risk for vaccine failure should have long-term follow-up; those with loss of antibody response or no seroconversion should receive booster immunizations. [ABSTRACT FROM AUTHOR]

Summary B lymphoblastic leukaemia (B-ALL) cells are characterized by the expression of various B-cell antigens. Expression of T/Natural Killer-cell antigens, however, has rarely been reported in B-ALL (TAg+ B-ALL), and the significance of this aberrant antigen expression is unclear. We thus analysed the frequency of TAg+ B-ALL at our institution and investigated its significance in the context of immunophenotypes, cytogenetic/molecular findings, and prognosis. We reviewed 134 consecutive cases of B-ALL and found 18 cases (13·4%) of TAg+ B-ALL. The most common aberrant T-cell antigens expressed were CD2, CD5, and CD7 at equivalent rates (each in six cases), CD4 (two cases), and CD56 (three cases). Adverse cytogenetic abnormalities were seen in a significantly larger proportion of the TAg+ cases (72·2%) than the TAg− cases (32·2%; P = 0·003). Multivariate Cox-regression analysis showed that the risk of relapse over time was higher in the TAg+ cases, independent of high risk status (based on age and white blood cell count) and the presence of adverse cytogenetic abnormalities (hazard ratio = 2·256, P = 0·065). These findings suggest that T-cell antigen expression in B-ALL may be an independent predictor of poor prognosis, and a useful marker to identify patients at increased risk for relapse and for harbouring adverse cytogenetic abnormalities. [ABSTRACT FROM AUTHOR]

Summary The occurrence of alloantibodies against Factor VIII (FVIII) is the main iatrogenic complication in haemophilia A (HA). Anti-FVIII autoantibodies may also spontaneously appear in non-HA patients, leading to acquired haemophilia A. In both contexts, the antibody response against FVIII is complex and difficult to analyse due to the lack of suitable tools. Our purpose was to comprehensively map, at the amino acid level, discontinuous epitopes of the C2 domain of FVIII targeted by patients' antibodies. We synthesized 33 synthetic peptides, which were predicted by the bioinformatic algorithm PEPOP to mimic C2 domain discontinuous epitopes. Using an inhibition assay based on the x-MAP technology, we evaluated their ability to block the binding to the C2 domain of anti-C2 domain antibodies from pooled plasma samples. Nine peptides were thus selected and tested again in individual plasma samples. Our results support the view that C2 domain epitopes are organized as an epitopic mosaic distributed around the molecule, showed that each patient displayed a specific anti-C2 epitopic profile, and confirmed the complexity and variability of the immune response against the C2 domain of FVIII. This ability to finely map epitopes could be further used to follow the antibody specificity modifications over time. [ABSTRACT FROM AUTHOR]

Summary In the absence of new outbreaks of transfusion-related infections, the occurrence of neutralizing antibodies currently remains the most prominent complication in haemophilia. Coagulation factor products that may circumvent the inadequate activation of factor X in classical haemophilia, often referred to as bypassing agents, have demonstrated a high degree of efficacy. A smaller number of patients have been described in whom either bypassing agent, or both, demonstrate diminished efficacy. In those cases, the use of both bypassing agents in parallel was attempted, either using simultaneous (combined) or alternating (sequential) infusion of the two drugs, reportedly with successful haemostasis. We speculated whether such treatment might cause thromboembolism. A thorough literature search disclosed 17 reports regarding the parallel use of bypassing agents in the same bleeding episode in 49 patients; reporting nine patients with acquired haemophilia and forty patients with congenital haemophilia with inhibitors. Notable incidences of thromboembolic manifestations were observed: in nine patients with acquired haemophilia, five and in 40 patients with congenital haemophilia five suffered from significant thrombotic complications, and overall four cases were fatal. Although efficacy of parallel treatment was reported excellent in most cases, thromboembolism is rare in haemophilia and parallel treatment with activated prothrombin complex concentrate and activated recombinant human factor VII appears to increase the risk of thrombosis in these patients. [ABSTRACT FROM AUTHOR]

We present previously unknown evidence that the immunoglobulin heavy chain binding protein BIP/HSPA5, also known as glucose regulated protein (GRP)78, serving as a pivotal component of the pro-survival axis of the unfolded protein response (UPR) signalling network, is abundantly expressed in relapsed B-lineage acute lymphoblastic leukaemia (ALL) and contributes to chemotherapy resistance of leukaemic B-cell precursors. The resistance of B-lineage ALL cells to the standard anti-leukaemic drug vincristine was overcome by the HSPA5 inhibitor epigallocatechin gallate, which inhibits the anti-apoptotic function of HSPA5 by targeting its ATP-binding domain. Notably, chemotherapy-resistant B-lineage ALL cells underwent apoptosis within 48 h of exposure to a doxorubicin-conjugated cell-penetrating cyclic anti-HSPA5 peptide targeting surface-expressed HSPA5 molecules on leukaemia cells. The identification of the HSPA5 as a chemoresistance biomarker and molecular target for B-lineage ALL may lead to new anti-leukaemic treatment strategies that are much needed. [ABSTRACT FROM AUTHOR]

Red blood cell (RBC) transfusion is the primary treatment for severe forms of thalassaemia. Pre-storage screening has resulted in decreased transfusion-transmitted infections, but anti-RBC antibodies remain a major problem. We report on 697 participants who had ever received transfusions. Allo- and autoantibody rates were compared with respect to splenectomy status, ethnicity, diagnosis, duration of transfusions, treatment centre, and age at transfusion initiation, together with rates before and after 1990, when leucoreduction methods were routine at thalassaemia treatment centres. Allo- and autoantibodies were reported in 115 (16·5%) and 34 (4·9%) subjects, respectively. Splenectomized patients were more likely to have alloantibodies [odds ratio (OR) = 2·528, P ≤ 0·0001], or autoantibodies (OR = 2·590, P = 0·0133). Alloantibodies occurred in 19 of 91 (21%) splenectomized subjects who started transfusion after 1990, and only 18 of 233 (7·7%) nonsplenectomized subjects ( P < 0·001). Data from this study demonstrate that RBC antibodies continue to develop in chronically transfused thalassaemia patients at a high rate. Splenectomy preceded the development of antibodies in most cases. Increased rates of RBC sensitization among splenectomized patients is concerning and deserves further study. [ABSTRACT FROM AUTHOR]

Activation-induced cytidine deaminase (AICDA) initiates somatic hypermutation and class-switch recombination of immunoglobulin (Ig) genes and induces mutations also in non-Ig genes. AICDA aberrant expression was detected in B-lineage acute lymphoblastic leukaemia (B-ALL), particularly BCR/ABL1+ B-ALL; patients expressing AICDA carried more copy number alterations than 'AICDA-negative' cases. To determine the role of AICDA, AICDA expression and gene expression profiling were studied in adult BCR/ABL1+ B-ALL. Patients displaying the full-length isoform AICDA are characterized by up-regulation of DNA repair/replication and cell cycle genes, suggesting their involvement in the genetic instability of BCR/ABL1+ B-ALL. [ABSTRACT FROM AUTHOR]

The effects of two CD20 antibodies, namely rituximab, the current standard for treatment of chronic lymphocytic leukaemia (CLL) in combination with chemotherapy, and GA101, a glyco-engineered type II antibody were compared on CLL cells ex vivo. Antibody-induced phosphatidylserine exposure was examined in isolated CLL cells. For a more comprehensive assessment of antibody-mediated cell killing including Fc-mediated mechanisms, B cell depletion from whole blood samples was monitored. Treatment with rituximab or GA101 reduced the average viability of isolated CLL cells by 6% or 11%, and the ratio of B to T cells in whole blood samples by 12% or 33%, respectively. Combination with GA101 enhanced the cytotoxicity of the chemotherapeutic agent chlorambucil on isolated CLL cells. CD20 surface expression on CLL cells correlated with GA101-induced B cell depletion, but not with direct cell death induction. Treatment of whole blood samples from CLL patients with a CpG-containing oligonucleotide increased CD20 expression on CLL cells and GA101-dependent B cell depletion. Despite the variable responses of individual CLL samples, the CLL cell depletion from whole blood by GA101 was consistently much stronger than by rituximab, which argues for clinical investigation of GA101 in CLL patients. [ABSTRACT FROM AUTHOR]

Toll like receptors (TLRs) are the major agents for innate immunity that recognize invading microbial products and regulate the growth of normal and malignant human B lymphocytes. Multiple myeloma (MM) is a clonal plasma cell malignancy, though the regulatory role of TLRs in MM plasma cells has been reported, the molecular mechanism remains unclear. We first compared the transcripts of TLR1 to TLR10 in MM patients and healthy donors and found that TLR2, -4 and - 9 transcripts were higher in bone marrow mononuclear cells (BMMCs) from patients than those from donors; in addition the expression of TLR4 and TLR9 were higher in MM cells than normal cells as demonstrated by flow cytometric analyses. The ligands of these two TLRs were capable to promote the growth of MM cells and protect them from serum-deprivation-induced apoptosis but not normal plasma cells, which could be attenuated with anti-IL6 neutralizing antibodies or blockage of NF-κB activities. Further investigation demonstrated that these TLR ligands could trigger the nuclear translocation of NF-κB p65 and the activated NF-κB was sufficient to increase the expression of IL6 transcript in MM cells. These data suggested that activated NF-κB signalling probably plays a crucial role for the ligands of TLR4 and TLR9 to promote the growth and survival of MM cells partially through IL6 autocrine. [ABSTRACT FROM AUTHOR]

Cytogenetic and molecular investigations of Acute Lymphoblastic Leukaemia (ALL) have identified the existence of distinct clinical subgroups. Molecular monitoring of clonal Immunoglobulin and T cell receptor (IG/TR) gene rearrangements has become an important tool in stratification of therapy of ALL. In order to determine whether certain features of the patient-specific rearrangements could hold further prognostic clues or provide information on the cell of origin of ALL, a comprehensive analysis of structural and biological features (V gene usage, coding frame and mutational status and complementarity-determining region -III length) of 473 IG/TR rearrangements identified in 229 adults with ALL was carried out. Distinct variable-gene usage profiles were identified between ALL subgroups, particularly for patients positive for BCR-ABL1 compared to MLL-AFF1 positive leukaemias; suggesting that the former is derived from a more mature B progenitor. Interestingly, occurrence of TRGV1- TRGV8 was prognostic for better event-free survival (31% at 4 years with vs. 0% at 4 years without, P = 0·05). The heterogeneity in clinical outcome is suggested by the basic molecular processes of antigen receptor gene rearrangements as shown in this work. [ABSTRACT FROM AUTHOR]