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The inbred Babraham pig serves as a valuable biomedical model for research due to its high level of homozygosity, including in the major histocompatibility complex (MHC) loci and likely other important immune-related gene complexes, which are generally highly diverse in outbred populations. As the ability to control for this diversity using inbred organisms is of great utility, we sought to improve this resource by generating a long-read whole genome assembly and transcriptome atlas of a Babraham pig. The genome was de novo assembled using PacBio long reads and error-corrected using Illumina short reads. Assembled contigs were then mapped to the porcine reference assembly, Sscrofa11.1, to generate chromosome-level scaffolds. The resulting TPI_Babraham_pig_v1 assembly is nearly as contiguous as Sscrofa11.1 with a contig N50 of 34.95 Mb and contig L50 of 23. The remaining sequence gaps are generally the result of poor assembly across large and highly repetitive regions such as the centromeres and tandemly duplicated gene families, including immune-related gene complexes, that often vary in gene content between haplotypes. We also further confirm homozygosity across the Babraham MHC and characterize the allele content and tissue expression of several other immune-related gene complexes, including the antibody and T cell receptor loci, the natural killer complex, and the leukocyte receptor complex. The Babraham pig genome assembly provides an alternate highly contiguous porcine genome assembly as a resource for the livestock genomics community. The assembly will also aid biomedical and veterinary research that utilizes this animal model such as when controlling for genetic variation is critical. [ABSTRACT FROM AUTHOR]

Purpose: Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signaling, and as such a critical regulator of cell proliferation and survival. Aberrant BCR signaling is important in the pathogenesis of various B cell malignancies and autoimmune disorders. Here, we describe the development of a novel positron emission tomography (PET) tracer for imaging BTK expression and/or occupancy by small molecule therapeutics. Methods: Radiochemistry was carried out by reacting the precursor with [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]BTK-1 with a 6% decay-corrected radiochemical yield, 100 ± 6 GBq/µmol molar activity, and a radiochemical purity of 99%. Following intravenous administration of [18F]BTK-1 (3.63 ± 0.59 MBq, 0.084 ± 0.05 µg), 60-min dynamic images were acquired in two xenograft models: REC-1, an efficacious mantle cell lymphoma model, and U87MG, a non-efficacious glioblastoma model. Subsequent studies included vehicle, pretreatment (10 min prior to tracer injection), and displacement (30 min post-tracer injection) studies with different reversible BTK inhibitors to examine BTK binding. Human radiation dosimetry was estimated based on PET imaging in healthy rats. Results: Uptake of [18F]BTK-1 was significantly higher in BTK expressing REC-1 tumors than non-BTK expressing U87MG tumors. Administration of BTK inhibitors prior to tracer administration blocked [18F]BTK-1 binding in the REC-1 tumor model consistent with [18F]BTK-1 binding to BTK. The predicted effective dose in humans was 0.0199 ± 0.0007 mSv/MBq. Conclusion: [18F]BTK-1 is a promising PET tracer for imaging of BTK, which could provide valuable information for patient selection, drug dose determination, and improving our understanding of BTK biology in humans. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma confined to the central nervous system. Diffuse large B cell lymphoma (DLBCL) is the most common subtype, and it follows a much more aggressive course than its systemic counterpart. Differential diagnosis of PCNSL and systemic DLBCL depends on clinical staging, which is expensive and time consuming. Protein kinase C delta (PKCD) is a protein with proapopitotic properties and has a major role in negative selection of B cells in germinal centers, a regulatory function in B cell receptor (BCR) pathway and MHC II expression. Mutations identified in its gene are reported to be unique for PCNSL and not encountered in systemic DLBCL. Our aim is to evaluate immunohistochemical (IHC) expression and the mutation status of PKCD in PCNSLs and systemic DLBCLs in order to find out whether PKCD could be a novel marker that could be used in differential diagnosis of both entities. A total of 43 cases diagnosed with PCNSL, and 43 cases diagnosed with systemic DLBCL were included in the study. Immunohistochemistry for PKCD antibody and Sanger sequencing targeting exon 16 and exon 18 of PKCD gene were performed. Although immunoreactivity for PKCD was observed in all PCNSL and 95.3% of systemic DLBCL cases, strong and diffuse staining was found to be more frequent in PCNSL than systemic diffuse large B cell lymphomas (p < 0.001). However, mutations defined in literature were not encountered in our cohort. While clinical staging is still the primary way for differential diagnosis of PCNSL and systemic DLBCL, the diffuse and strong PKCD expression can be used as a supportive feature for PCNSL diagnosis. [ABSTRACT FROM AUTHOR]

In people living with HIV (PLWH), the susceptibility to malignancies is notably augmented, with lymphoma emerging as a predominant malignancy. Even in the antiretroviral therapy (ART) era, aggressive B-cell lymphoma stands out as a paramount concern. Yet, the pathogenesis of HIV related lymphoma (HRL) largely remains an enigma. Recent insights underscore the pivotal role of the dysregulated B cell receptor (BCR) signaling cascade, evidencing its oncogenic potential across a spectrum of lymphomas. Intricate interplays between HIV and BCR structural-functional integrity have been identified in PLWH. In this review, we elucidated the mechanism by which the BCR signaling pathway is involved in HRL, mainly including the following aspects: HIV can reshape BCR structure by modulating of activation-induced cytidine deaminase (AID) and recombination-activating gene (RAG) dynamics; HIV can act as a chronic antigen to activate the BCR signaling pathway, such as upregulating PI3K and MAPK signaling pathway and reducing the expression of CD300a; HIV co-infection with other oncogenic viruses may also influence tumor formation mediated by the BCR signaling pathway. This review aims to elucidate the intricate regulation of the BCR signaling pathway by HIV in B cell lymphoma, providing a novel perspective on the pathogenesis of lymphoma in HIV-affected environments. [ABSTRACT FROM AUTHOR]

Purpose of review: Many prognostic and predictive biomarkers have been proposed for chronic lymphocytic leukaemia (CLL). Here, we aim to discuss the evidence showing a prognostic potential for extracellular vesicles (EV) and their associated microRNAs (miRNAs). Recent Findings: EV are produced by several cells in the body as a physiological event; however, there is evidence suggesting that an elevated EV concentration is present in the circulation of CLL patients. Moreover, some studies have associated EV concentration with advanced Rai stage and unmutated CLL while others have demonstrated its potential as an independent prognostic factor for TTFT and OS. Finally, some studies have shown that CLL EV shared some dysregulated microRNAs with CLL cells and plasma. On the other hand, it was found that CLL EV has a distinctive microRNA expression profile. Until now, EV-associated miR-155 is the most studied miRNA. Summary: Despite methodological diversity and limitations in study design, unanimity in CLL EV concentration behaviour and miRNA content has been found. [ABSTRACT FROM AUTHOR]

Purpose of Review: The outcome of patients with lymphoid malignancies has markedly improved in recent years which is likely due to a combination of advances in supportive care, and therapeutic options. In this article, we will provide an overview over the role PI3-kinase signalling, one of the most important dysregulated pathways in cancer, and its successful inhibition in lymphoma. Recent Findings: PI3-kinase inhibitors have shown remarkable activity in an increasing subset of patients with non-Hodgkin lymphomas. The first drug to be approved was idelalisib for patients with relapsed/refractory follicular lymphoma and CLL/SLL as monotherapy, or in combination with rituximab, respectively. After an initial setback related to increased toxicity including deaths observed in several upfront studies, there has been a resurgence in interest in this pathway following the promising efficacy of second-generation PI3K inhibitors including in patients with T cell lymphomas. Summary: PI3K inhibition continues to be an invaluable tool in the therapy of patients with lymphoid malignancies if managed cautiously. Preclinical models are helpful in predicting possible side effects and identifying new lymphoma subtypes that may be susceptible to this class of agents. The future will likely involve rationally designed combinatorial approaches to deepen the response rate and prevent the emergence of resistance. [ABSTRACT FROM AUTHOR]

Purpose of Review: Treatment for chronic lymphocytic leukemia has changed substantially in the past decade with an increasing shift towards use of targeted therapies, in particular agents targeting the B cell receptor pathway. Inhibition of PI3K, downstream of the B cell receptor pathway, represents an active therapeutic strategy in CLL. Here, we explore the relevance of PI3K inhibition in CLL, examine efficacy and toxicity of approved PI3K inhibitors in CLL, examine barriers to use of PI3K inhibitors, and explore strategies to optimize use of PI3K inhibitors in CLL. Recent Findings: Current generation PI3K inhibitors are active agents in CLL but their use may be limited by immune-mediated toxicities. Clinical trials of next generation PI3K inhibitors are ongoing and early data suggests these agents are highly active with potentially differentiated toxicity profiles. Furthermore, alternative dosing schedules may reduce toxicities of these agents. Summary: Inhibition of PI3K remains an important strategy in management of CLL and novel approaches to limit toxicities of PI3K inhibitors represent an important area of clinical research in CLL. [ABSTRACT FROM AUTHOR]

Purpose of Review: While the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL), current limitations include off-target toxicities and the development of resistance. In this review, we summarize the emerging data for alternative BTKi. Recent Findings: Second-generation BTKi include acalabrutinib, zanubrutinib, and tirabrutinib which offer greater BTK selectivity. While these agents may limit off-target toxicity, they do not overcome common mechanisms of ibrutinib resistance. Reversible BTKi including vecabrutinib and LOXO-305 inhibit BTK in the presence of C481S mutation, and non-selective reversible BTKi, including ARQ-531, may retain activity despite mutations within PLCG2. Early-phase studies are underway to establish the clinical efficacy and toxicity of these agents. Summary: A randomized trial of ibrutinib versus acalabrutinib is ongoing, and acalabrutinib may be an option for ibrutinib-intolerant patients. Results from ongoing trials of alternate BTKi will help to define their role in CLL therapy as single agents or in combination therapy. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL), a disorder for which B cell heterogeneity and increased cellular proliferation play central pathogenic roles, displays several genetic abnormalities that are associated with poor prognosis and have therapeutic implications. In this review, we discuss the prognostic role and therapeutic implications of chromosome 17p deletions and TP53 mutations in CLL. Unlike other recurrent genetic abnormalities, the frequency of TP53 alterations is relatively low in newly diagnosed patients, but increases sharply with disease progression, which suggests that these alterations represent an evolutionary mechanism of resistance. In comparison with patients without such abnormalities, those with 17p deletions and TP53 mutations have lower response rates and more aggressive disease. One important consequence of the diverse molecular mechanisms that affect the TP53 pathway is the need to assess both the presence of 17p deletion and TP53 mutations before treatment initiation. Several authors have attempted to incorporate TP53 abnormalities in different prognostic models for CLL, and the recent International Prognostic Index for Chronic Lymphocytic Leukemia formally considers patients with TP53 abnormalities (deletion 17p or TP53 mutation or both) as high-risk. Several novel agents may improve results in patients with CLL, including in those with TP53 mutations. Ibrutinib, idelalisib, and venetoclax have been approved in various settings and countries for treatment of CLL. Further progress in targeted therapy and judicious use of chemotherapy, monoclonal antibodies, and reduced-intensity allogeneic transplantation will provide patients with CLL in general, and those with TP53 abnormalities in particular, with a better prognosis. [ABSTRACT FROM AUTHOR]

The domestic goat (Capra hircus) is an important ruminant species both as a source of antibody-based reagents for research and biomedical applications and as an economically important animal for agriculture, particularly for developing nations that maintain most of the global goat population. Characterization of the loci encoding the goat immune repertoire would be highly beneficial for both vaccine and immune reagent development. However, in goat and other species whose reference genomes were generated using short-read sequencing technologies, the immune loci are poorly assembled as a result of their repetitive nature. Our recent construction of a long-read goat genome assembly (ARS1) has facilitated characterization of all three antibody loci with high confidence and comparative analysis to cattle. We observed broad similarity of goat and cattle antibody-encoding loci but with notable differences that likely influence formation of the functional antibody repertoire. The goat heavy-chain locus is restricted to only four functional and nearly identical IGHV genes, in contrast to the ten observed in cattle. Repertoire analysis indicates that light-chain usage is more balanced in goats, with greater representation of kappa light chains (~ 20-30%) compared to that in cattle (~ 5%). The present study represents the first characterization of the goat antibody loci and will help inform future investigations of their antibody responses to disease and vaccination. [ABSTRACT FROM AUTHOR]

A mature and diverse T and B cell receptor repertoire is a prerequisite for immunocompetence. In light of its increased susceptibility to infection, the human fetus has long been considered deficient in this regard. However, data accumulated since the 1990s and in earnest in the past couple of years paints a more complicated picture. As we describe in this review, mechanisms responsible for generating a diverse receptor repertoire, such as somatic recombination, class switch recombination, and somatic hypermutation, are all operational to surprising extents in the growing fetus. The composition of the fetal repertoire differs from that of adults, with preferential usage of certain variable (V), diversity (D), and joining (J) gene segments and a shorter complementarity determining (CDR3) region, primarily due to decreased terminal deoxynucleotidyl transferase (TdT) expression. Both T and B cell receptor repertoires are extremely diverse by the end of the second trimester, and in the case of T cells, are capable of responding to an invading pathogen with in utero clonal expansion. Thus, it would appear as though the T and B cell receptor repertoires are not a hindrance towards immunocompetence of the newborn. Our improved understanding of fetal receptor repertoire development is already bearing fruit in the early diagnosis of primary immunodeficiencies (PID) and may help clarify the pathogenesis of congenital infections, recurrent abortions, and autoimmune disorders in the near future. [ABSTRACT FROM AUTHOR]

In recent years, a revolution in the management of chronic lymphocytic leukemia (CLL) has centered on the targeting of the B cell receptor (BCR) signaling pathway. Our improved understanding of the biology of cell signaling in CLL and the development of oral kinase inhibitors directed at the BCR pathway has led to the approval of two new agents and has the potential to radically change the treatment of CLL in both the relapsed/refractory and upfront settings. In this review, we will describe the underlying biology of the BCR signaling pathway. We will discuss the landmark clinical trials resulting in the approval of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We will highlight ongoing trials that are evaluating the use of combinations of these agents with standard chemotherapy. We will evaluate some of the emerging data regarding toxicity, potential off-target effects, and mechanisms of resistance to BCR signaling pathway blockade. Finally, we will highlight some of the next-generation BCR pathway inhibitors currently in development. [ABSTRACT FROM AUTHOR]

BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. The BTK inhibitor ibrutinib (PCI-32765, brand name: Imbruvica) demonstrated high clinical activity in B-cell malignancies, especially in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia (WM). Therefore, ibrutinib was granted a 'breakthrough therapy' designation for these indications and was recently approved for the treatment of relapsed MCL by the U.S. Food and Drug Administration. Other BTK inhibitors in earlier clinical development include CC-292 (AVL-292), and ONO-4059. In CLL and MCL, ibrutinib characteristically induces redistribution of malignant B cells from tissue sites into the peripheral blood, along with rapid resolution of enlarged lymph nodes and a surge in lymphocytosis. With continuous ibrutinib therapy, growth- and survival-inhibitory activities of ibrutinib result in the normalization of lymphocyte counts and remissions in a majority of patients. This review discusses the clinical advances with BTK inhibitor therapy, as well as its pathophysiological basis, and outlines perspectives for future use of BTK inhibitors. [ABSTRACT FROM AUTHOR]

It is becoming increasingly apparent that tonic signaling through the B cell receptor provides a growth and survival signal in many types of B cell lymphomas, and that disruption of B cell receptor signaling can be lethal to malignant B cells. Several small molecule tyrosine kinase inhibitors, which block signaling pathways downstream from the B cell receptor, are in active clinical development. Preliminary data suggests impressive activity in relapsed and refractory B cell lymphomas. Among the kinases which have been targeted are Spleen tyrosine kinase (Syk), the Bruton's tyrosine kinase (BTK), and phosphoinositide 3-kinase (PI3K). This article discusses the rationale for targeting these pathways and summarizes the current clinical trial data for agents targeting Syk, BTK, and PI3K. [ABSTRACT FROM AUTHOR]

Age related changes in the structure and function of the immune system, collectively termed immunosenescence, result in poor responses to infections, increased susceptibility to cancers and increased incidence of autoimmune diseases. The humoral immune response, maintained by the B cell compartment, has a key role in an effective immune system—not only in producing high affinity antibodies that are crucial for vaccination strategies, but in assisting other components of the immune system in their function. Hence an understanding of B cell immunosenescence in particular is vital in designing strategies to combat the effects of age on immune function. Numerous studies have been undertaken using small animal models in order to understand immunosenescence, and these have contributed greatly to our understanding of the events that underpin impaired immune responses. However, there are key differences between the human and the mouse and a clear understanding of these differences is required when extrapolating from one species to the other. In this article we present an overview of B cell development and summarise current data on age-related B cell changes, at both the population level and at the individual mechanistic level. Areas of similarity and difference between human and mouse models are highlighted. [ABSTRACT FROM AUTHOR]

T cell receptor (TCR) and B cell receptors (BCR) junctions, also known as the CDR3, are where the V, D, and J gene segments converge, coding for a loop structure important for contacting ligands. J segments contribute to the formation of the CDR3 loop through their 5′ ends that vary in length and show high sequence variability. The 5′ ends of J segments of TCRα genes show nucleotide sequence similarities to TCRDδ segments as high as 89% and show a preponderance of murine TCRDδ2 or human TCRDδ3 amino acid sequence similarities. Surprisingly, most of the 5′ ends of TCRJγ segments show nucleotide and amino acid sequence similarities with TCRDβ segments. All murine and human BCRJH segments and most TCRJδ segments contain amino acid sequences at their 5′ ends that resemble their own D segments, a finding that is not seen with TCRJβ segments. TCRα and TCRγ genes thus make up for their lack of separate D segments with distinct D-like segments that are built into the 5′ ends of their J segments. Additionally, in some cases, TCR and BCR genes that utilize separate D segments also receive additional D-like contributions though the 5′ ends of their J segments to add additional diversity to their CDR3 loops. [ABSTRACT FROM AUTHOR]

The molecular basis of B cell receptor (BCR)-induced apoptosis during the negative selection of immature B cells is largely unknown. We use transitional immature B cells that are highly susceptible to BCR-induced apoptosis to show that Pten is selectively required for BCR-mediated initiation of the mitochondrial death pathway. Specifically, deleting Pten, but not other pro-apoptotic molecules, abrogates BCR-elicited apoptosis and improves viability in wild-type immature B cells. We further identify a physiologically and significantly higher intracellular Pten level in immature B cells, as compared to mature B cells, which is responsible for low AKT activity and the propensity towards death in immature B cells. Restoration of AKT activity using a constitutive form of AKT or reduction of Pten to a level comparable with that seen in mature B cells rescues immature B cells from BCR-induced apoptosis. Thus, we provide evidence that Pten is an essential mediator of BCR-induced cell death, and that differential regulation of intracellular Pten levels determines whether BCR ligation promotes cell death or survival. Our findings provide a valuable insight into the mechanisms underlying negative selection and clonal deletion of immature B cells.Cell Research (2009) 19:196–207. doi: 10.1038/cr.2008.284; published online 9 September 2008 [ABSTRACT FROM AUTHOR]

The mouse genome possesses five genes encoding proteins homologous to human Leu-13. The Leu-13 protein associates with immune cell receptor activation complexes: a monoclonal antibody against Leu-13 induces T and B cells to form homotypic aggregates, inhibits activation-induced proliferation and induces the shedding of L-selectin. The mouse fragilis proteins have not been previously analyzed as components of the immune response. Antibody and nucleic acid reagents were generated that are specific for each of the five fragilis gene products. Expression of some of these genes (fragilis and fragilis3) is wide spread in a variety of mouse immune (and nonimmune) tissues while others (fragilis5) appear to be much more restricted. These proteins have been predicted to span the membrane twice with both amino- and carboxyl-terminal sequences extracellular: we show that a highly conserved loop of the protein between the transmembrane domains is intracellular. The fragilis proteins are associated with tetraspanin proteins CD81 and CD9: B cell activation positions fragilis into lipid rafts along with the CD81, CD19, and CD21. The mouse functional equivalent to human Leu-13 may not be single gene product, but instead may require the contribution of multiple fragilis proteins.Genes and Immunity (2006) 7, 113–121. doi:10.1038/sj.gene.6364278; published online 5 January 2006 [ABSTRACT FROM AUTHOR]

B cell receptor (BCR)-mediated apoptosis plays a key role in the negative selection (deletion) of autoreactive B cells. Mechanisms of BCR-mediated apoptosis have been widely studied in cell lines representing both immature (bone marrow) and mature (germinal center) B cells. However, there is much inconsistency and controversy concerning the possible mechanisms of BCR-mediated apoptosis, which may reflect differences in the origin or the maturational stage of the cell line used. Based on recent studies, collapse of mitochondrial membrane potential (Δ Ψ m) seems to be an essential event for BCR-mediated apoptosis in both mature and immature cells. The collapse of Δ Ψ m is dependent on the synthesis of new proteins, which are involved in the permeability change of mitochondrial membranes. Mitochondrial dysfunction induces activation of caspases, cysteine proteases, which play a central role in apoptosis. However, instead of caspases, other effector proteases, such as cathepsins or calpains, may also be responsible for the organized destruction of cell components seen during BCR-mediated apoptosis. [ABSTRACT FROM AUTHOR]

The generation and maintenance of B lymphocytes is controlled by biochemical signals tramsitted by the B cell antigen receptor (BCR) complex. These signals are transduced by multiple cytoplasmic protein tyrosine kinases (PTKs) including Lyn, Syk, and Bruton's tyrosine kinase (BTK). Upon BCR engagement, these PTKs activate downstream effectors, including transcription factors that modulate gene expression. In turn activation of down stream effectors is critical for B cell survival, cell cycle progression, and antibody production. Our studies focus on the role of BTK in these biological responses. We have discovered that BTK is required for activation of the BCR-responsive transcription factor, NF-κB. Furthermore, BTK-dependent activation of NF-κB isessential for reprogramming the expression of genes that control B cell survival and proliferation. The biochemical mechanisms by which BTK regulates signaling components that activate NF-κB, and the identification of BTK-responsive genes are under investigation. Elucidation of these regulatory mechanisms is expected to reveal new therapeutic targets for B cell pathologies involving defects in BTK, including X-linked agammaglobulinemia (XLA). [ABSTRACT FROM AUTHOR]

Recent findings suggest that lymphocyte survival is a continuous active process and support the role of B cell receptor engagement in B cell survival. In this context the conflict of survival interests between the diverse B cells gives rise to a pattern of interactions which mimics the behavior of complex ecological systems. In response to competition lymphocytes modify their survival requirements and diverge to occupy different immunological niches through differentiation. Thus naive and memory-activated B cell populations show independent homeostatic regulation. We discuss how niche differentiation allows the coexistence of different cell types and guarantees both repertoire diversity and efficient immune responses. [ABSTRACT FROM AUTHOR]

The role of self-antigen recognition in the development of T and B cells of the adaptive immune system has been studied in several different ways. We have shown that CD4 T cells are selected on selfpeptide:self-MHC class II ligands, and in the periphery, they are sustained by contact with the same or similar ligands. We have also observed that B cells are positively selected on unknown and presumed self-ligands. We have used this information to explore autoimmune diseases as well. Finally, we have recently identified the innate immune system as playing a crucial role in regulating expression of costimulatory molecules that are required for induction of adaptive immune responses. [ABSTRACT FROM AUTHOR]

B-CLL patients have a high prevalence of autoimmune phenomena due to polyclonal autoantibodies (Abs) restricted to blood cell self-antigens (Ag) and progressively develop a severe hypogammaglobulinemia. Autoimmunity and immunodeficiency have been related to B-CLL biological properties and cellular origin. Three major issues have emerged: 1) the relevance of B cell receptor abnormalities. More specifically, the importance of the defective expression of CD79b which may explain the faint to virtually undetectable amounts of monoclonal sig, the anomalous signal transduction and the failure to present antigens (Ag). 2) the possibility that the relentless accumulation of B-CLL cells is also under microenvironmental influences. These are brought about by the interplay of cytokines produced through cell/cell contacts among malignant B cells, macrophages and T cells. 3) the view that the very properties of accumulating anergic self-reactive CD5+ B lymphocytes may provide a bridge between autoimmunity and immune incompetence. CD5+ malignant B cells influence the cytokine production by T cells, but are inefficient Ag presenting cells (APC). As such they are a hurdle to the production of normal Ab. However, by stimulating in vitro the CD40 molecule on the membrane of CLL cell with the CD40 ligand the inefficient APC is turned into an efficient APC. In vivo, such an activation may conceivably occur in specific environments like the spleen and favour the production by normal residual B-cells of polyclonal autoAb against red cell or platelet self Ag. [ABSTRACT FROM AUTHOR]

The negative regulation of antigen receptor signal transduction is essential for the maintenance of thresholds for activation in lymphocytes. CD45 and SHP-1 are tyrosine phosphatases that are important in maintaining the proper level of tyrosine phosphorylation. Regulation of the src family of tyrosine kinases is mediated by the coordinated action of the tyrosine kinase Csk and the tyrosine phosphatase CD45. B cell receptor signaling is negatively regulated by the recruitment of SHP-1 to bind the B cell transmembrane proteins CD22 and FcγRIIb1. SHP-1 also functions to negatively regulate T cell receptor signaling by dephosphorylating and inactivating tyrosine kinases. [ABSTRACT FROM AUTHOR]