Immune dysregulation as a leading principle for lymphoma development in diverse immunological backgrounds

Lymphoma is a heterogeneous group of malignancies arising from lymphocytes, which poses a significant challenge in terms of diagnosis and treatment due to its diverse subtypes and underlying mechanisms. This review aims to explore the shared and distinct features of various forms of lymphoma predisposing conditions, with a focus on genetic, immunological and molecular aspects. While diseases such as autoimmune disorders, inborn errors of immunity and iatrogenic immunodeficiencies are biologically and immunologically distinct, each of these diseases results in profound immune dysregulation and a predisposition to lymphoma development. Interestingly, the increased risk is often skewed towards a particular subtype of lymphoma. Patients with inborn errors of immunity in particular present with extreme forms of lymphoma predisposition, providing a unique opportunity to study the underlying mechanisms. External factors such as chronic infections and environmental exposures further modulate the risk of lymphoma development. Common features of conditions predisposing to lymphoma include: persistent inflammation, recurrent DNA damage or malfunctioning DNA repair, impaired tumor surveillance and viral clearance, and dysregulation of fundamental cellular processes such as activation, proliferation and apoptosis. Our growing understanding of the underlying mechanisms of lymphomagenesis provides opportunities for early detection, prevention and tailored treatment of lymphoma development.</p

Regulation of PDGF chain and receptor expression in human malignant mesothelioma cell lines

In normal, untransformed cells, growth is a tightly regulated process, A single cell is capable of controlling its growth by integrating the input from both positive growthstimulating and negative growth-inhibiting signals. Unrestrained cell proliferation is the hallmark of carcinogenesis and arises as a consequence of aberrations in this normal growth control. The importance of such disturbed growth-regulating mechanisms is underscored by the observation that in vitro tumour cells were found to proliferate independently of exogenous growth factors. The apparent ability to be able to grow without mitogenic factors supported the earlier suggestion of Temin that growth of transformed cells may be caused by endogenous production of growth factors. This concept was later extended to the autoerine growth stimulation model. It has become generally accepted that genetic damage is a central event in the process of loss of growth control. Disturbances in the growth-regulating mechanisms by changes in the genes til at govern these processes, consequently enable cells to escape normal growth control. Genes, whose products contribute to uncontrolled growth, once they are genetically altered, can be classified as oncogenes and tumour suppressor genes. In the former category such genetic alterations give rise to a gain-of-function resulting in positive growth stimulation (e.g. by changes in growth factor-encoding genes), whereas in the latter growth-inhibiting properties are lost

Recent revelations and future directions using single-cell technologies in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disease with varying outcomes. In the last decade, the application of next-generation sequencing technologies has allowed extensive mapping of disease-specific genomic, epigenomic, immunogenetic, and transcriptomic signatures linked to CLL pathogenesis. These technologies have improved our understanding of the impact of tumor heterogeneity and evolution on disease outcome, although they have mostly been performed on bulk preparations of nucleic acids. As a further development, new technologies have emerged in recent years that allow high-resolution mapping at the single-cell level. These include single-cell RNA sequencing for assessment of the transcriptome, both of leukemic and non-malignant cells in the tumor microenvironment; immunogenetic profiling of B and T cell receptor rearrangements; single-cell sequencing methods for investigation of methylation and chromatin accessibility across the genome; and targeted single-cell DNA sequencing for analysis of copy-number alterations and single nucleotide variants. In addition, concomitant profiling of cellular subpopulations, based on protein expression, can also be obtained by various antibody-based approaches. In this review, we discuss different single-cell sequencing technologies and how they have been applied so far to study CLL onset and progression, also in response to treatment. This latter aspect is particularly relevant considering that we are moving away from chemoimmunotherapy to targeted therapies, with a potentially distinct impact on clonal dynamics. We also discuss new possibilities, such as integrative multi-omics analysis, as well as inherent limitations of the different single-cell technologies, from sample preparation to data interpretation using available bioinformatic pipelines. Finally, we discuss future directions in this rapidly evolving field.</p

A very low thymus function identifies patients with substantial increased risk for long-term mortality after kidney transplantation

Background: End-stage renal disease is associated with premature ageing of the T cell immune system but inter-individual variation is substantial. The hypothesis was tested that advanced immunological T cell ageing assessed by peripheral T cell differentiation increases the long-term mortality risk after renal transplantation. Results: Circulating T cells of 211 recipients of a kidney from a living donor were analyzed before and in the first year after transplantation. The number of CD31-positive naive T cells (as a marker for recent thymic emigrants) and the differentiation status of the memory T cells was assessed. Thirty recipients died during follow-up of at least 5 years. Absolute numbers of naive CD4+ (living:258 cells/μl vs. deceased:101 cells/μl, p < 0.001) and naive CD8+ T cells (living:97 cells/μl vs. deceased:37 cells/μl, p < 0.001) were significantly lower in the deceased group prior to transplantation. In a multivariate proportional hazard analysis the number of naive CD4+ T cells remained associated with all-cause mortality (HR 0.98, CI 0.98-0.99, p < 0.001). The low number of naive T cells in the deceased patient group was primarily caused by a decrease in recent thymic emigrants (i.e. less CD31+ naive T cells) indicating a lowered thymus function. In addition, the physiological age-related compensatory increase in CD31- naïve T cells was not observed. Within the first year after transp