Autoimmune haemolytic anaemias
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Proteolysis of TAM receptors in autoimmune diseases and cancer: what does it say to us?
Proteolytic processing of Receptor Tyrosine Kinases (RTKs) leads to the release of ectodomains in the extracellular space. These soluble ectodomains often retain the ligand binding activity and dampen canonical pathways by acting as decoy receptors. On the other hand, shedding the ectodomains may initiate new molecular events and diversification of signalling. Members of the TAM (TYRO3, AXL, MER) family of RTKs undergo proteolytic cleavage, and their soluble forms are present in the extracellular space and biological fluids. TAM receptors are expressed in professional phagocytes, mediating apoptotic cell clearance, and suppressing innate immunity. Enhanced shedding of TAM ectodomains is documented in autoimmune and some inflammatory conditions. Also, soluble TAM receptors are present at high levels in the biological fluids of cancer patients and are associated with poor survival. We outline the biology of TAM receptors and discuss how their proteolytic processing impacts autoimmunity and tumorigenesis. In autoimmune diseases, proteolysis of TAM receptors likely reflects reduced canonical signalling in professional phagocytes. In cancer, TAM receptors are expressed in the immune cells of the tumour microenvironment, where they control pathways facilitating immune evasion. In tumour cells, ectodomain shedding activates non-canonical TAM pathways, leading to epithelial-mesenchymal transition, metastasis, and drug resistance.
Models for T-large granular lymphocytic leukemia: how to mimic the cellular interplays in malignant autoimmunity
T-large granular lymphocytic leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by clonal expansions of cytotoxic T-cells. It presents with cytopenias that are not explained by the typically low leukemic burden. Notably, T-LGLL is frequently accompanied by autoimmune disorders, particularly rheumatoid arthritis (RA). As clonal T-cell expansions are also increasingly identified in autoimmune-driven conditions, better models of T-LGLL’s pathogenesis as a spectrum of (auto)antigen-driven oligoclonal hierarchies towards overt leukemic escape with associated immune dysregulations would provide details to a valuable prototype for determinants of T-cell fitness and transformation as well as T-cell instructed dysfunctions of other immune cells. Such insights would advance our concepts of cancer biology and immunology. Common molecular links between T-LGLL and autoimmune diseases include activation of JAK/STAT signaling, proinflammatory cytokine environments, and antigen-driven immune responses. Current murine models address these mechanisms rather individually: JAK/STAT based systems replicate pathway activation, cytokine-driven models simulate inflammatory conditions, and RA models often mimic antigen stimulation. However, none of these fully captures the duality of clonal T-cell expansion and the complex immune dysregulations, inherent to T-LGLL. This review examines criteria for autochthonous in-vivo T-LGLL models and evaluates existing systems, identifying their strengths, limitations, and specific representations of clinico-pathologic aspects of LGLL. Prominent transgenic models, for example, not only manipulate the T-cell compartment but also indiscriminately alter the tumor microenvironment, impeding research on the specific role of elements of the LGLL micromilieu. We propose strategies to overcome such insufficiencies of present models. Overall, our critical appraisal emphasizes the need for novel comprehensive models that more faithfully integrate the key features of T-LGLL or for models that, by featuring specific pathogenetic aspects of the disease, would supplement existing incomplete systems. We expect such new model systems to aid in better understanding the cancer-immunity interface and in assessing novel therapeutic approaches for T-LGLL.
NF-κB RelB suppresses the inflammatory gene expression programs of dendritic cells by competing with RelA for binding to target gene promoters
A group of autoinflammatory disorders termed relopathies arise as a consequence of NF-κB dysregulation. Genetic loss of the NF-κB subunit RelB in humans and mice leads to autoimmunity and lethal multi-organ inflammatory pathology. Our recent study showed that this inflammatory pathology is independent of type I interferon signaling, and further identified dysregulation of a set of pro-inflammatory NF-κB target genes. However, it remains unknown how the loss of RelB leads to the dysregulation of these NF-κB motif-containing pro-inflammatory genes. Here, we report epigenome profiling studies revealing that RelB is associated with pro-inflammatory genes in dendritic cells. While these genes recruit RelA binding upon exposure to a maturation stimulus, we observed substantially more RelA recruitment in the absence of RelB. For these genes, we found that elevated RelA recruitment is correlated with elevated gene expression. To test whether RelB may compete with RelA for binding to NF-κB-regulated gene promoters via competition for κB sites, we generated a new mouse strain (RelBDB/DB) that harbors targeted point mutations in the RelB DNA binding domain that eliminates high-affinity DNA binding. We found that this targeted mutation in the RelB DNA binding domain is sufficient to drive multi-organ inflammatory pathology. These results provide insights into the biological mechanism of RelB as a suppressor of pro-inflammatory gene expression and autoimmune pathology.
Addressing the Gaps in the Vitamin B12 Deficiency 2024 NICE Guidelines: Highlighting the Need for Better Recognition, Diagnosis, and Management of Pernicious Anaemia
The 2024 NICE guidelines on vitamin B12 deficiency have significant implications for the diagnosis and management of pernicious anaemia (PA), the commonest non-dietary cause of such deficiency. This perspective discusses the guidelines in relation to PA itself, suggests that clearer diagnostic protocols are required, and calls for clinician education to improve the patient journey for those with PA.
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