Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche.

Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to inflammation and neoplasia remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations across mouse strains and accurately surveys both niche locations.

Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.

Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche.

Made to order: emergency myelopoiesis and demand-adapted innate immune cell production.

Definitive haematopoiesis is the process by which haematopoietic stem cells, located in the bone marrow, generate all haematopoietic cell lineages in healthy adults. Although highly regulated to maintain a stable output of blood cells in health, the haematopoietic system is capable of extensive remodelling in response to external challenges, prioritizing the production of certain cell types at the expense of others. In this Review, we consider how acute insults, such as infections and cytotoxic drug-induced myeloablation, cause molecular, cellular and metabolic changes in haematopoietic stem and progenitor cells at multiple levels of the haematopoietic hierarchy to drive accelerated production of the mature myeloid cells needed to resolve the initiating insult.

Maternal inflammation regulates fetal emergency myelopoiesis.

Neonates are highly susceptible to inflammation and infection. Here, we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPCs) respond to inflammation, testing the hypothesis that deficits in the engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical adult-like EM transcriptional program.

Comparison of timing of relapse in dogs with nonassociative immune-mediated hemolytic anemia, thrombocytopenia, or polyarthritis.

Background: Relapse is a clinical concern in dogs diagnosed with immune-mediated hemolytic anemia (IMHA), thrombocytopenia (ITP), or polyarthritis (IMPA). The average time to relapse is unknown, and evidence that vaccination is associated with disease relapse is lacking.

Hypothesis/objectives: Compare the incidence of relapse in groups of dogs with IMHA, ITP, or IMPA over a 24-month period after diagnosis and compare proportions of dogs that received vaccines in those dogs that did and did not relapse.

Maternal IL-10 restricts fetal emergency myelopoiesis.

Unlabelled: Neonates, in contrast to adults, are highly susceptible to inflammation and infection. Here we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPC) respond to inflammation, testing the hypothesis that deficits in engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that despite similar molecular wiring as adults, fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical EM transcriptional program.

Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.

Unlabelled: Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction ( ). Autophagy is central for the benefits associated with activation of longevity signaling programs ( ), and for HSC function and response to nutrient stress ( ). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional ( ).

Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production.

Hematopoietic stem cells (HSC) and downstream lineage-biased multipotent progenitors (MPP) tailor blood production and control myelopoiesis on demand. Recent lineage tracing analyses revealed MPPs to be major functional contributors to steady-state hematopoiesis. However, we still lack a precise resolution of myeloid differentiation trajectories and cellular heterogeneity in the MPP compartment.

Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing.

Haematopoietic ageing is marked by a loss of regenerative capacity and skewed differentiation from haematopoietic stem cells (HSCs), leading to impaired blood production. Signals from the bone marrow niche tailor blood production, but the contribution of the old niche to haematopoietic ageing remains unclear. Here we characterize the inflammatory milieu that drives both niche and haematopoietic remodelling.

Splenectomy in the management of primary immune-mediated hemolytic anemia and primary immune-mediated thrombocytopenia in dogs.

Background: Current reports about the use of splenectomy for the management of immune-mediated hemolytic anemia (IMHA) or immune-mediated thrombocytopenia (ITP) or both in dogs are limited.

Objectives: To retrospectively describe the use of splenectomy as part of the management for IMHA, ITP, and concurrent IMHA and severe thrombocytopenia (CIST) in dogs. It was hypothesized that splenectomy would be beneficial in allowing for reduction of dose of immunosuppressive drugs or discontinuation in 1 or more of these groups.

Investigation of single-nucleotide polymorphisms in the NR3C1a glucocorticoid receptor gene in Cocker Spaniels with primary immune thrombocytopenia.

Background: In dogs, 6 single-nucleotide polymorphisms (SNPs) have been described in the glucocorticoid receptor gene NR3C1a, 2 of which were nonsynonymous SNPs in exons 2 and 8. The clinical importance of these SNPs is unknown.

Objectives: To investigate whether SNPs in NR3C1a are associated with clinical outcome in Cocker Spaniels with primary immune thrombocytopenia (pITP).

Cross-sectional study of approaches to diagnosis and management of dogs with immune-mediated haemolytic anaemia in primary care and referral veterinary practices in the United Kingdom.

Objectives: To determine whether veterinarians in primary care practices (PCPs) and board-certified clinicians (BCCs) approach treatment of dogs with immune-mediated haemolytic anaemia (IMHA) similarly, and whether practitioners with more experience treat similarly to those with less experience. We hypothesised those in PCPs would show more variation in their approach to similar cases than BCCs.

Methods: A cross-sectional study was conducted by distributing a questionnaire to BCCs and veterinarians in PCPs.

Breed predispositions, clinical findings, and prognostic factors for death in dogs with nonregenerative immune-mediated anemia.

Background: Breed predispositions, survival, and prognostic factors have not been evaluated in dogs with nonregenerative immune-mediated anemia (nrIMA).

Hypothesis/objectives: To describe clinicopathologic variables, evaluate their associations with survival, and determine breed predispositions for dogs with nrIMA.

Animals: Fifty-nine client-owned dogs with nrIMA.

Prospective observational study of the use of omeprazole and maropitant citrate in veterinary specialist care.

The proton pump inhibitor omeprazole is administered to dogs with gastroduodenal ulceration or oesophagitis, whereas the neurokinin-1 receptor antagonist maropitant citrate is licensed as an antiemetic drug. In people, omeprazole is overprescribed in hospitals, increasing the risk of adverse effects and imposing unnecessary costs in healthcare. To investigate the use of omeprazole and maropitant in our veterinary specialist hospital, we conducted a prospective observational study in its Medicine and Surgery wards, recording patient data and obtaining contemporaneous information from clinicians about their reasons for administering either drug.

IL-33 promotes anemia during chronic inflammation by inhibiting differentiation of erythroid progenitors.

An important comorbidity of chronic inflammation is anemia, which may be related to dysregulated activity of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). Among HSPCs, we found that the receptor for IL-33, ST2, is expressed preferentially and highly on erythroid progenitors. Induction of inflammatory spondyloarthritis in mice increased IL-33 in BM plasma, and IL-33 was required for inflammation-dependent suppression of erythropoiesis in BM.

GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis.

Dysregulated hematopoiesis occurs in several chronic inflammatory diseases, but it remains unclear how hematopoietic stem cells (HSCs) in the bone marrow (BM) sense peripheral inflammation and contribute to tissue damage in arthritis. Here, we show the HSC gene expression program is biased toward myelopoiesis and differentiation skewed toward granulocyte-monocyte progenitors (GMP) during joint and intestinal inflammation in experimental spondyloarthritis (SpA). GM-CSF-receptor is increased on HSCs and multipotent progenitors, favoring a striking increase in myelopoiesis at the earliest hematopoietic stages.

Randomised controlled trial of fractionated and unfractionated prednisolone regimens for dogs with immune-mediated haemolytic anaemia.

Methods: A randomised non-blinded non-inferiority trial was conducted to determine whether treatment with an unfractionated regimen of oral prednisolone was inferior to a fractionated regimen for dogs with primary immune-mediated haemolytic anaemia. Dogs received the same total daily dose of prednisolone as unfractionated (group 1, starting at 4 mg/kg orally once daily) or fractionated (group 2, starting at 2 mg/kg orally twice daily) doses. Questionnaires were administered to owners to assess adverse effects and quality of life (QoL).

ACVIM consensus statement on the treatment of immune-mediated hemolytic anemia in dogs.

Immune-mediated hemolytic anemia (IMHA) causes severe anemia in dogs and is associated with considerable morbidity and mortality. Treatment with various immunosuppressive and antithrombotic drugs has been described anecdotally and in previous studies, but little consensus exists among veterinarians as to the optimal regimen to employ and maintain after diagnosis of the disease. To address this inconsistency and provide evidence-based guidelines for treatment of IMHA in dogs, we identified and extracted data from studies published in the veterinary literature.

ACVIM consensus statement on the diagnosis of immune-mediated hemolytic anemia in dogs and cats.

Immune-mediated hemolytic anemia (IMHA) is an important cause of morbidity and mortality in dogs. IMHA also occurs in cats, although less commonly. IMHA is considered secondary when it can be attributed to an underlying disease, and as primary (idiopathic) if no cause is found.

Characterisation of the Immunophenotype of Dogs with Primary Immune-Mediated Haemolytic Anaemia.

Background: Immune-mediated haemolytic anaemia (IMHA) is reported to be the most common autoimmune disease of dogs, resulting in significant morbidity and mortality in affected animals. Haemolysis is caused by the action of autoantibodies, but the immunological changes that result in their production have not been elucidated.

Aims: To investigate the frequency of regulatory T cells (Tregs) and other lymphocyte subsets and to measure serum concentrations of cytokines and peripheral blood mononuclear cell expression of cytokine genes in dogs with IMHA, healthy dogs and dogs with inflammatory diseases.

Canine autoimmune hemolytic anemia: management challenges.

Immune-mediated hemolytic anemia is one of the most common manifestations of canine immune-mediated disease, yet treatment regimens remain nonstandardized and, in some cases, controversial. The main reason for this, as for most diseases in veterinary medicine, is the lack of large-scale placebo-controlled trials so that the efficacy of one treatment over another can be established. Most of the evidence used for treatment comes from retrospective studies and from personal preference and experience, and because of this, treatment regimens tend to vary among institutions and individual clinicians.

Novel immunotherapies for immune-mediated haemolytic anaemia in dogs and people.

Therapy of autoimmune diseases in dogs and people currently relies on use of broad-spectrum immunosuppressive drugs, which are associated with unacceptable adverse effects in some patients. Detractions of such drugs are particularly apparent in people and animals with autoimmune haemolytic anaemia (AIHA), when high doses are often required and for prolonged periods. Greater understanding of the immune aberrations that occur in patients with AIHA has permitted development of several forms of novel immunotherapy, which are intended to re-establish tolerance of self-antigens rather than suppressing all parts of the immune system.

Prevalence and risk factors for development of hemorrhagic gastro-intestinal disease in veterinary intensive care units in the United Kingdom.

Objective: To determine the prevalence of hemorrhagic gastro-intestinal (GI) disease developing in dogs and cats admitted for management of non-GI disease in veterinary intensive care units (ICUs).

Design: Retrospective study of animals presented between October 2012 and July 2013.

Setting: Three ICUs located in veterinary teaching hospitals in the United Kingdom.

Histologic and clinical features of primary and secondary vasculitis: a retrospective study of 42 dogs (2004-2011).

Inflammation of the blood vessel wall has been reported infrequently in dogs, and it may occur without apparent cause (primary vasculitis) or as a pathologic reaction to a range of initiating insults (secondary vasculitis). The aims of our study were to report histologic, clinical, and survival data from a large series of cases with primary and secondary vasculitis, and to compare the clinical parameters and outcome data between groups. Clinical data was collected retrospectively from the medical records of 42 client-owned dogs with a histologic diagnosis of primary or secondary vasculitis, and follow-up information was obtained.