Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow was collected from control and THS-exposed mice and transplanted into bone-marrow-ablated recipient mice, which were followed for tumor development for one year. We found that in utero and early life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen and bone marrow B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in bone marrow transplantation recipient mice, potentially caused by THS-induced B cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS exposed bone marrow stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early life developmental periods represent vulnerable windows of susceptibility for these effects.

Primary biliary cholangitis (PBC), an autoimmune liver disease occurring predominantly in women, is characterized by high titers of serum anti-mitochondrial antibodies (AMAs) and progressive intrahepatic cholestasis. The immune system plays a critical role in PBC pathogenesis and a variety of immune cell subsets have been shown to infiltrate the portal tract areas of patients with PBC. Amongst the participating immune cells, CD4 T cells are important cytokine-producing cells that foster an inflammatory microenvironment. Specifically, these cells orchestrate activation of other immune cells, including autoreactive effector CD8 T cells that cause biliary epithelial cell (BEC) injury and B cells that produce large quantities of AMAs. Meanwhile, other immune cells, including dendritic cells (DCs), natural killer (NK) cells, NKT cells, monocytes, and macrophages are also important in PBC pathogenesis. Activation of these cells initiates and perpetuates bile duct damage in PBC patients, leading to intrahepatic cholestasis, hepatic damage, liver fibrosis, and eventually cirrhosis or even liver failure. Taken together, the body of accumulated clinical and experimental evidence has enhanced our understanding of the immunopathogenesis of PBC and suggests that immunotherapy may be a promising treatment option. Herein, we summarize current knowledge regarding immunological abnormalities of PBC patients, with emphasis on underlying pathogenic mechanisms. The differential immune response which occurs over decades of disease activity suggests that different therapies may be needed at different stages of disease.

The immune system has long been known to play a critical role in the body’s defence against cancer, and there have been multiple attempts to harness it for therapeutic gain. Renal cancer was, historically, one of a small number of tumour types where immune manipulation had been shown to be effective. The current generation of immune checkpoint inhibitors are rapidly entering into routine clinical practice in the management of a number of tumour types, including renal cancer, where one drug, nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody (mAb), is licensed for patients who have progressed on prior systemic treatment. Ongoing trials aim to maximize the benefits that can be gained from this new class of drug by exploring optimal timing in the natural course of the disease as well as combinations with other checkpoint inhibitors and drugs from different classes.

Cardiovascular disease is the leading cause of death in several countries. The underlying process is atherosclerosis, a slowly progressing chronic disorder that can lead to intravascular thrombosis. There is overwhelming evidence for the underlying importance of our immune system in atherosclerosis. Monocytes, which comprise part of the innate immune system, can be recruited to inflamed endothelium and this recruitment has been shown to be proportional to the extent of atherosclerotic disease. Monocytes undergo migration into the vasculature, they differentiate into macrophage phenotypes, which are highly phagocytic and can scavenge modified lipids, leading to foam cell formation and development of the lipid-rich atheroma core. This increased influx leads to a highly inflammatory environment and along with other immune cells can increase the risk in the development of the unstable atherosclerotic plaque phenotype. The present review provides an overview and description of the immunological aspect of innate and adaptive immune cell subsets in atherosclerosis, by defining their interaction with the vascular environment, modified lipids and other cellular exchanges. There is a particular focus on monocytes and macrophages, but shorter descriptions of dendritic cells, lymphocyte populations, neutrophils, mast cells and platelets are also included.

T1DM (Type I diabetes mellitus) results from selective destruction of the insulin-producing β-cells of the pancreas by the immune system, and is characterized by hyperglycaemia and vascular complications arising from suboptimal control of blood glucose levels. The discovery of animal models of T1DM in the late 1970s and early 1980s, particularly the NOD (non-obese diabetic) mouse and the BB (BioBreeding) diabetes-prone rat, had a fundamental impact on our ability to understand the genetics, aetiology and pathogenesis of this disease. NOD and BB diabetes-prone rats spontaneously develop a form of diabetes that closely resembles the human counterpart. Early studies of these animals quickly led to the realization that T1DM is caused by autoreactive T-lymphocytes and revealed that the development of T1DM is controlled by numerous polymorphic genetic elements that are scattered throughout the genome. The development of transgenic and gene-targeting technologies during the 1980s allowed the generation of models of T1DM of reduced genetic and pathogenic complexity, and a more detailed understanding of the immunogenetics of T1DM. In this review, we summarize the contribution of studies in animal models of T1DM to our current understanding of four fundamental aspects of T1DM: (i) the nature of genetic elements affording T1DM susceptibility or resistance; (ii) the mechanisms underlying the development and recruitment of pathogenic autoreactive T-cells; (iii) the identity of islet antigens that contribute to the initiation and/or progression of islet inflammation and β-cell destruction; and (iv) the design of avenues for therapeutic intervention that are rooted in the knowledge gained from studies of animal models. Development of new animal models will ensure continued progress in these four areas.

Cardiotrophin-1 (CT-1) leads to a specific form of ventricular hypertrophy characterized by sarcomeres added in series, and has been reported to be elevated in heart failure. Previous competitive assays for CT-1 necessitate the extraction of plasma and involve prolonged incubations. We describe the development of a non-competitive assay for CT-1 that can measure plasma levels without the need for extraction. Two antibodies specific for the mid-section (amino acids 105-120) and C-terminal (amino acids 186-199) portions of CT-1 were developed in rabbits. One antibody was immobilized and used as the capture antibody. The other antibody was affinity purified and biotinylated. Unextracted plasma was incubated with these antibodies, and detection was with methylacridinium ester-labelled streptavidin. Plasma was obtained from 40 patients with heart failure and 40 normal control subjects. The non-competitive assay demonstrated a linear increase in chemiluminescence (measured as relative light units) with increasing amounts of full-length recombinant CT-1, with no evidence of a hook effect at high concentrations. The lower limit of detection was 2.9 fmol/ml. Intra-assay coefficients of variation ranged from 3.1% to 4.2% in the 10-40fmol/well concentration range, and interassay coefficients of variation ranged from 3.5% to 4.5% in the 550-950fmol/ml range. Measurements of CT-1 levels in patients with heart failure (median 166.5fmol/ml; range 49.5-2788fmol/ml) revealed very significantly elevated levels compared with those in normal controls (median 43.5fmol/ml; range 11.2-258.6fmol/ml; P < 0.0001 by Mann-Whitney test). At a CT-1 concentration of 68fmol/ml, sensitivity and specificity were 95% and 82.5% respectively. Thus this new non-competitive immunochemiluminometric assay for CT-1 could successfully detect full-length recombinant CT-1 in unextracted plasma, and demonstrated that plasma levels of CT-1 were significantly elevated in patients with heart failure.

The aim of the present study was to establish whether gastro-intestinal (GI) complaints observed during and after ultra-endurance exercise are related to gut ischaemia-associated leakage of endotoxins [lipopolysaccharide (LPS)] into the circulation and associated cytokine production. Therefore we collected blood samples from 29 athletes before, immediately after, and 1, 2 and 16 h after a long-distance triathlon for measurement of LPS, tumour necrosis factor-α and interleukin-6 (IL-6). As the cytokine response would trigger an acute-phase response, characteristic variables of these responses were also measured, along with creatine kinase (CK) to obtain an indicator of muscle damage. There was a high incidence (93% of all participants) of GI symptoms; 45% reported severe complaints and 7% of the participants abandoned the race because of severe GI distress. Mild endotoxaemia (5–15 pg/ml) was evident in 68% of the athletes immediately after the race, as also indicated by a reduction in IgG anti-LPS levels. In addition, we observed production of IL-6 (27–fold increase immediately after the race), leading to an acute-phase response (20-fold increase in C-reactive protein and 12% decrease in pre-albumin 16 h after the race). The extent of endotoxaemia was not correlated with the GI complaints or the IL-6 response, but did show a correlation with the elevation in C-reactive protein ( r s 0.389; P = 0.037). Creatine kinase levels were increased significantly immediately post-race, and increased further in the follow-up period. Creatine kinase levels did not correlate with those of either IL-6 or C-reactive protein. It is therefore concluded that LPS does enter the circulation after ultra-endurance exercise and may, together with muscle damage, be responsible for the increased cytokine response and hence GI complaints in these athletes.

Chronic fatigue syndrome is a debilitating illness of unknown aetiology, with estimated levels of prevalence of up to about 8.7/100 000 in the U.S.A. Like pain fatigue it is a personal, emotionally rich experience, which may originate from peripheral or central sites (or both). The nature of the symptoms is complex and reflects the interaction of the patient with the environment and cultural milieu. Accordingly the common use of the same terminology for different types of fatigue may be misleading. Autonomic activation is a key component of both real and simulated physical exercise. Alterations in autonomic nervous system activity are a key component of several physiopathological conditions. In chronic fatigue syndrome disturbances in autonomic activity, and in other homoeostatic mechanisms, such as the hormonal and immune systems, have been reported recently. In this review we followed the hypothesis that in chronic fatigue syndrome the paradoxical condition of disturbing somatic symptoms in the absence of organic evidence of disease might be addressed by focusing on attending functional correlates. In particular we addressed possible alterations in cardiovascular autonomic control, as can be assessed by spectral analysis of R–R interval and systolic arterial pressure variability. With this approach, in subjects complaining of unexplained fatigue, we obtained data suggesting a condition of prevailing sympathetic modulation of the sino-atrial node at rest, and reduced responsiveness to excitatory stimuli. Far from considering the issue resolved, we propose that in the context of the multiple physiological and psychological interactions involved in the perception and self-reporting of symptoms , attendant changes in physiological equivalents might furnish a convenient assessment independent from subjective components. Indices of sympathetic modulation could, accordingly, provide quantifiable signs of the interaction between subject's efforts and environmental demands, independently of self descriptions, which could provide convenient measurable outcomes, both for diagnosis and treatment titration in chronic fatigue syndrome.