Protein arginine N-methyltransferase 4 (PRMT4) contributes to lymphopenia in experimental sepsis.

BACKGROUND: One hallmark of sepsis is the reduced number of lymphocytes, termed lymphopenia, that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by their epigenetic and non-epigenetic functions; however, the role of these enzymes in lymphopenia remains elusive. METHODS: We used molecular biological approaches to investigate the high expression and function of a chromatin modulator protein arginine N-methyltransferase 4 (PRMT4)/coactivator-associated arginine methyltransferase 1 in human samples from septic patients and cellular and animal septic models. RESULTS: We identified that PRMT4 is elevated systemically in septic patients and experimental sepsis. Gram-negative bacteria and their derived endotoxin lipopolysaccharide (LPS) increased PRMT4 in B and T lymphocytes and THP-1 monocytes. Single-cell RNA sequencing results indicate an increase of PRMT4 gene expression in activated T lymphocytes. Augmented PRMT4 is crucial for inducing lymphocyte apoptosis but not monocyte THP-1 cells. Ectopic expression of PRMT4 protein caused substantial lymphocyte death via caspase 3-mediated cell death signalling, and knockout of PRMT4 abolished LPS-mediated lymphocyte death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. CONCLUSIONS: These findings demonstrate a previously uncharacterised role of a key chromatin modulator in lymphocyte survival that may shed light on devising therapeutic modalities to lessen the severity of septic immunosuppression.

SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage.

PURPOSE: The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients. METHODS: A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission. RESULTS: We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation. CONCLUSIONS: The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality.

Dosimetry of the brain and hypothalamus predicting acute lymphopenia and the survival of glioma patients with postoperative radiotherapy.

BACKGROUND: The aim of this study was to investigate dosimetric factors for predicting acute lymphopenia and the survival of glioma patients with postoperative intensity-modulated radiotherapy (IMRT). METHODS: A total of 148 glioma patients were reviewed. Acute lymphopenia was defined as a peripheral lymphocyte count (PLC) lower than 1.0 × 109 /L during radiotherapy with a normal level at pretreatment. PLCs with the corresponding dates and dose volume histogram parameters were collected. Univariate and multivariate Cox regression analyses were constructed to assess the significance of risk factors associated with lymphopenia and overall survival (OS). RESULTS: Sixty-nine (46.6%) patients developed lymphopenia during radiotherapy. Multivariate analyses revealed that the risk increased with the maximal dose of the hypothalamus (HT Dmax) ≥56 Gy (58.9% vs 28.5%, P = 0.002), minimal dose of the whole brain (WB Dmin) ≥2 Gy (54.3% vs 33.9%, P = 0.006), or mean dose of the WB (WB Dmean) ≥34 Gy (56.0% vs 37.0%, P = 0.022). Patients with older age, high-grade glioma, development of lymphopenia, high HT Dmax, WB Dmin, and WB Dmean had significantly inferior OS in the multivariate analyses. CONCLUSIONS: HT Dmax, WB Dmin, and WB Dmean are promising indicators of lymphopenia and the survival of glioma patients undergoing postoperative IMRT. The necessity and feasibility of dosimetric constraints for HT and WB is warranted with further investigation.

Neurological presentations revealing acquired copper deficiency: diagnosis features, aetiologies and evolution in seven patients.

BACKGROUND: Acquired copper deficiency (ACD) is a rare condition usually diagnosed from haematological changes. AIMS: To characterise the diagnosis features and the evolution of patients with ACD revealed by neurological symptoms. METHODS: Clinical, biological and magnetic resonance imaging (MRI) data were prospectively analysed at diagnosis and during follow up under copper supplementation. RESULTS: Seven patients were studied over a 5-year period. Time to diagnosis ranged from 2.5 to 15 months. Subacute ascending paraesthesias and gait disorder were the first symptoms. All patients had a posterior cord syndrome (PCS) with sensory ataxic gait associated with superficial hypoesthesia of the feet; 50% had also lateral cord signs. Electrodiagnostic tests diagnosed a lower limb sensory neuropathy in four patients. Spinal cord MRI was normal in three of seven patients. Anaemia and lymphopenia were diagnosed in six of seven patients. Serum copper was always low, and urinary copper was low or normal. Serum and urinary zinc were high in four patients. Decreased copper intake (stoma/parenteral nutrition, malnutrition, malabsorption with lack of vitamin supplementation after bariatric or other digestive surgeries) was found in four patients, and the chronic use of denture adhesive paste containing zinc was discovered in four patients. One patient had both the causes recorded. After copper supplementation, copper balance and then haematological disturbances were the first features to normalise gradually in 2 months. Radiological myelitis disappeared in 10 months, whereas neurological symptoms improved in six of seven patients after a mean follow up of 2 years. CONCLUSIONS: Progressive PCS with anaemia and lymphopenia must raise the possibility of an ACD. Early copper supplementation could increase the neurological prognosis.

Immunological abnormalities associated with hereditary haemorrhagic telangiectasia.

OBJECTIVE: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder related to mutations in one of the coreceptors to the transforming growth factor-ß superfamily (ALK1 or endoglin). Besides the obvious vascular symptoms (epistaxis and arteriovenous malformations), patients have an unexplained high risk of severe bacterial infections. The aim of the study was to assess the main immunological functions of patients with HHT using the standard biological tests for primary immunodeficiencies. DESIGN, SETTING AND SUBJECTS: A prospective single-centre study of 42 consecutive adult patients with an established diagnosis of HHT was conducted at the National French HHT Reference Center (Lyon). Lymphocyte subpopulations and proliferation capacity, immunoglobulin levels and neutrophil and monocyte phagocytosis, oxidative burst and chemotaxis were assessed. RESULTS: Innate immunity was not altered in patients with HHT. With regard to adaptive immunity, significant changes were seen in immunological parameters: primarily, a lymphopenia in patients with HHT compared with healthy control subjects affecting mean CD4 (642 cells µL(-1) vs. 832 cells µL(-1) , P < 0.001), CD8 (295 cells µL(-1) vs. 501 cells µL(-1) , P < 0.0001) and natural killer (NK) cells (169 cells µL(-1) vs. 221 cells µL(-1) , P < 0.01), associated with increased levels of immunoglobulins G and A. This lymphopenia mainly concerned naïve T cells. Proliferation capacities of lymphocytes were normal. Lymphopenic patients had a higher frequency of iron supplementation but no increase in infection rate. Lower levels of immunoglobulin M and a higher rate of pulmonary arteriovenous malformations were found amongst patients with a history of severe infection. CONCLUSIONS: Patients with HHT exhibit immunological abnormalities including T CD4, T CD8 and NK cell lymphopenia and increased levels of immunoglobulins G and A. The observed low level of immunoglobulin M requires further investigation to determine whether it is a specific risk factor for infection in HHT.

Changes in lymphocyte function and subsets in dogs with naturally occurring chronic renal failure.

Chronic renal failure (CRF) causes immunosuppresion in humans and is thought to be one of the causes of noninfectious secondary immunosuppression in dogs. Hematological, biochemical, and immunological examinations were performed on blood samples obtained from dogs in various stages of CRF. The number of dogs with lymphopenia increased with the progression of clinical signs. All main subsets of lymphocytes were decreased, but more considerable reduction was detected in B-cells, Tc-cells, and NK cells. Depressed lymphocyte response to concanavalin A and pokeweed mitogen was found in dogs with severe clinical signs and lymphopenia. Our results, showing impaired immunological functions, are similar to results obtained from uremic humans, suggesting that infection may be an important complication in dogs with CRF.

Immune defects in breast cancer patients after radiotherapy.

The purpose of this study was to evaluate the immune status of women with stage I-III breast cancer after receiving external beam radiotherapy (RT). Fourteen stage I-III, estrogen or progesterone receptor-positive or-negative (FER/PR +\-), postsurgical breast cancer patients undergoing a standard course of chemotherapy and radiation were studied. Complete blood counts (CBC) with differential, phagocytic activity, natural killer (NK) cell functional activity, and tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma cytokine activity were measured immediately before and for the six weeks following the completion of radiation therapy. Fatigue levels after completion of RT were measured using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. Nonparametric statistical methods (Wilcoxon rank and Spearman correlations) were used to analyze the data. Compared with postchemotherapy, following the completion of RT, these breast cancer patients showed lymphopenia, low functional activity of natural killer lymphocytes, decreased monocyte phagocytic activity, and decreased TNF-alpha production but no neutropenia, no anemia, and no change in interferon-gamma production. Lymphocyte count did not return to normal by the end of the 6-week post-RT observation period. The severity of lymphopenia and low natural killer cell activity was related to RT area but not radiation dose. Patients did not report significant fatigue levels for the 6 weeks after completing RT. Significant decreases in the numbers and functions of cells from both the innate and adaptive immune system were detected following a standard course of radiation therapy for the treatment of breast cancer. Immune deficits in lymphocyte populations and TNF-alpha production, should they persist, may have consequences for immune response to residual or recurrent malignancy following completion of conventional treatment. The use of adjunctive immune therapies which target these specific defects may be warranted in the post-treatment period.

What caused lymphopenia in SARS and how reliable is the lymphokine status in glucocorticoid-treated patients?

Severe Acute Respiratory Syndrome (SARS) outbreak in 2002-03 caused morbidity in over 8000 individuals and mortality in 744 in 29 countries. Lymphopenia along with neutrophilia was a feature of SARS, as it is in respiratory syncytial virus (RSV) and Ebola infections, to name a few. Direct infestation of lymphocytes, neutrophils and macrophages by SARS coronavirus (CoV) has been debated as a cause of lymphopenia, but there is no convincing data. Lymphopenia can be caused by glucocorticoids, and thus any debilitating condition has the potential to induce lymphopenia via stress mechanism involving the hypothalamic-pituitary-adrenal axis. Cortisol levels are elevated in patients with RSV and Ebola, and cortisol was higher in SARS patients with lymphopenia before any steroid therapy. Glucocorticoids also down-regulate the production of proinflammatory lymphokines. Because of the insidious presentation, SARS was treated with antibacterial, antiviral and supra-physiological doses of glucocorticoids. Treatment with glucocorticoids complicated the issue regarding lymphopenia, and certainly calls into question the status of lymphokines and their prognostic implications in SARS.

A phase I study of fever-range whole body hyperthermia (FR-WBH) in patients with advanced solid tumours: correlation with mouse models.

Various studies in animal tumour models have revealed the potential of fever-range whole body hyperthermia (FR-WBH) to be used in cancer therapy. To determine the safety of FR-WBH treatment in the clinic, patients with advanced solid tumours were heated in the outpatient setting to 39-39.5 degrees C for 3 or 6h, or 39.5-40 degrees C for 6h using the Heckel-HT 2000 apparatus. These WBH treatments were well tolerated, with no significant adverse events related to cardiac, hepatic, renal or pulmonary systems. In the majority of patients, flow cytometric analysis of peripheral blood leukocyte populations indicated that there were transient decreases in the number of circulating T lymphocytes and a concomitant decrease in the number of L-selectin positive lymphocytes in the peripheral blood. These findings closely mimic the affects seen previously in pre-clinical murine studies in which this same fever-like treatment was shown to inhibit tumour growth. These studies have established the safety of this treatment and will allow for future clinical trials where application of FR-WBH treatment can be combined with other anti-cancer therapies, including immunotherapy and chemotherapy.

Markers of health status in an HTLV-I-positive cohort.

The health effects of chronic human T-cell lymphotropic virus type I (HTLV-I) infection were examined in a cohort of Japanese men who had emigrated from Okinawa, Japan, and had been participants in a prospective study in Hawaii since 1965. In the present follow-up study carried out in 1987-1988, various health indicators were measured in the subjects, whose mean age was 72.5 years. Participation rates were lower in the HTLV-I seropositives than in the seronegatives (46.7% vs. 76.0%) in the > or = 75-year age group. Lack of participation was significantly correlated with a high HTLV-I antibody titer. Among the participants, seropositive subjects were significantly more likely than the seronegatives to have lymphocytopenia (32.7% vs. 17.7%) and mild anemia (25.5% vs. 14.1%) after adjustment for age and socioeconomic status. The seropositives also had a higher frequency of acupuncture therapy (age-adjusted odds ratios were 2.1 and 4.2 for 1-5 treatments and > or = 6 treatments, respectively). Proportions of subjects who had been hospitalized at least twice were higher among the seropositives in the oldest age groups, 70-74 years and > or = 75 years, but not in those aged 65-69 years. Although specific disease conditions were not identified in this study, hematologic data, treatment histories, and the correlation between participation status and HTLV-I antibody titers suggest that chronic HTLV-I infection may be associated with as yet undefined adverse health effects, particularly in older age groups.

A diet enriched in essential fatty acids protects against the loss of lymphocytes which occurs in rats suffering from streptozotocin-induced diabetes.

Blood glucose, circulating lymphocyte numbers, and the percentage of T- and B-lymphocytes were measured in diabetic and non-diabetic rats which had been fed on control diets, or diets which included oil of evening primrose or coconut oil. In diabetic animals fed on the control or coconut oil diet the number of circulating lymphocytes decreased; this was caused by a decrease in both T- and B-lymphocytes. The decreases in lymphocyte numbers was less in the diabetic animals fed on the diet enriched in evening primrose oil. In these animals the decrease in T-lymphocytes was less and the percentage of B-lymphocytes was increased. It is suggested that the diet enriched in evening primrose oil exerts its protective effect by providing gamma-linolenic acid which is necessary for biosynthesis of prostaglandin E1.

[Early diagnosis and immunocorrective therapy of recurrent facial neuritis as a manifestation of Melkersson-Rosenthal syndrome in adults and children]. / Ranniaia diagnostika i immunokorrigiruiushchaia terapiia retsidivi- ruiushchego nevrita litsevogo nerva kak proiavlenie sindroma Mel'kerssona-Rossolimo-Rozentalia u vzroslykh i detei.

Clinical and immunological examinations of adults and children with Melkersson-Rossolimo-Rosenthal syndrome have revealed immunity deficiency: a decrease of the number of T and B cells, a low immunoglobulin content and the presence of the ++neuro-allergic syndrome according to the increased level of cerebral antibodies. The role of deembiogenetic stigmas in the diagnosis establishment has been demonstrated. The authors suggest the use of immunomodulating therapy including interferogens and immunostimulants of T and B cells (galascorbin and myelopide). Provide evidence for the efficacy of the treatment elaborated.

Peripheral T lymphocytopenia under exogenous thermal stress.

A transient decrease in T lymphocytes in peripheral blood was observed in twelve healthy volunteers immersed in hot water baths which raised their mean rectal temperature by 1.35 C. T lymphocytes declined from 59 to 41 rel % (2p less than 0.001) or from a mean of 1990 to 1300 per mm3. T lymphocytopenia was accompanied by a relative increase in the fraction of B lymphocytes. Total lymphocyte count remained unchanged. In vitro heating alone to 39 C did not influence the total of SRBC-labelled lymphocytes. The findings are interpreted to be the result of a change in lymphocyte distribution with increased recirculation of mobile T lymphocytes.