ABSTRACT
Although natural killer (NK) cells are often described as first line defence against infected or malignant cells which act without the need of prior activation, it is known now that the NK cell activity is tightly regulated by other cells and soluble factors. We show here that the stress-inducible heat shock protein (HSP) 70 activates human NK cells to kill target cells expressing major histocompatibility complex class I chain-related molecule A (MICA) in a natural killer group 2 member D (NKG2D-) dependent manner. The HSP70-derived peptide TKD (TKDNNLLGRFELSG) was able to replace the full-length HSP70 and to exert the same function. Interestingly, the expression of the cytotoxic effector protease granzyme B in NK cells was increased after TKD stimulation. When MICA and MICB expression was induced in human tumour cells by a histone deacetylase inhibitor and NK cells were activated by HSP70 or TKD, both treatments jointly improved the killing of the tumour cells. Thus, the synergistic activity of two stress-inducible immunological danger signals, HSP70 and MICA/B, leads to activation and enhanced cytotoxicity of human NK cells against tumour cells.
Subject(s)
Cytotoxicity, Immunologic , HSP70 Heat-Shock Proteins/metabolism , Histocompatibility Antigens Class I/metabolism , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Lymphocyte Activation/immunology , Signal Transduction/immunology , Amino Acid Sequence , Animals , Antibody Specificity/drug effects , Cell Line, Tumor , Cytotoxicity, Immunologic/drug effects , Granzymes/metabolism , HSC70 Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/chemistry , Humans , Killer Cells, Lymphokine-Activated/cytology , Killer Cells, Lymphokine-Activated/immunology , Killer Cells, Natural/drug effects , Killer Cells, Natural/enzymology , Lymphocyte Activation/drug effects , Mice , Molecular Sequence Data , NK Cell Lectin-Like Receptor Subfamily D/metabolism , Peptides/chemistry , Peptides/pharmacology , Rats , Signal Transduction/drug effects , Solubility/drug effects , TransfectionABSTRACT
BACKGROUND: While previous attempts to elucidate the factor structure of depression tended to agree on a central focus on depressed mood, other factors were not replicated across studies. By examining data from a large number of items covering the range of depressive symptoms, the aim of the present study is to contribute to the identification of the structure of depression on a lifetime perspective. METHODS: The study sample consisted of 598 patients with unipolar depression who were administered the Mood Spectrum Self-Report (lifetime version) in Italian (N=415) or English (N=183). In addition to classical exploratory factor analysis using tetrachoric correlation coefficients, an IRT-based factor analysis approach was adopted to analyze the data on 74 items of the instrument that explore cognitive, mood and energy/activity features associated with depression. RESULTS: Six factors were identified, including 'Depressive Mood', 'Psychomotor Retardation', 'Suicidality', 'Drug/Illness related depression', 'Psychotic Features' and 'Neurovegetative Symptoms', accounting overall for 48.3% of the variance of items. LIMITATIONS: Clinical information on onset of depression and duration of illness is available only for 350 subjects. Therefore, differences between sites can only be partially accounted using available data. CONCLUSIONS: Our study confirms the central role of depressed mood, psychomotor retardation and suicidality and identifies the factors 'Drug/Illness related depression', 'Psychotic features' and the neurovegetative dysregulation not captured by the instruments most frequently used in previous studies. The identification of patients with specific profiles on multiple factors may be useful in achieving greater precision in neuroimaging studies and in informing treatment selection.
Subject(s)
Depressive Disorder/diagnosis , Personality Inventory/statistics & numerical data , Adolescent , Adult , Affect , Aged , Comorbidity , Cross-Cultural Comparison , Depressive Disorder/epidemiology , Depressive Disorder/psychology , Factor Analysis, Statistical , Feeding and Eating Disorders/diagnosis , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/psychology , Female , Humans , Interview, Psychological , Italy , Male , Middle Aged , Mood Disorders/diagnosis , Mood Disorders/epidemiology , Mood Disorders/psychology , Psychometrics/statistics & numerical data , Psychomotor Disorders/diagnosis , Psychomotor Disorders/epidemiology , Psychomotor Disorders/psychology , Reproducibility of Results , Suicide, Attempted/psychology , Suicide, Attempted/statistics & numerical data , United States , Young AdultABSTRACT
The aim of this study was to evaluate the degree of insight and resistance in a sample of obsessive-compulsive patients, and the predictive value of poor insight with respect to response to treatment with serotonin reuptake inhibitors (SRIs). Ninety-three patients fulfilling DSM-IV criteria for obsessive-compulsive disorder were evaluated. Seventy patients were treated with an SRI in a 24-week open-label trial. Sixteen percent of the patients did not recognize obsessions and compulsions as unreasonable or senseless. Fifty-two percent of the patients did not try to resist, 72% had little or no control over obsessions, and 64% were not able to exercise an effective control over compulsions. Patients with poor insight had a greater severity of obsessive-compulsive symptoms, a higher rate of schizophrenia spectrum disorders in their first-degree relatives and a higher frequency of a history of psychiatric disorders during childhood. Fifty-two percent of the patients with normal insight responded to SRIs, whereas none of the patients with poor insight were found to be responders. These results suggest the utility of the assessment of insight and resistance in obsessive-compulsive patients, also for the prediction of response to treatment with SRIs.
