Autoantibodies against alpha -MSH, ACTH, and LHRH in anorexia and bulimia nervosa patients.

The hypothalamic arcuate nucleus is involved in the control of energy intake and expenditure and may participate in the pathogenesis of eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). Two systems are of particular interest in this respect, synthesizing alpha-melanocyte-stimulating hormone (alpha-MSH) and synthesizing neuropeptide Y, respectively. We report here that 42 of 57 (74%) AN andor BN patients studied had in their plasma Abs that bind to melanotropes andor corticotropes in the rat pituitary. Among these sera, 8 were found to bind selectively to alpha-MSH-positive neurons and their hypothalamic and extrahypothalamic projections as revealed with immunostaining on rat brain sections. Adsorption of these sera with alpha-MSH peptide abolished this immunostaining. In the pituitary, the immunostaining was blocked by adsorption with alpha-MSH or adrenocorticotropic hormone. Additionally, 3 ANBN sera bound to luteinizing hormone-releasing hormone (LHRH)-positive terminals in the rat median eminence, but only 2 of them were adsorbed with LHRH. In the control subjects, 2 of 13 sera (16%) displayed similar to ANBN staining. These data provide evidence that a significant subpopulation of ANBN patients have autoantibodies that bind to alpha-MSH or adrenocorticotropic hormone, a finding pointing also to involvement of the stress axis. It remains to be established whether these Abs interfere with normal signal transduction in the brain melanocortin circuitryLHRH system andor in other central and peripheral sites relevant to food intake regulation, to what extent such effects are related to andor could be involved in the pathophysiology or clinical presentation of ANBN, and to what extent increased stress is an important factor for production of these autoantibodies.

The adaptive response of the immune system to the particular malnutrition of eating disorders.

Despite the seriously undernourished state of patients with anorexia nervosa (AN) and bulimia nervosa (BN), controversial findings have been published regarding some aspects of the immune system that are otherwise impaired in more typical types of malnutrition, such as protein-energy malnutrition. In general, adaptation processes seem to occur enabling immune function to be preserved during long periods of the illness. However, cell-mediated immunity is usually altered in AN and BN as reflected by lymphocyte subset counts and the response to delayed hypersensitivity tests. Regarding the helper/cytotoxic T cell ratio (CD4:CD8), an immunological marker of the nutritional status, the results of our studies on AN and BN patients showed that the duration of the eating disorder and the time when appropriate treatment is achieved are likely contributors to the alteration of this ratio. Despite these findings, it has been repeatedly pointed out that anorexic patients seem to be free of common viral infections at least until the most advanced stages of debilitation. Some hypotheses that could explain the lack of infection symptoms are reviewed. Cytokines and the altered acute phase response to infection, as well as cortisol and leptin, are considered to be potential factors involved in the adaptation processes occurring in these syndromes. Further progress in the knowledge of the psychoneuroendocrine-immune interactions established in AN and BN will be relevant to the understanding of the aetiology and maintenance mechanisms of these pathologies.

Eating disorders: a role for dipeptidyl peptidase IV in nutritional control.

Dipeptidyl peptidase IV (DPP IV), a serine protease with broad tissue distribution and known activity in serum, has been postulated to modulate nutrition control by modification or inactivation of peptide hormones operating in the enteroinsular axis. We hypothesized that changes of DPP IV activity in serum are related to the nutrition status of patients with eating disorders. Serum DPP IV activity was measured in 52 patients (28 with anorexia nervosa and 24 with bulimia nervosa) in four consecutive weekly analyses. Simultaneously, the number of CD26 (DPP IV)-positive peripheral blood lymphocytes was counted. The same analyses were carried out in 28 healthy female volunteers. In week 1 and throughout the observation period, DPP IV activity in the sera of patients with anorexia nervosa and, to a lesser extent, those with bulimia nervosa was elevated in comparison to that of healthy controls (week 1: means = 92.8 U/L for anorexia-nervosa patients and 89.3 U/L for bulimia-nervosa patients versus 74.7 U/L for healthy control subjects, P = 0.014; weeks 1-4: 91.8 U/L for anorexia-nervosa patients and 86.2 U/L for bulimia-nervosa patients versus 77.6 U/L for healthy controls, P < 0.001). We assume that the increase in DPP IV serum activity will increase the turnover of distinct peptide hormones with known effects on nutrition control and susceptibility to degradation by DPP IV. The potential impact of an increase in DPP IV activity in serum on satiety and nutrition control contributes to previously reported implications for immune function.

Cytokine production in patients with anorexia nervosa, bulimia nervosa, and obesity.

OBJECTIVE: We previously reported elevated serum levels of the cytokines interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) in patients with anorexia nervosa (AN). We investigated the cellular production of these two cytokines and of interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), and tumor necrosis factor-alpha (TNF-alpha) in subjects with AN, bulimia nervosa (BN), and obesity as well as in normal-weight control subjects. METHODS: Supernatant fluids from isolated peripheral blood mononuclear cells (PBMC) incubated with and without concanavalin A (ConA) were assayed for cytokine concentrations by enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant differences across the four groups were found in the stimulated cellular production of IFN-gamma and IL-6. Stimulated IFN-gamma production was elevated in the AN group compared to controls. IL-6 production was significantly elevated in obese subjects relative to the two normal-weight groups, BN and controls, and tended to be higher in the AN group than in the controls, but not significantly so. IL-1alpha production was greater in obese subjects. CONCLUSION: The findings of increased IFN-gamma production and a tendency toward increased IL-6 production (both of which suppress food intake in animals) in individuals who severely restrict food intake suggest a potential role for these cytokines in the pathogenesis of AN. Elevated IL-6 and IL-1alpha production by PBMC in obese individuals requires further investigation to determine if these cytokines contribute to the development or perpetuation of obesity.

Dipeptidyl peptidase IV (DPP IV, CD26) in patients with mental eating disorders.

The notion that patients with eating disorders maintain a functional immunosurveillance in spite of severe malnutrition has attracted researchers for years. Dipeptidyl Peptidase IV (DPP IV), a serine protease with broad tissue distribution and known activity in serum, operates in the cascade of immune responses. Membrane-bound DPP IV expressed on lymphocytes, also known as the leukocyte antigen CD26, is considered to participate in T cell activation. We hypothesized that the activity of DPP IV in serum and expression of CD26 in lymphocytes may be altered in patients with eating disorders. Serum DPP IV activity and the number of CD26 (DPP IV)-positive peripheral blood lymphocytes were measured in 44 patients (anorexia nervosa (AN): n = 21, bulimia (B): n = 23) in four consecutive weekly analyses. The analysis of CD26-positive cells included the characterization of CD26-bright and CD26-dim positive subsets. Additionally, the expression of CD25 (IL-2 Receptor alpha chain) was evaluated to estimate the degree of T cell activation. The same analyses were carried out in healthy female volunteers (HC, n = 20). CD26-positive cells were reduced in patients as compared to healthy controls (mean 40.2% (AN) and 41.1% (B) vs. 47.4% (HC), p < 0.01), while the DPP IV activity in serum was elevated (mean 108.4 U/l (AN) and 91.1 U/l (B) vs. 80.3 U/l (HC), p < 0.01). The potential implications of changes in DPP IV expression and serum activity on--and beyond--immune function are discussed.

Eating disorders: a situation of malnutrition with peculiar changes in the immune system.

Eating disorders, such as anorexia nervosa and bulimia nervosa, are significant public health concerns for a great deal of the population, and thus are even considered to be epidemics. These syndromes have a common aim: the pursuit of a desirable and extremely low weight, which is obviously very far from the ideal body weight. Therefore, these patients show abnormal food behavior, leading to a situation of malnutrition. Nutrients play an important role in the development and functionality of the immune system. Thus, the assessment of immunological parameters acquires great interest as a useful tool to evaluate the nutritional status of these patients. In addition, it is very well known that a depleted immune system as a consequence of malnutrition is linked to an increased susceptibility to infections. However, an extensive literature has pointed out that anorexic patients, even though severely malnourished, are relatively free from infectious diseases. As the immune system is altered by distorted food behaviors, such as in case of eating disorders, the awareness of the characteristics of other systems involved in these pathologies, and therefore altered, would be very helpful for the understanding of the mechanisms triggered in these syndromes. In fact, the interactions among the immune system and the remaining systems in eating disorders are beginning to be studied. Finally, the main goal is to limit the evolution of these illnesses through an early diagnosis and appropriate therapy to subsequently get a constant and definitive cure for the patients.

Alterations in expression and in serum activity of dipeptidyl peptidase IV (DPP IV, CD26) in patients with hyporectic eating disorders.

The notion that patients with eating disorders maintain a functional immunosurveillance in spite of severe malnutrition has attracted researchers for years. Dipeptidyl peptidase IV (DPP IV), a serine protease with broad tissue distribution and known activity in serum, operates in the cascade of immune responses. Membrane-bound DPP IV expressed on lymphocytes, also known as the leucocyte antigen CD26, is considered to participate in T-cell activation. We hypothesized that the activity of DPP IV in serum and expression of CD26 in lymphocytes may be altered in patients with eating disorders. Serum DPP IV activity and the number of CD26 (DPP IV)-positive peripheral blood lymphocytes were measured in 34 patients [anorexia nervosa (AN): n = 11, bulimia (B): n = 23] in four consecutive weekly analyses. In addition, the expression of CD25 (interleukin-2 receptor alpha chain) was evaluated to estimate the degree of T-cell activation. The same analyses were carried out in healthy female volunteers (HC, n = 20). CD2-CD26-positive cells were reduced in patients compared with healthy controls [mean 40.2% (AN) and 41.1% (B) versus 47.4% (HC), P < 0.01], while the DPP IV activity in serum was elevated [mean 108.4 U/l (AN) versus 91.1 U/l (B) and 80.3 U/l (HC), P < 0.01]. The potential implications of our observations on, and beyond, immune function are discussed.

Bulimia nervosa and autoimmunity.

The autoantibodies that react with dopamine and serotonin are of interest in the study of bulimia nervosa. These neurotransmitters play an important role in appetite control, sexual and social behavior, and stress responses, all of which form a part of the clinical picture of bulimia nervosa. Are these autoantibodies involved in the serotoninergic hypofunctioning present in bulimia nervosa? Are they a part of an immunity regulation system essential for the cerebral system's homeostasis? To address these questions, 31 bulimic females (diagnosed according to DSM-III-R criteria) were compared with 10 control subjects (matched to the patients for sex, age, and demographic/psychosocial features). Measurement of the activity of natural autoantibodies reacting with dopamine, dopamine-beta-hydroxylase and serotonin was performed by an enzyme-linked immunosorbent assay (ELISA) for typical immunoglobulins (IgG, IgM, IgA). All of the autoantibodies of the IgG type were lower in the bulimic group than in the control group, a difference that was statistically significant for IgG anti-serotonin and IgG anti-dopamine. There was a trend for the amount of IgM anti-dopamine to be lower in patients than in controls. Dopamine and serotonin are specific components of brain cells. It can therefore be hypothesized that these antigens acting with autoantibodies could be the antigenic cerebral targets reacting with 'anti-brain' antibodies. The study of these specific autoantibodies provides information about the immunological characteristics that may be related to brain disturbances.

Immunoendocrine findings in patients with eating disorders.

Immune changes may occur in patients with anorexia nervosa (AN) or bulimia nervosa (BN), and a role for proinflammatory cytokines has been proposed in the pathogenesis of both disorders. We measured plasma levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), soluble forms of the cytokine receptor proteins gp130 and leukemia inhibitory factor receptor (LIF-R), the anti-inflammatory Clara cell 16-kD protein (CC16), prolactin (PRL), cortisol and 17beta-estradiol in 21 anorexic women, 21 bulimic women and 21 healthy females. As compared to healthy subjects, anorexics exhibited significantly increased plasma levels of gp130 and LIF-R, whereas bulimics had significantly decreased blood concentrations of CC16. No significant differences emerged in the blood levels of the remaining immune parameters. Both patient groups manifested higher plasma levels of cortisol and reduced plasma concentrations of PRL and 17beta-estradiol. In anorexics, a significant negative correlation was found between plasma levels of gp130 or LIF-R and the body mass index. These findings do not support the hypothesis that proinflammatory cytokines may play a pathogenetic role in eating disorders.

[Somatic complications in anorexia and bulimia nervosa]. / Somatiska komplikationer vid anorexia och bulimia nervosa.

Although the pathogenesis and treatment of anorexia nervosa and bulimia nervosa have traditionally been discussed in psychological terms, these eating disorders are always accompanied by somatic symptoms, symptoms which may become very serious. Moreover, as the anorexic or bulimic patient seeking medical treatment does not as a rule reveal the self-inflicted nature of her symptoms to the doctor, it is vital that physicians recognize such symptoms as manifestations of eating disorders. The article consists in a review of somatic complications commonly accompanying anorexia and bulimia, and their relationship to different body systems.

[Anorexia nervosa and bulimia nervosa. II. Somatic complications of undernourishment]. / Anorexia nervosa en boulimia nervosa. II. Somatische gevolgen van ondervoeding.

In anorexia nervosa and bulimia nervosa, cachexia and deficient nourishment cause various physical abnormalities, especially of the endocrine and digestive systems and the heart. Disorders in the serotoninergic and dopaminergic systems contribute to development of an eating disorder, whereas an acquired deficiency of tryptophan impairs the serotoninergic system. Any problems of nutritional deficiencies, low blood sugar levels and gastrointestinal disorders disappear after normal nourishment is resumed. Hypotension and sinus bradycardia are manifestations of a physiological adjustment to a lower basal metabolism and need no treatment. Osteoporosis occurs from two years after the onset of weight loss; oestrogen supplementation may protect against this. In patients with infections, symptoms such as fever, leukocytosis and high BSE may be lacking. Hypoglycaemia incidentally leads to coma and death, and a lengthened QT interval to acute cardiac death. During restoration of the nutritional status, the intake of fluid and calories should initially be limited. During the first two weeks, the risk of cardiovascular complications is increased.

[Bulimia and autoimmunity]. / Boulimie et auto-immunité.

In the first part of this study, we investigated the rate of natural autoantibodies, in a sample of 31 female inpatients with bulimia nervosa according to DSM III-R criteria. The control (age and sex matched) group consisted in high school students including 10 females without eating disorders, depressive disorder or immunological disease. We investigated especially natural autoantibodies reacting with compounds of the central nervous system (Dopamine, Dopamine beta Hydroxylase, Serotonin). Our first conclusion is that there is a lower level of these natural auto-antibodies among female patients with bulimia nervosa. In the second part of the study, we have especially investigated the correlation between impulsivity in bulimia nervosa and the rate of natural autoantibodies against serotonin.

The immune system in eating disorders: an overview.

Eating disorders, such as anorexia nervosa and bulimia nervosa, are becoming more and more common in our society. Although they are psychiatric illnesses, there are many factors involved, including abnormal food behavior. Nutrients play an important role in the development and functionality of immunocompetent cells. An impaired immunocompetence has been shown to be an important causal factor in the increased susceptibility of malnourished individuals to infectious disease. Therefore, studies on the immune system are of great interest when assessing the extent to which the nutritional status of these patients could be affected. However, the literature in this field is controversial, and the mechanisms are not yet completely defined, although some hypotheses try to clarify the disturbances caused in the organism under these bizarre circumstances. In spite of the fact that the immune system is altered by distorted food behaviors, such as in eating disorders, the awareness of characteristics of other systems involved, and therefore altered, by these pathologies would be very helpful for understanding the mechanisms triggered in these syndromes. In fact, the interactions among the immune and other systems in eating disorders are beginning to be studied. Finally, the main goals are to limit the evolution of these illnesses through early diagnosis, and to devise a long-lasting, definitive cure for these patients through appropriate therapy.

Evaluation of nutritional status by immunologic assessment in bulimia nervosa: influence of body mass index and vomiting episodes.

The nutritional status of 21 patients suffering from bulimia nervosa was evaluated by anthropometric and immunologic indexes in comparison with a control group (n = 15). In addition, the influence of body mass index (BMI; in kg/m2) values and vomiting episodes on the nutritional status of bulimic patients was assessed. Anthropometry showed no signs of malnutrition in either group, except for those patients with low weights (BMI < 19). Bulimic patients had lower lymphocyte counts than did control subjects, except for those without vomiting (NVBN). All T lymphocyte subsets tested as well as CD57 cells were lower (22% and 55%, respectively) in bulimic patients than in control subjects, but the CD19 cell subset remained unmodified. The low-weight bulimic group (LWBN) had lower CD4 cell counts than did the normal-weight (BMI > 19) bulimic group. The NVBN group had lymphocyte subpopulations similar to those in the control group, except for CD57, which was lower. The bulimic patients with vomiting had the lowest cell subset values. These results suggest a depleted nutritional status in all bulimic patients studied, even those with normal weights. The LWBN group had the most depleted nutritional status and the NVBN group was least affected at a subclinical level. CD57 can be considered a good marker of nutritional status in this syndrome because it was the only subpopulation altered in all groups.

Case study of fulminant meningococcal septicemia diagnosed in a twenty-year-old woman with bulimia nervosa.

Fulminant meningococcal septicemia accounts for 5% to 10% of patients with meningococcemia; it is rapidly progressive and is associated with high morbidity and mortality rates. The highest meningococcal incidence is found in the 6- to 20-month-old age group; whereas immunoincompetence is suggested in adults with the condition. Coincidentally, eating disorders are purported to be the most prevalent psychiatric or behavioral disturbance affecting adolescents, and studies indicate that vulnerability to infectious disease may be present in this group as a result of a subclinical malnutrition state. I report a case of fulminant meningococcal septicemia in a patient with a comorbid eating disorder of bulimia nervosa, who had a tumultuous disease course, and with rapid and aggressive management of her condition--an impressive recovery.

[Characterization of leukocytes, lymphocytes and lymphocyte subsets in eating disorders]. / Caractérisation des leucocytes, lymphocytes et populations lymphocytaires dans les maladies du comportement alimentaire.

Mental anorexia patients have severe denutrition and high cortisol levels. Nervous bulimia presents a particular psychic profile. The aim of this study was to evaluate lymphocyte population in eating disorders in order to understand the effect of these disturbances on immune system. We have found that patients with mental anorexia or bulimia present a significant decrease of leucocytes, lymphocytes, CD2 and CD4. Patients with post-anorexia bulimia have no significant variants. There is no difference between mental anorexia and nervous bulimia. There is a tendential variation between mental anorexia and controls in relation to CD45Ra. Considering the similar patterns of immune disturbance in anorexia and bulimia it looks like a dominance of neuroimmune network over malnutrition. Naive cells are particularly sensitive to malnutrition.

The role of tumor necrosis factor-alpha in the pathogenesis of anorexia and bulimia nervosa, cancer cachexia and obesity.

In this paper a new immunological model of anorexia and bulimia nervosa will be presented in which the inflammatory cytokines are conceived as the fundamental regulators of body metabolism. This conception differs from the conventional view in which the inflammatory cytokines are perceived primarily as peptide molecules utilized by the immune system to control infection, inflammation and tissue or neuronal damage. Given that the inflammatory cytokines are also fundamental regulators of body metabolism, when they become dysregulated they create physiological chaos which results in the development of a number of autoimmune, metabolic and psychiatric disorders. In this proposed immunological model of anorexia and bulimia nervosa, elevated tumor necrosis factor-alpha features as the primary cause of these conditions. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia in terms of the causal role the cytokines, neuropeptides and neurotransmitters play in the manifestation of shared symptoms. These shared symptoms include elevated tumour necrosis factor-alpha, down-regulated interleukin-2 and interleukin-4 and depletion of lean body mass. Furthermore, the following neuropeptides are dysregulated in both anorexia nervosa and cancer cachexia: vasoactive intestinal peptide, cholecystokinin, corticotropin-releasing factor, neuropeptide Y, peptide YY and beta-endorphin. In addition, in anorexia and bulimia nervosa, secretion of the neurotransmitter serotonin is inhibited while norepinephrine is enhanced. It will be argued that the causal interplay between the cytokines, neuropeptides and neurotransmitters initiates a cascade of biochemical events which may result in either anorexia or bulimia nervosa, or cancer cachexia. The extent to which these inflammatory cytokines, neuropeptides and neurotransmitters are causally efficacious in the pathogenesis of other autoimmune disorders, such as diabetes mellitus and rheumatoid arthritis, will also be addressed.

Immunoendocrine aspects of anorexia nervosa.

The T-lymphocyte proliferative response to phytohemoagglutinin (PHA) stimulation was the same in 11 anorexic women, 6 restricted (AN-R) and 5 bulimic (AN-B), and in 11 sex- and age-matched controls, in basal conditions and after acute administration of corticotropin-releasing hormone (CRH). Basal plasma levels of ACTH and cortisol were higher in patients than in controls, while beta-endorphin (beta-EP), growth hormone (GH) and prolactin (PRL) concentrations did not differ in the two groups. ACTH and beta-EP responses to CRH stimulation were blunted in patients, while those of cortisol did not differ in the two groups. ACTH, beta-EP and cortisol responses to the dexamethasone suppression test were impaired in 55% of the patients. Baseline T-lymphocyte concentrations of cholecystokinin-8 (CCK-8) and beta-EP were measured in another group of 56 anorexics, 33 restricted and 23 bulimic, and in 24 controls. CCK-8 values were significantly lower and beta-EP values significantly higher in patients than in controls.

Nutritional status and immunocompetence in eating disorders. A comparative study.

Nutritional status and immunocompetence were evaluated in 26 patients suffering from anorexia nervosa (AN) (n = 16) or bulimia nervosa (BN) (n = 10) in comparison with a control group (n = 22). Body mass index (BMI) was lower in all patients than in controls, AN patients having the lowest values. Slight leukopenia together with relative lymphocytosis was shown in both AN and BN. The CD4/CD8 ratio was low in all patients, but more so for BN patients, although cell-mediated immune function was impaired to the same extent for both eating disorders. The complement system appeared to be damaged in all the patients in comparison with controls. These results may mean that the nutritional status of both syndromes was different. Although anthropometric measurements in the BN group may suggest a more acceptable nutritional status, immunological parameters were shown to be depleted at the same level as the AN group and even more impaired when judged by the lower CD4/CD8 values.