Low Immune Activation Research Articles

The Brain-Gut Axis in the Pathophysiology of Irritable Bowel Syndrome

Summarypathophysiology of irritable bowel syndrome (IBS) is attributed in cumulative neural, hormonal and immunological alterations. We retrospectively reviewed literature data from MEDLINE and EMBASE about the role of brain-gut interactions in the pathophysiology of IBS. Different patterns of regional brain activation, spinal hyperexcitability, autonomic nervous system dysregulation, exaggerated hypothalamus-pituitary-adrenal axis stress response, altered serotonin metabolism, psychiatric comorbidity and low level immune activation are common in patients with IBS. The factors mentioned above mainly sensitize visceral perception and secondarily contribute in the occurrence of both abnormal gastrointestinal motility and extraintestinal symptoms. Visceral hypersensitivity is considered to be the mutual and final result of a multiple level dysregulation of the brain-gut axis in patients with functional gastrointestinal disorders. Immunogastroenterology 2012; 1:23-26

Generalized immune activation and innate immune responses in simian immunodeficiency virus infection

Chronic immune activation is a key factor driving the immunopathogenesis of AIDS. During pathogenic HIV/simian immunodeficiency virus (SIV) infections, innate and adaptive antiviral immune responses contribute to chronic immune activation. In contrast, nonpathogenic SIV infections of natural hosts such as sooty mangabeys and African green monkeys (AGMs) are characterized by low immune activation despite similarly high viremia. This review focuses on the role of innate immune responses in SIV infection. Several studies have examined the role of innate immune responses to SIV as potential drivers of immune activation. The key result of these studies is that both pathogenic SIV infection of macaques and nonpathogenic SIV infections of natural hosts are associated with strong innate immune responses to the virus, high production of type I interferons by plasmacytoid dendritic cells, and upregulation of interferon-stimulated genes (ISGs). However, SIV-infected sooty mangabeys and AGMs (but not SIV-infected macaques) rapidly downmodulate the interferon response within 4-6 weeks of infection, thus resulting in a state of limited immune activation during chronic infection. Studies in nonhuman primates suggest that chronic innate/interferon responses may contribute to AIDS pathogenesis. Further, the ability of natural host species to resolve innate immune responses after infection provides a novel avenue for potential immunotherapy.

Mutations in SCN5A From Patients With IBS Result in Abnormal Na V1.5 Function

Background: Central and peripheral serotonergic systems have been implicated in symptom pathogenesis in Irritable Bowel Syndrome (IBS) on the basis of serotonin's involvement in regulating gastrointestinal tract (GIT) homeostasis, in addition to its central role in the regulation of mood; accumulating evidence also points to the presence of low level immune activation in the condition. We previously showed that the activity of indoleamine-2,3dioxygenase (IDO), the immunoresponsive enzyme which is responsible for the degradation of tryptophan along the kynurenine pathway, is enhanced in IBS. The mechanism underpinning this phenomenon is not well understood. Recently, altered function in specific members of the toll-like receptor (TLR) family (TLR1-10) has also been demonstrated in IBS. However, the relationship between TLR activation and IDO activity in IBS is unknown. Aim: To investigate whether specific TLR activation elicits exaggerated kynurenine production in IBS patients compared to controls. Methods: 25 IBS patients and 37 healthy controls (HC) were recruited and venous blood was donated. Whole blood was cultured with a panel of nine different TLR agonists for 24 hours. Cell culture supernatants were then analysed for both trytophan and kynurenine by HPLC in a single isocratic run using sequential fluorescent and UV detection. Results: Kynurenine concentrations were elevated to similar levels in both IBS (240.9 ± 11.58 vs 322.4 ± 19.73ng/ml, p<0.001) and HC samples (224.2 ± 6.330 vs 316.5 ± 13.60ng/ml, p<0.001) following treatment with the TLR4 agonist lipopolysaccheride (LPS). A corresponding elevation in the kynurenine:tryptophan ratio, an indicator of IDO activity, was observed in both IBS patients (0.01774 ± 0.00089 vs 0.02367 ± 0.00137, p<0.001) and HCs (0.01681 ± 0.0006 vs 0.02354 ± 0.001117, p<0.001). In contrast, this ratio was elevated in IBS patients alone (0.01774 ± 0.00089 vs 0.02166 ± 0.00162, p<0.05) following treatment with the TLR8 ligand ssRNA40. Conclusion: These results demonstrate that TLR activation can drive elevations in IDO activity in a manner that corresponds to previously described functional TLR-agonist mediated responses in IBS. Moreover, it implicates TLR8 in the differential IDO activity observed in IBS patients compared to controls. This provides novel evidence for a putative TLR-dependant mechanism underpinning IDO activation in IBS and may point to new therapeutic avenues in this debilitating condition.

Strong mucosal immune responses in SIV infected macaques contribute to viral control and preserved CD4+ T-cell levels in blood and mucosal tissues

BackgroundSince there is still no protective HIV vaccine available, better insights into immune mechanism of persons effectively controlling HIV replication in the absence of any therapy should contribute to improve further vaccine designs. However, little is known about the mucosal immune response of this small unique group of patients. Using the SIV-macaque-model for AIDS, we had the rare opportunity to analyze 14 SIV-infected rhesus macaques durably controlling viral replication (controllers). We investigated the virological and immunological profile of blood and three different mucosal tissues and compared their data to those of uninfected and animals progressing to AIDS-like disease (progressors).ResultsLymphocytes from blood, bronchoalveolar lavage (BAL), and duodenal and colonic biopsies were phenotypically characterized by polychromatic flow cytometry. In controllers, we observed higher levels of CD4+, CD4+CCR5+ and Gag-specific CD8+ T-cells as well as lower immune activation in blood and all mucosal sites compared to progressors. However, we could also demonstrate that immunological changes are distinct between these three mucosal sites.Intracellular cytokine staining demonstrated a significantly higher systemic and mucosal CD8+ Gag-specific cellular immune response in controllers than in progressors. Most remarkable was the polyfunctional cytokine profile of CD8+ lymphocytes in BAL of controllers, which significantly dominated over their blood response. The overall suppression of viral replication in the controllers was confirmed by almost no detectable viral RNA in blood and all mucosal tissues investigated.ConclusionA strong and complex virus-specific CD8+ T-cell response in blood and especially in mucosal tissue of SIV-infected macaques was associated with low immune activation and an efficient suppression of viral replication. This likely afforded a repopulation of CD4+ T-cells in different mucosal compartments to almost normal levels. We conclude, that a robust SIV-specific mucosal immune response seems to be essential for establishing and maintaining the controller status and consequently for long-term survival.

Early Short-Term Antiretroviral Therapy Is Associated with a Reduced Prevalence of CD8+FoxP3+T Cells in Simian Immunodeficiency Virus-Infected Controller Rhesus Macaques

Regulatory T cells contain a mix of CD4 and CD8 T cell subsets that can suppress immune activation and at the same time suppress immune responses, thereby contributing to disease progression. Recent studies have shown that an increased prevalence of CD8(+)FoxP3(+) T regulatory cells was associated with immune suppression and diminished viral control in simian immunodeficiency virus (SIV)-infected rhesus macaques. Preventing an increase in the prevalence of CD8 T regulatory subsets is likely to lead to a better long-term outcome. Here we show that short-term antiretroviral therapy initiated within 1 week after SIV infection was associated with lower viral set point and immune activation after withdrawal of therapy as compared to untreated animals. Early short-term treated controller animals were found to have better SIV-specific immune responses and a significantly lower prevalence of immunosuppressive CD8(+)FoxP3(+) T cells. Lower levels of CD8(+)FoxP3(+) T cells coincided with preservation of CD4(+)FoxP3(+) T cells at homeostatic levels, and significantly correlated with lower immune activation, suggesting a role for viral infection-driven immune activation in the expansion of CD8(+)FoxP3(+) T cells. Interestingly, initiation of continuous therapy later in infection did not reduce the increased prevalence of CD8(+)FoxP3(+) T cells to homeostatic levels. Taken together, our results suggest that early antiretroviral therapy preserves the integrity of the immune system leading to a lower viral set point in controller animals, and prevents alterations in the homeostatic balance between CD4(+) and CD8(+) T regulatory cells that could aid in better long-term outcome.

From cytokines to toll-like receptors and beyond - current knowledge and future research needs in irritable bowel syndrome.

The irritable bowel syndrome (IBS) is a complex disorder in which psychosocial, cultural and biological factors, interact. Recent knowledge in the pathophysiology of IBS, seem to combine issues such as a low grade inflammation or immune activation and dysbiosis that can trigger or exacerbate IBS. On the other hand, stress mediated through the hypothalamic-pituitary-adrenal axis can produce motility abnormalities that can modify the microbiota as well, with the subsequent immune activation in the mucosa and stimulation of nerve terminals, generating symptoms of IBS. Also, we speculate that, stress, dysbiosis or an underlying genetic predisposition, may increase the epithelial permeability leading to a contact between pathogens-associated molecular patterns and toll-like receptors in the deeper layers of the gut, developing a host immunity response and IBS generation. We believe that the role of toll-like receptors in IBS and elucidating the communication processes between the immune and the nervous system, warrant future research.

The Influence of Commensal Bacteria on the Gut-Brain Axis: Implications for Understanding and Treating Functional GI Disorders

The gut-brain axis has been described as a bi-directional neuro-humeral communication system and is implicated in the pathogenesis of functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Recent work has shown that a subset of patients with IBS show evidence of low grade immune activation and inflammation in the colonic mucosa. This review focuses on the role of the intestinal microbiota and discusses the interrelationship between the intestinal microbiota and maintaining of low grade inflammation, gut dysfunction or behavioral changes using murine models and clinical studies. The findings in murine models show that perturbation of gut flora is a putative mechanism for gut dysfunction in IBS and together with clinical studies they indicate that dysbiosis in patients with IBS psychiatric co-morbidity.

The putative role of the intestinal microbiota in the irritable bowel syndrome

The irritable bowel syndrome (IBS) is a chronic abdominal symptom complex that is heterogeneous in terms of its clinical presentation and underlying pathophysiology and pathogenesis. It is now established that enteric infection can trigger the syndrome in at least a subset of patients. In addition, there is growing evidence of low grade inflammation and immune activation in the distal bowel of some IBS patients. These observations now prompt the question as to what maintains gut dysfunction in these patients. The intestinal microbiota influences a broad array of host organs that include the gut and the brain, and is an important determinant of normal function in these systems. Disruption of the delicate balance between the host and its intestinal microbiota (termed dysbiosis) results in changes in the mucosal immune system that range from overt inflammation as seen in Crohn's Disease, to low grade inflammation without tissue injury, as seen in a subset of IBS patients. Under experimental conditions, disruption of the microbiota also produces changes in gut sensory-motor function and immune activity. Thus, dysbiosis induced by infection, dietary change or drugs such as antibiotics could produce low grade inflammation and chronic gut dysfunction, reminiscent of that seen in IBS. Fluctuations in gut physiology destabilize the habitat of commensal bacteria and provide a basis for chronic dysbiosis. Recent observations in animal models that changes in gut flora influence behavior provide a basis for a novel unifying hypothesis that accommodates both gut dysfunction and behavioral changes that characterize many IBS patients. This hypothesis states that dysbiosis exists in at least a subset of IBS patients, as a result of infection, dietary change or drugs and contributes to gut inflammatory and functional change in addition to psychiatric co-morbidity.

PARKINSONISM IN HIV-INFECTED PATIENTS ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

Highly active antiretroviral therapy (HAART) has significantly prolonged the lives of HIV-infected patients but low level chronic immune activation remains in some. Neurodegenerative diseases are often associated with immune activation which likely plays a role in their pathogenesis.1 Recently, increased alpha-synuclein deposition in the substantia nigra in aging HIV-infected patients has been identified,2 although there was no clear clinical correlate. These observations suggest that HIV and HAART may facilitate the development of neurodegeneration and accelerate the appearance of diseases such as Parkinson disease (PD) via mechanisms including inflammation, mitochondrial dysfunction, and interference with the ubiquitin proteasome pathway.1 Here we describe 3 patients with relatively young onset of parkinsonism in the context of HIV and HAART. ### Case series. The patients were HIV-infected men aged between 44 and 55 years on HAART who were examined prior to the development of parkinsonism. None had been exposed to neuroleptic medications or recent amphetamine use. All developed initial unilateral upper extremity rest tremor, followed by rigidity, bradykinesia, and mild gait involvement with preserved postural stability. Importantly, cognitive, oculomotor, pyramidal, cerebellar, and autonomic features were absent. Only patient 3 responded well to levodopa; however, the dose …

B‐cell activation in patients with irritable bowel syndrome (IBS)

Patients with irritable bowel syndrome (IBS) may have a low grade immune activation. However, little is known about the properties of B cells of IBS patients. We therefore investigated activation level and antigen presenting phenotype of blood B cells of IBS patients. We also examined B-cell responses to lipopolysaccharide (LPS) and probiotic bacteria. Blood samples were obtained from 74 IBS patients and 30 healthy subjects. Peripheral blood mononuclear cells were isolated and stimulated with LPS or an UV-light inactivated bacterial cocktail consisting of the probiotic Gram-positive strains; Lactobacillus paracasei ssp. paracasei 19, Lactobacillus acidophilus La5, Bifidobacterium lactis B612. The phenotype of CD19(+) B cells was investigated by flow cytometry before and after 72 h cell culture. Furthermore, IBS symptom severity was assessed. B cells isolated from blood of IBS patients displayed an amplified activation level as demonstrated by increased cell surface expression of IgG, and also the costimulatory molecules CD80 and CD86. Expression of antigen presenting HLA-DR and costimulatory molecule CD40 on B cells was, however comparable in IBS patients and controls. B cells of IBS patients displayed an impaired ability to increase expression of CD80, but not CD86, in response to both LPS as well as probiotic bacteria stimulations. To conclude, blood B cells of IBS patients have an increased activation level. Bacterial component induced expression of the costimulatory molecule CD80, regarded as important for tolerance induction, is impaired. These data suggest that B-cell antigen presentation in IBS patients is associated with altered capacity of providing costimulation to T cells.

Early Immunological Predictors of Neurodevelopmental Outcomes in HIV‐Infected Children

A previous analysis of children infected with human immunodeficiency virus (HIV) in the Women and Infants Transmission Study showed a strong correlation between low activated CD8(+) T lymphocytes in the first 2 months of life and good immunological prognosis. We sought to extend these observations to neurodevelopmental prognosis. Ninety-eight HIV-infected children born before 1994 with flow cytometric data from the first 2 months of life and adequate neurodevelopmental testing through age 30 months were studied. Children were divided into those with low (<or=5% CD8(+)HLA-DR(+) cells or <or=25% CD8(+)CD38(+) cells) or high (>5% CD8(+)HLA-DR(+) cells or >25% CD8(+)CD38(+) cells) immune activation at 1 and/or 2 months of age. Analysis was performed using survival analysis, Cox's proportional hazard regression, and longitudinal regression models. Absence of immune activation, measured as <or=5% CD8(+)HLA-DR(+) cells, was strongly associated with better performance on the psychomotor developmental index of the Bayley scales of infant development through the third year of life. This association persisted after adjustment for CD4 cell count, viral load, and progression to acquired immunodeficiency syndrome (P= .005). An association with the mental development index was also present (P= .048). Significant association between neurodevelopmental outcomes and <or=25% CD8(+)CD38(+) cells was not seen. In this prospective cohort study of HIV-infected children, there was a significant favorable association of low immune activation in peripheral T cells at age 1 or 2 months, measured by a low percentage of CD8(+)HLA-DR(+) cells, with subsequent psychomotor and mental development. This association was independent of other indices of severity and progression of HIV infection.

Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort

BackgroundIrritable bowel syndrome (IBS) is a common disorder that affects 10–15% of the population. Although characterised by a lack of reliable biological markers, the disease state is increasingly viewed as a disorder of the brain-gut axis. In particular, accumulating evidence points to the involvement of both the central and peripheral serotonergic systems in disease symptomatology. Furthermore, altered tryptophan metabolism and indoleamine 2,3-dioxygenase (IDO) activity are hallmarks of many stress-related disorders. The kynurenine pathway of tryptophan degradation may serve to link these findings to the low level immune activation recently described in IBS. In this study, we investigated tryptophan degradation in a male IBS cohort (n = 10) and control subjects (n = 26).MethodsPlasma samples were obtained from patients and healthy controls. Tryptophan and its metabolites were measured by high performance liquid chromatography (HPLC) and neopterin, a sensitive marker of immune activation, was measured using a commercially available ELISA assay.ResultsBoth kynurenine levels and the kynurenine:tryptophan ratio were significantly increased in the IBS cohort compared with healthy controls. Neopterin was also increased in the IBS subjects and the concentration of the neuroprotective metabolite kynurenic acid was decreased, as was the kynurenic acid:kynurenine ratio.ConclusionThese findings suggest that the activity of IDO, the immunoresponsive enzyme which is responsible for the degradation of tryptophan along this pathway, is enhanced in IBS patients relative to controls. This study provides novel evidence for an immune-mediated degradation of tryptophan in a male IBS population and identifies the kynurenine pathway as a potential source of biomarkers in this debilitating condition.

Immune depression induced by acanthocephalan parasites in their intermediate crustacean host: Consequences for the risk of super-infection and links with host behavioural manipulation

Parasite survival in hosts mainly depends on the capacity to circumvent the host immune response. Acanthocephalan infections in gammarids are linked with decreased activity of the prophenoloxidase (ProPO) system, suggesting an active immunosuppression process. Nevertheless, experimental evidence for this hypothesis is lacking: whether these parasites affect several immune pathways is unknown and the consequences of such immune change have not been investigated. In particular, the consequences for other pathogens are not known; neither are the links with other parasite-induced manipulations of the host. Firstly, using experimental infections of Pomphorhynchus laevis we confirmed that the lower immune activity in parasitised Gammarus pulex is induced by the parasite infection. Second, using natural infections of three different parasites, P. laevis, Pomphorhynchus tereticollis and Polymorphus minutus, we showed that acanthocephalan infection was associated with reduction of the activity of the ProPO system and the haemocyte concentration (two major parameters of crustacean immunity) suggesting that immune depression is a phenomenon affecting several immunological activities. This was confirmed by the fact that acanthocephalan infection (whatever the parasite species) was linked to a lower efficiency to eliminate a bacterial infection. The result suggests a cost of parasite immune depression. Finally, acanthocephalans are also known to induce behavioural alterations in the intermediate host which favour their transmission to definitive hosts. We did not find any correlation between behavioural and immunological alterations in both experimentally and naturally-infected gammarids. Overall, this study suggests that whilst immune depression might be beneficial to acanthocephalan survival within the intermediate gammarid host, it might also be costly if it increases host mortality to additional infections before transmission of the parasite.

Low Immune Activation despite High Levels of Pathogenic Human Immunodeficiency Virus Type 1 Results in Long-Term Asymptomatic Disease

Long-term asymptomatic human immunodeficiency virus (HIV)-infected individuals (LTA) usually have low viral load and low immune activation. To discern whether viral load or immune activation is dominant in determining progression to AIDS, we studied three exceptional LTA with high viral loads. HIV type 1 isolates from these LTA were as pathogenic as viruses from progressors in organ culture. Despite high viral loads, these LTA had low levels of proliferating and activated T cells compared to progressors, like other LTA. In contrast to those in progressors, HIV-specific CD4(+) T-cell responses in these LTA were maintained. Thus, low immune activation despite a high viral load preserved HIV-specific T-cell responses and resulted in a long-term asymptomatic phenotype.

Platelet-Lysate for In Vitro Expansion of Human Multipotent Mesenchymal Stromal Cells in Approaches of Cell-Therapy.

There is large interest in the use of mesenchymal stromal cells (MSCs) in approaches of cell-therapy and tissue engineering. MSCs are currently expanded in vitro in the presence of fetal calf serum (FCS); however, FCS raises concerns in the case of clinical grade cellular preparations because of the theoretical risk of transmission of zoonoses and triggering immune reactions in the host. Therefore, the identification of a serum-free medium appropriate for both the extensive expansion necessary to reach the large numbers of MSCs required for clinical application, and the exclusion of risks connected with the use of animal products, is warranted. Aim of this study was to evaluate whether MSCs expanded in medium supplemented with platelet-lysate (PL) are endowed with biological properties appropriate for cell-therapy approaches. MSCs were generated from bone-marrow of 8 healthy hematopoietic stem cell donor; 4 different culture conditions were tested:10 % FCS;5% PL;2,5% PL;1% PL.MSCs were harvested when reaching ≥ 80% confluence and replated for expansion at 4.000 cells/cm² until passage 5. CFU-F frequency, proliferative capacity, morphology, surface phenotype and differentiation capacity were evaluated. In particular, the immune regulatory effect on alloantigen-specific immune response, the kinetics of cytokine production and the resistance to spontaneous transformation into tumor cells of MSC expanded in the presence of either PL or FCS were investigated. Our results demonstrate that MSCs expanded in either FCS or PL display comparable morphology, phenotype and differentiation capacity, while PL-MSCs were superior in terms of clonogenic efficiency and proliferative capacity. Immune-regulatory effect of MSCs was investigated on alloantigen-specific immune response in mixed lymphocyte culture (MLC). We found that MSCs-PL are comparable to MSCs-FCS in their capacity to:decrease alloantigen-induced cytotoxic activity;favor differentiation of CD4+ T-cell subsets expressing Treg phenotype;increase early secretion of IL-10 in MLC supernatant, as well as to induce a striking augmentation of IL-6 production.As compared with MSCs-PL, MSCs-FCS were more efficient in suppressing alloantigen-induced lymphocyte subset proliferation and in reducing early IFNg-secretion. Resistance to spontaneous transformation into tumor cells of expanded MSCs was demonstrated by both molecular karyotyping (array-comparative genomic hybridization) and maintenance of normal morphology/phenotype after prolonged in vitro culture. Our data support the hypothesis of a remarkable immune functional plasticity of human MSCs and suggest that the use of MSCs-PL, which seem to be endowed with a relatively low immune suppressive activity, could be more appropriate in approaches of reparative/regenerative cell-therapy or in strategies aimed at improving hematopoietic/immune recovery after hematopoietic stem cell transplantation (HSCT). On the contrary, as MSCs-FCS seem to display a more pronounced immune suppressive function, they might be more suitable for preventing or treating alloreactive-related immune complications, such as severe Graft-versus-host disease (GvHD) in HSCT and graft rejection in HSCT and solid organ transplantation.

Impact of nutrition on ageing and disease

The globe is suffering a tsunami of chronic diseases, affecting especially the elderly and those with a dysfunctioning immune system. The fundamental principles of optimal health and optimal ageing are abstaining from smoking, modest alcohol consumption, regular physical exercise and a diet rich in fish and plants and low in condensed calories, sugar and dairy products. Dietary supply and production of advanced glycation end products leads to the accumulation of these products in the tissues and is strongly associated with ageing of the vascular endothelium, nervous system, eyes and other vital organs. Telomeres, which are not involved in DNA repair, remain unrepaired and loose with time. A decline in innate and acquired immunity is seen with increasing age and maintenance of low basal immune activity (degree of inflammation) seems important for health and longevity: 'people who are predisposed to weak inflammatory activity may live longer'. Supplementation with vitamins has little effect on ageing/prevention of chronic diseases, but antiinflammatory molecules like polyphenols are more effective, especially when combined with reduced intake of calorie-condensed foods. The effect of probiotics on ageing needs further exploration. The effects of caloric restriction, proven effective in other species to control aging and prolong lifespan, have not been fully explored in humans.

Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis.

Subclinical inflammation has been implicated in the initiation and/or progression of atherosclerosis. Diabetes mellitus and obesity are risk factors for atherosclerosis, and asymptomatic low grade inflammation occurs prior to overt vascular lesions in these patients. In contrast to adults, little information exists concerning low grade inflammation in young type 1 diabetes and juvenile obesity. To investigate low grade inflammation and immune activation in juvenile diabetes mellitus and obesity. hs-CRP, soluble interleukin-2 receptor (sIL-2R), C-peptide, insulin, cortisol, vitamin B12, folic acid, leptin, and homocysteine were determined in 148 patients with juvenile type 1 diabetes, 86 obese children and 142 normal weighted age-matched healthy controls. Intima-media thickness (IMT) and lumen diameter of both common carotid arteries (CCA) was measured by ultrasonography in 52 healthy pediatric controls, 10 diabetics, and 34 obese juveniles. Serum hs-CRP was significantly elevated in patients with type 1 diabetes (p < 0.0001), and obese children (p < 0.0001) as compared to the control group. The obese juveniles (p < 0.0001) and the diabetics (p < 0.0001) showed significantly increased values for IMT of CAAs. Levels of homocysteine, sIL-2R, insulin, cortisol, vitamin B12, and folic acid did not differ from the controls. The elevation of hs-CRP was more pronounced in obesity as compared to type 1 diabetes (p < 0.0001), and the hs-CRP values correlated significantly with body mass index standard deviation score (BMI-SDS) values. Furthermore, the IMT and the luminal diameter of CCAs showed significant correlations with BMI-SDS values. A low grade inflammation as determined by serum hs-CRP is significantly increased in children with type 1 diabetes, and even more pronounced in apparently healthy juveniles with obesity. The increased IMT of CCAs strongly argues for an association between this low grade inflammation and early atherosclerotic vessel injury.

Relationship between immune activity, senile amyloidosis and life span of hybrids of SAMP1 and B10.BR mice

SAMP1 mice show impaired immune activity as young adults and suffer from senile amyloidosis due to Apoa2 gene expression at around a year of age, and this factor may be responsible for their short life. To examine the relationship between low immune activity, senile amyloidosis and a shortened life span, we investigated hybrid mice from original parental strains of SAMP1 ( Apoa2c) and B10.BR ( Apoa2a), an ordinary strain of mice. Our results show that more than 90% of Apoa2c-homozygous siblings had shortened life spans with either low or high immune activity in equal proportions. Thus, the development of senile amyloidosis may directly cause the shorter life span, while low immune activity does not seem to correlate with a shorter life span. Siblings with both the Apoa2 gene of a/c heterozygous type and high immune activity showed a wide distribution in length of life. Among those who died early there was a heavy deposit of inflammatory amyloyd A-protein (AA)- but not any deposits of AApoAII senile amyloid. It is interesting that 2 out of 24 mice homozygous for Apoa2c displayed relatively long life spans, even though they showed heavy deposition of AApoAII and that these two were found to have low autoimmune antibodies. This means that age-related pathogenesis and life span could be delayed and controlled by some factors other than senile amyloidogenesis.

Spinal Glia and Proinflammatory Cytokines Mediate Mirror-Image Neuropathic Pain in Rats

Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes. Allodynia refers to pain in response to light touch/pressure stimuli, which normally are perceived as innocuous. Mirror-image allodynia arises from the healthy body region contralateral to the actual site of trauma/inflammation. Virtually nothing is known about the mechanisms underlying such pain. A recently developed animal model of inflammatory neuropathy reliably produces mirror-image allodynia, thus allowing this pain phenomenon to be analyzed. In this sciatic inflammatory neuropathy (SIN) model, decreased response threshold to tactile stimuli (mechanical allodynia) develops in rats after microinjection of immune activators around one healthy sciatic nerve at mid-thigh level. Low level immune activation produces unilateral allodynia ipsilateral to the site of sciatic inflammation; more intense immune activation produces bilateral (ipsilateral + mirror image) allodynia. The present studies demonstrate that both ipsilateral and mirror-image SIN-induced allodynias are (1) reversed by intrathecal (peri-spinal) delivery of fluorocitrate, a glial metabolic inhibitor; (2) prevented and reversed by intrathecal CNI-1493, an inhibitor of p38 mitogen-activated kinases implicated in proinflammatory cytokine production and signaling; and (3) prevented or reversed by intrathecal proinflammatory cytokine antagonists specific for interleukin-1, tumor necrosis factor, or interleukin-6. Reversal of ipsilateral and mirror-image allodynias was rapid and complete even when SIN was maintained constantly for 2 weeks before proinflammatory cytokine antagonist administration. These results provide the first evidence that ipsilateral and mirror-image inflammatory neuropathy pain are created both acutely and chronically through glial and proinflammatory cytokine actions.