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Is there a psychoneuroimmunological pathway between alexithymia and immunity? Immune and physiological correlates of alexithymia.

The term "alexithymia" was coined by Sifneos. It is characterised by a lack of words to express emotion (a: absence of; lexi: words; thymia: emotions, affects). Its characteristics were suggested to occur more frequently in individuals with so-called "psychosomatic disorders", but this is still a matter of controversy. Here we review the psychosomatic network of alexithymia, i.e. the immune and physiological correlates of alexithymia. Some studies suggest that inaccuracy in recognising emotional states, or the way of coping with negative emotions, may influence immune function. Alexithymia is associated with higher tonic baseline levels of sympathetic activity and lower sympathetic reactivity during acute stress. Few studies have reported a diminished immune-mediated cellular response in alexithymics with oversecretion of glucocorticoids. We hypothesise that alexithymic subjects may suffer from unnoticed chronic stress with physiological and endocrine and immune consequences. Alexithymia may skew the Th-1/Th-2 balance toward Th-2 dominant immunity and lower cell-mediated (Th-1) immune response and may increase an individual's risk for stress-related disorder.

Affective Symptoms↗

T cell immune response is correlated with fibrosis and inflammatory activity in hepatitis B cirrhotics.

AIM: To explore the relationship among interferon-gamma (IFN-gamma) activity, fibrogenesis, T cell immune responses and hepatic inflammatory activity. METHODS: Peripheral blood samples from a total of 43 hepatitis B cirrhotic patients (LC) and 19 healthy controls (NC) were collected to measure their serum levels of IFN-gamma, interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), interleukin-10 (IL-10) and three serological markers of fibrosis including hyaluronic acid (HA), procollagen type III peptide (PIIIP), and type IV collagen were measured using a double antibody sandwich ELISA. Also, serum total bilirubin (TB) and alanine aminotransferase (ALT) were measured by routine measures. RESULTS: The concentrations of serological markers of fibrosis in patients with active cirrhosis (ALC) were significantly higher than those in stationary liver cirrhosis (SLC) or NC groups. The levels of serological markers in HBeAg-positive patients were significantly higher than those in HBeAg-negative patients. In SLC and ALC patients, a negative linear correlation was found between IFN-gamma levels and the serological markers of fibrosis. IFN-gamma and IL-2 levels in the ALC group were significantly higher than those in the SLC and NC groups, but the statistical difference was not significant between the latter two. In contrast, IL-10 levels in the SLC group were significantly higher than that in the NC group, but no significant difference was found between SLC and ALC groups. The sIL-2R level was elevated gradually in all these groups, and the differences were significant. Positive linear correlations were seen between IFN-gamma activity and ALT levels (r = 0.339, P < 0.05), and IL-2 activity and TB levels (r = 0.517, P < 0.05). sIL-2R expression was positively correlated with both ALT and TB levels (r = 0.324, 0.455, P < 0.05), whereas there was no statistically significant correlation between IL-10 expression and serum ALT and TB levels (r = -0.102, -0.093, P > 0.05). Finally, there was a positive correlation between IFN-gamma and IL-2 levels. CONCLUSION: T cell immune responses are correlated with fibrosis and hepatic inflammatory activity and may play an important role in liver cirrhosis.

Case-Control Studies↗

Induction of nitric oxide release from the human alveolar epithelial cell line A549: an in vitro correlate of innate immune response to Mycobacterium tuberculosis.

In view of the presence of a large number of epithelial cells in the alveoli of the lung and their ability to produce various cytokines and chemokines, the possible role of alveolar epithelial cells in the innate immune response to tuberculosis was examined. The human alveolar epithelial cell line A549 was used as a model. The ability of A549 cells to induce nitric oxide (NO) in response to Mycobacterium tuberculosis infection was taken as an in vitro correlate of innate immunity. M. tuberculosis infection induced A549 cells to produce significant levels of NO and to express inducible nitric oxide synthase mRNA at 48 hr of infection. However, the amount of NO released at this point was not mycobactericidal. Cytokine stimulation (interferon-gamma, tumour necrosis factor-alpha, interleukin-1beta, alone or in combination) of the infected A549 cells induced a higher concentration of NO. The study of colony-forming units (CFU) as a measure of the mycobactericidal capacity of A549 cells revealed a reduction in CFU of M. tuberculosis by 39.29% (from 10.62 +/- 0.48 - 6.392 +/- 0.54) following cytokine stimulation of the infected cells. Interestingly gamma-irradiated M. tuberculosis H37Rv could also induce higher than basal level of NO. Therefore we examined mycobacterial antigenic components for their possible role in NO production. We observed that A549 cells produced significantly higher amounts of NO at 48 hr when treated with mycobacterial whole cell lysates, cell wall or cell membrane preparations. The release of NO and the resultant mycobactericidal activity could be further enhanced by simultaneously conditioning the M. tuberculosis infected A549 cells with cytokine and mycobacterial components. These results suggest that alveolar epithelial cells respond to their microenvironment, which is constituted of various cytokines and macrophage-processed antigens and may contribute to the innate immune response to tuberculosis.

Cell Line↗

Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor genotype.

PURPOSE: The unique immunoglobulin idiotype (Id) expressed by each B-cell lymphoma is a target for immunotherapy. Vaccination with Id induces humoral and/or cellular anti-Id immune responses. However, the clinical impact of these anti-Id immune responses is unknown. We and others have previously reported that immunoglobulin G Fc receptor (FcgammaR) polymorphisms predict the clinical response of lymphoma patients to passive anti-CD20 antibody infusions. In this study, we tested whether anti-Id immune responses or FcgammaR polymorphisms associate with clinical outcome of patients who received Id vaccination. PATIENTS AND METHODS: We analyzed 136 patients with follicular lymphoma who had received Id vaccination. The anti-Id immune responses were measured and FcgammaRIIIa and FcgammaRIIa polymorphisms were determined and correlated with clinical outcome for these patients. RESULTS: Patients who mounted humoral immune responses had a longer progression-free survival (PFS) than those who did not (8.21 v 3.38 years; P = .018). Patients with FcgammaRIIIa 158 valine/valine (V/V) genotype also had a longer PFS than those with valine/phenylalanine (V/F) or phenylalanine/phenylalanine (F/F) genotypes (V/V, 8.21 v V/F, 3.38 years; P = .004; v F/F, 4.47 years; P = .035). Multivariate analysis using the Cox proportional hazards model showed that V/V genotype and humoral immune responses were independent positive predictors for PFS. CONCLUSION: This study is the first to identify the predictive value of FcgammaR polymorphism on clinical outcome in patients who received active immunotherapy with tumor antigen vaccines. Our results imply that the antibodies induced against a tumor antigen are beneficial and that FcgammaR-bearing cells mediate an antitumor effect by killing antibody-coated tumor cells.

Antigens, CD↗

Correlation of specific immune responses with survival in melanoma patients with distant metastases receiving polyvalent melanoma cell vaccine.

PURPOSE: The mechanisms that underlie the clinical efficacy of melanoma vaccines are not well understood. We hypothesized that the type and strength of the immune response generated by CancerVax (John Wayne Cancer Institute, Santa Monica, CA), a polyvalent melanoma cell vaccine (PMCV), might be correlated with its effect on overall survival (OS). PATIENTS AND METHODS: Seventy-seven patients began PMCV therapy after complete surgical resection of distant metastatic melanoma. During the first two treatments, PMCV was administered with bacille Calmette-Guerin (BCG). Blood was drawn at 0, 2, 4, 8, and 12 weeks to measure serum titers of immunoglobulin G (IgG) and IgM antibodies against a tumor-associated 90-kd glycoprotein antigen (TA90) expressed on most melanoma cells, including those of PMCV. Cellular immune response to PMCV was assessed by delayed-type hypersensitivity (DTH). General immune competence was assessed by skin tests to purified protein derivative (PPD), mumps, and candida. RESULTS: Median follow-up time was 31.5 months. Within the first 12 weeks of PMCV immunotherapy, there was a significant increase in the anti-TA90 IgM (P=.0001) and IgG titers (P=.0001), and in the DTH response to PMCV (P=.0001). Univariate analysis showed that high anti-TA90 IgM titer and strong PMCV-DTH were associated with improved survival (P=.051 and .0173, respectively), whereas elevated anti-TA90 IgG was correlated with decreased survival (P=.0119). Multivariate analysis considering clinical variables and PMCV immune responses identified anti-TA90 IgM, anti-TA90 IgG, and PMCV-DTH as significant independent variables influencing survival following PMCV immunotherapy (P=.0342, .0105, and .0082, respectively). These responses to PMCV were not correlated with immune responses to BCG and therefore were not a manifestation of general immune competence for responses to unrelated antigens. The median survival time and 5-year survival rate were more than 76 months and 75%, respectively, if both anti-TA90 IgM and PMCV-DTH responses were strong (> or = 800 and > or = 7 mm, respectively; n=29); 32 months and 36%, respectively, if only one response was strong (n=35); and 19 months and 8%, respectively, if neither was strong (n=13) (P < .0001). CONCLUSION: PMCV induces both humoral and cell-mediated immune responses to melanoma-associated tumor antigens, the type and strength of which appear to be directly related to its therapeutic efficacy.

Adult↗

Parallel tubular structures in lymphocytes. II. Correlation with cellular immunity and cytomegalovirus and Epstein-Barr virus antibodies in Hodgkin's disease.

The increased incidence of parallel tubular structures in lymphocytes of patients with Hodgkin's disease was investigated for a correlation with either impairment of cellular immunity (measured by DNCB-skin test and PHA-induced lymphocyte stimulation in vitro) or an increase of antibodies against cytomegalovirus or Epstein-Barr virus. No correlations were found. Statistical analysis revealed antibody titers especially in the group of patients with high percentages of lymphocytes containing the tubular inclusions. This probably reflects only the connection between these findings and the progression of the disease. The nature and function of the parallel tubular structures have to be investigated further. In Hodgkin's disease they may have significance for the understanding of an alteration in lymphocyte function and morphology.

Antibodies, Viral↗

Correlation between donor cytomegalovirus immunity and chronic graft-versus-host disease after allogeneic bone marrow transplantation.

Chronic graft-versus-host disease (GvHD) in bone marrow allograft recipients is frequently preceded by a cytomegalovirus (CMV) infection. To elucidate whether an immune reaction of transplanted donor cells against CMV was involved in the pathogenesis of chronic GvHD, the effect of donor pretransplant CMV immune status on chronic GvHD incidence was analyzed. In 43 bone marrow recipients at risk, the 2-yr cumulative chronic GvHD probability was 55% when the donor was immune, in contrast to 16.5% when the donor was non-immune (p less than 0.002). No correlation between recipient pretransplant CMV immunity and chronic GvHD was observed. Donor CMV immunity did not correlate with acute GvHD or posttranplant CMV infection and seemed to predispose for chronic GvHD regardless of donor and recipient age. However, the proportion of CMV immune donors increased with increasing donor and recipient age. This may account for the higher incidence of chronic GvHD in older patients. The present study suggests that chronic GvHD may be mediated by a reaction of immune donor cells against CMV infected recipient cells.

Acute Disease↗

Correlations between antibody immune responses at different mucosal effector sites are controlled by antigen type and dosage.

Monitoring specific secretory immunoglobulin A (IgA) responses in the intestines after mucosal immunization or infection is impeded by the fact that sampling of small intestinal secretions requires invasive methods not feasible for routine diagnostics. Since IgA plasma cells generated after intragastric immunization are known to populate remote mucosal sites as well, secretory IgA responses at other mucosal surfaces may correlate to those in the intestines and could serve as proxy measures for IgA secretion in the gut. To evaluate the practicability of this approach, mice were immunized intragastrically with 0.2, 2, and 20 mg of ovalbumin plus 10 microg of cholera toxin, and the antigen-specific local secretory IgA responses in duodenal, ileal, jejunal, rectal, and vaginal secretions, saliva, urine, and feces, as well as serum IgG and IgA responses were analyzed by enzyme-linked immunosorbent assay. Correlation analysis revealed significant relationships between serum IgG and IgA, urinary IgA, salivary IgA, and secretory IgA in duodenal, jejunal, ileal, and rectal secretions for the 0.2-mg but not for the 20-mg ovalbumin dose. Fecal samples were poor predictors for intestinal antiovalbumin IgA responses, and no correlations could be established for cholera toxin, neither between local anti-cholera toxin levels nor to the antiovalbumin responses. Thus, specific IgA in serum, saliva, or urine can serve as a predictor of the release of specific IgA at intestinal surfaces after intragastric immunization, but the lack of correlations for high ovalbumin doses and for cholera toxin indicates a strong dependency on antigen type and dosage for these relationships.

Animals↗

Correlation between histopathology, immune response, clinical presentation, and evolution in Leishmania braziliensis infection.

Skin biopsies from 221 parasitologically confirmed cases of tegumentary leishmaniasis caused by Leishmania braziliensis spp. were evaluated with respect to histopathology, the qualitative and quantitative nature of the cellular infiltrate, and the presence of Leishmania amastigotes. These variables were cross correlated with the Leishmania-specific immune response, clinical presentation, and response to treatment. Physical evidence of prior leishmanial lesions was associated with the absence of amastigotes (P less than or equal to 0.001) and the presence of giant (P = 0.03) and epitheloid cells (P = 0.03) in the biopsy of the active lesion. The presence of amastigotes was inversely related to the duration of the lesion (P less than or equal to 0.001) and the presence of eosinophils (P less than or equal to 0.01), whereas the presence of adenopathy (P = 0.01), necrosis (P = 0.001), histiocytes (P = 0.001), and increased serum antibody titer (P = 0.02) were directly associated with the presence of amastigotes. The lymphocyte transformation response was correlated with the presence of granulomas (P = 0.001), but showed no correlation with cutaneous delayed type hypersensitivity. The presence of epithelioid (P = 0.04) and giant cells (P = 0.03) was associated with less drug being required to achieve healing. In contrast, necrosis was associated with a greater amount of drug to achieve healing (P = 0.05). The observed correlations between tissue responses and immune and clinical parameters provide further evidence for the role of antibody and other soluble mediators of the cellular immune response in the evolution of disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Correlation of circulating immune complexes and complement breakdown products with the severity of the disease in human schistosomiasis mansoni.

Circulating immune complexes and complements compounds were measured in serum and plasma from 66 patients with three different clinical forms of chronic schistosomiasis mansoni: intestinal, hepato-intestinal and hepatosplenic. Three different methods were used: the 125I-C1q-binding assay, conglutinin-binding assay (KgB) and Raji cell-binding assay. Approximately 25% of the patients were positive for circulating immune complexes as measured by the C1q and Raji assays. The levels of complexes increased significantly with the severity of the disease. 60% of the patients were positive for immune complexes as measured by the KgB-assay but the incidence of positive results was not clearly influenced by the stage of the disease. There was no significant correlation between immunoglobulin levels and immune complexes. The complement profile of these patients does not suggest a dramatic activation of the complement system. However, there was a progressive decrease in the plasma levels of C4 and an increase of C3d levels which correlated significantly with the severity of the disease.

Adolescent↗

The measles outbreak in Chikuhou District, Fukuoka, Japan, 1990: correlation between herd immunity level and outbreak size.

A measles outbreak occurred in the Chikuhou district of Fukuoka, Japan from May to October 1990, during which 71 patients were cared for at the Itoda Public Hospital. Hospital records revealed a large outbreak in the adjacent town of Kanada. In order to characterize the outbreak, questionnaires were sent to all preschool-age children in Itoda (73% effective response) and in Kanada (76% effective response) requesting information about their vaccination and/or history of measles. The number of patients was 22 (4%) in Itoda and 63 (14%) in Kanada, most of these being preschoolers, while the vaccination rate was 61% and 44%, respectively. The herd immunity levels in age-specific groups were compared between the two towns. Before the epidemic, the immunity level of 1 year old children in Kanada, who showed the higher attack rate, was lower (18%) than that in Itoda (39%), while after the epidemic it rose above 60% in both towns. When we studied the correlation between the attack rate and the vaccination rate, or the number of children susceptible to measles (susceptibility rate) in each preschool, the attack rate correlated negatively with the vaccination rate (correlation coefficient [CC] = -0.818; P less than 0.01), and positively with the susceptibility rate (CC 0.860; P less than 0.01). The regressed equation on the correlation indicated that the immunity level should be more than 70% to keep the attack rate under 5% in preschools. After the epidemic, the immunity levels of all preschoolers reached above 70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

Search for correlates of protective immunity conferred by anthrax vaccine.

Vaccination by anthrax protective antigen (PA)-based vaccines requires multiple immunization, underlying the need to develop more efficacious vaccines or alternative vaccination regimens. In spite of the vast use of PA-based vaccines, the definition of a marker for protective immunity is still lacking. Here we describe studies designed to help define such markers. To this end we have immunized guinea pigs by different methods and monitored the immune response and the corresponding extent of protection against a lethal challenge with anthrax spores. Active immunization was performed by a single injection using one of two methods: (i) vaccination with decreasing amounts of PA and (ii) vaccination with constant amounts of PA that had been thermally inactivated for increasing periods. In both studies a direct correlation between survival and neutralizing-antibody titer was found (r(2) = 0.92 and 0.95, respectively). Most significantly, in the two protocols a similar neutralizing-antibody titer range provided 50% protection. Furthermore, in a complementary study involving passive transfer of PA hyperimmune sera to naive animals, a similar correlation between neutralizing-antibody titers and protection was found. In all three immunization studies, neutralization titers of at least 300 were sufficient to confer protection against a dose of 40 50% lethal doses (LD(50)) of virulent anthrax spores of the Vollum strain. Such consistency in the correlation of protective immunity with anti-PA antibody titers was not observed for antibody titers determined by an enzyme-linked immunosorbent assay. Taken together, these results clearly demonstrate that neutralizing antibodies to PA constitute a major component of the protective immunity against anthrax and suggest that this parameter could be used as a surrogate marker for protection.

Animals↗

Mechanisms of bacterial opsonization by immune globulin intravenous: correlation of complement consumption with opsonic activity and protective efficacy.

To study the mechanism of bacterial opsonization by immune globulin intravenous (IGIV) complement consumption and polymorphonuclear leukocyte (PMNL) membrane receptor (FcRlo, CR1, and CR3)-mediated phagocytosis of Staphylococcus epidermidis, Klebsiella pneumoniae, and groups A and B streptococci were examined. IGIV alone did not consume complement and showed no opsonic activity by itself for these organisms. When these bacteria were preopsonized in IGIV, significant amounts of complement were consumed (44%-94%) and the uptake and killing of bacteria occurred. The in vitro opsonic activity of IGIV for these organisms was significantly correlated with the amount of complement consumed by the IGIV-opsonized bacteria (r = .85, P less than .05). The in vivo protective efficacy of IGIV also appeared to be directly associated with its ability to activate and consume complement (r = 1.0, P less than .001). Antibodies to FcRlo (Leu 11) markedly inhibited phagocytosis of bacteria opsonized in IGIV but not that of bacteria opsonized in specific IgM. Both CR1 and CR3 receptors on PMNLs were involved in uptake, but the contribution of each is different with different organisms.

Animals↗

A positive correlation between declining immune competence and early mortality associated with diethylnitrosamine carcinogenesis in aging mice.

The effect of age (2.5, 9.5, and 17 months) at time of treatment upon diethylnitrosamine (DEN) carcinogenesis and immune competence has been assessed in female BALB/c mice. Median times of death were 193, 168, and 125 days, respectively, after termination of DEN treatment. Immune competence as a measure by both cell-mediated and humoral immune parameters immediately after DEN treatment was not significantly different among treated and age-matched non-treated control animals. In contrast, a significant age-related decline in immune competence was seen in both DEN-treated and non-treated controls, thereby demonstrating a direct and positive correlation between the natural age-related decrease in immune competence and cancer-induced advanced mortality.

Aging↗

[Correlation of local immune system indices of patients with tuberculous and serous meningitis].

The method of discrete-dynamic analysis was used for studying the immunity system state in 60 patients with tuberculous meningitis (TM) of various degree of severity and in 35 patients with serous meningitis of nontuberculous etiology (SMNE). A significant difference was established of the correlation between parameters in the combinations comprising lymphocytes immune to Mycobacterium tuberculosis which enables TM and SMNE differentiation. TM was characterized by a sharp increase in the number of correlations (intensity) in the parameters as compared with SMNE. Intensity significantly declines in the fatal outcome of TM as compared with this parameter in the survived patients. In SMNE local immunity state normalizes (intensity decline) in 1.5-2 months, in TM of moderate severity in 3 months and in a serious course (during the follow-up) intensity does not decline.

Adolescent↗