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Environmental chemical-induced immune dysfunction.

Antibody formation, endotoxin sensitivity, and resistance to a challenge malarial infection were evaluated in mice fed a diet containing polychlorinated biphenyl (PCB) (Aroclor 1242) or hexachlorobenzene (HCB). Antibody synthesis to the antigen sheep RBC (SRBC) was significantly depressed in the PCB- and HCB-treated (167 ppm) animals as evidenced by the fact that control mice elicited an approximate twofold increase in antibody formation over the chemical-treated mice. Serum IgA concentrations in the PCB- and HCB-treated mice were consistently 40--80 mg/dl lower than control values. Gram-negative endotoxin (Salmonella typhosa) sensitivity in PCB- and HCB-treated mice was increased 5.2- and 32-fold, respectively, following the dietary administration of 167 ppm of Aroclor 1242 or HCB for 6 weeks. An endotoxin hypersusceptibility was also noted at 3 weeks after dietary administration. Decreased resistance to a malaria challenge was also demonstrated in the xenobiotic-treated mice. A 20% decrease in mean survival time of mice fed Aroclor 1242 for 3 to 6 weeks and inoculated with Plasmodium berghei (NYU-2) was observed. Infected mice which had received HCB for 3 or 6 weeks manifested reductions in mean survival time of 24 and 31%, respectively. The data indicated that environmental chemical contaminants impair host resistance and, since no concomitant histopathological alterations were observed in the treated mice, the evaluation of immune parameters may possibly be a sensitive indicator of toxicity.

Animals

Lymphopenia induced by acute bacterial infections in the elderly: a sign of age-related immune dysfunction of major prognostic significance.

These studies were undertaken to investigate the effect of acute bacterial infections on the absolute number of peripheral blood lymphocytes (PBL) in an elderly population and to evaluate the prognostic significance of a decreased number of PBL in critically ill aged patients. The results show that a significant lymphopenia develops in elderly patients during the course of an acute bacterial infection whereas the same type of acute illness has no effect on the PBL count of younger subjects. The lymphopenia is not related to a particular localization of the infection nor to the type of bacterial pathogen. The prognosis of the bacterial infection is closely linked to the severity of the lymphocyte depletion and its outcome can nearly be predicted by monitoring the variation of the number of circulating lymphocytes during the early course of the disease.

Acute Disease

In vitro effects of interleukin-2 and gamma globulin on immune dysfunction in a patient with severe mucocutaneous herpes simplex virus infection.

A previously healthy woman developed severe, recurrent mucocutaneous herpes simplex virus (HSV) infection at 21 years of age. Immunologic assessment over the past 2 years has revealed persistent T-cell and natural killer cell dysfunction despite normal numbers of these cells as measured by flow cytometry. We studied the effect of recombinant interleukin 2 (rIL-2) and gamma globulin on the patient's mononuclear cells in 18-hour 51Cr release assays using HSV-infected and uninfected target cells. Both gamma globulin and rIL-2 significantly enhanced target cell lysis of HSV-infected target cells (P less than .001), but did not increase lysis of uninfected target cells. Addition of the patient's serum had no effect on HSV-infected target cell lysis despite a high HSV IgG titer, indicating a possible specific abnormality in production of antibody-dependent cellular cytotoxicity antibody.

Adult

Immune dysfunction in hypophosphatemic vitamin D-resistant rickets: immunoregulatory reaction of 1 alpha(OH) vitamin D3.

We investigated immunologic function in six cases with hypophosphatemic vitamin D-resistant rickets (VDRR) before and after treatment with 1 alpha-hydroxycholecalciferol (1 alpha(OH) vitamin D3). All cases suffered frequent episodes of infection, which tended to be more severe in the older patients. OKT9-, OKT10-, and OKM1-positive cells and adenosine deaminase (ADA) were significantly increased, whereas numbers and activity of natural killer (NK) cells were lower than normal before treatment. After administration of 1 alpha(OH) vitamin D3, however, the susceptibility to infection apparently decreased, and NK cell number and activity increased in all patients. ADA was also significantly decreased and remained in the normal range after treatment. These results suggest that vitamin D plays a role in the impaired immunoregulatory functions of NK cells in VDRR. Furthermore, ADA may be one parameter reflecting this immunologic impairment.

Adenosine Deaminase

Neurological consequences of immune dysfunction: lessons from HIV infection and multiple sclerosis.

In a recent workshop held on Sanibel Island, Florida (18-21 January 1992), the two most common neuroimmunologic diseases of young adults, multiple sclerosis (MS) and HIV encephalopathy, were jointly discussed. The logic of assembling investigators from these two fields was based not on an assumed etiologic connection between MS and retroviral infection of the central nervous system (CNS), but rather in the hope of uncovering potential common pathogenic mechanisms, particularly as might relate to trafficking of mononuclear cells into the central nervous system, the distribution and function of macrophages and microglia, the structure and function of the blood-brain barrier, and the role of cytokines released by activated cells. Multiple sclerosis is a disease without a known etiologic agent or pathogenesis. While the causative agent for HIV leukoencephalopathy is known, the pathogenesis of the disease remains entirely enigmatic (a topic covered by R. Johnson). This meeting brought together two different groups of investigators to compare and contrast the diseases and to share perspectives, paradigms, and data with the aim of cross-fertilizing the disciplines and generating healthy hybrids.

Acquired Immunodeficiency Syndrome

Relationship between antibody to LAV/HTLV-III and the natural course of subclinical cellular immune dysfunction in homosexual men.

To assess the epidemiology and natural history of persistent generalized lymphadenopathy (PGL) and subclinical immunodeficiency in relation to serologic evidence of lymphadenopathy-associated virus/human T-lymphotropic virus type III (LAV/HTLV-III) infection, 109 homosexual men with PGL, 47 homosexual men without lymphadenopathy who attended a sexually transmitted disease (STD) clinic, 25 homosexual male university students, and 26 heterosexual men who attended the STD clinic were studied. In 1982-1983 antibody to LAV/HTLV-III was present in 97%, 35%, 21%, and 4% of the four groups, respectively (P less than .001). Subclinical immunodeficiency was more closely associated with LAV/HTLV-III seropositivity than with lymphadenopathy. Cohorts of 78 homosexual subjects with PGL, 35 homosexual subjects from STD clinic, and 15 homosexual university students were followed for median periods of 13.5, 20, and 14.5 months, respectively. The seroconversion rate was 23% per year among seronegative subjects, and 4% of seropositive subjects developed overt acquired immunodeficiency syndrome (AIDS). Among seronegative subjects, there was significant improvement in T4:T8 ratios (P = .001), whereas most seropositive subjects continued to have subnormal total counts of T4 lymphocytes and low T4:T8 ratios. Some cases of subclinical cellular immunodeficiency apparently are unrelated to LAV/HTLV-III infection, and the presence of antibody to this virus is associated with an unfavorable immunologic prognosis.

AIDS-Related Complex

[Cellular immune dysfunction in the NOD mouse: suppression of concanavalin A-induced responses in spleen cells by activated macrophages].

It is generally accepted that T lymphocyte-mediated autoimmunity contributes to the pathogenesis of Type 1 diabetes in humans and animals. Using spleen cells from nonobese diabetic (NOD) mice, a model of human Type 1 diabetes, we have analyzed the subset of T lymphocytes by flow cytometry and investigated concanavalin A (Con A)-induced interleukin 2 (IL-2) production and cell proliferation. NOD mice showed a higher percentage of Thy1.2+, L3T4+, and Lyt2+ T lymphocytes than did control ICR mice through the whole age examined. Spleen cells from a large majority of NOD mice were found to generate very low IL-2 production and cell proliferation in response to Con A. However, a few mice preserved their responsiveness to Con A. The following reasons may indicate that macrophage-mediated suppression participates in the deficient function of NOD spleen cells. (a) Macrophage depletion from NOD spleen cells retrieved Con A-induced IL-2 production. (b) Thioglycollate-induced peritoneal exudate cells containing many activated macrophages could completely suppress cell proliferation. (c) Prostaglandin synthetase inhibitor indomethacin reversed the suppression of IL-2 production by macrophages. (d) Conversely, exogenous prostaglandins could show the partial suppression of IL-2 production. These results suggest that activated macrophages suppress the response of NOD spleen cells to Con A mostly through prostaglandins. This impairment may contribute to the pathogenesis of Type 1 diabetes in NOD mice.

Animals

Animal model for immune dysfunction associated with adenosine deaminase deficiency.

An in vivo murine model for immunodeficiency of both B and T cells is produced by continuous intraperitoneal infusion of 2'-deoxycoformycin (DCF), a specific tightly binding inhibitor of adenosine deaminase (ADase; adenosine aminohydrolase, EC 3.5.4.4). After DCF infusion, ADase of thymus, spleen, and lymph nodes was inhibited to varying degrees ranging from 57% to 100%. Immunodeficiency under these conditions was indicated by: (i) a striking decrease in lymphocyte response to the T-cell mitogens concanavalin A and phytohemagglutinin; (ii) an impairment of delayed hypersensitivity measured by the footpad reaction; (iii) a decrease in antibody production measured in both in vivo and in vitro plaque-forming cell assay; (iv) a significant prolongation of mouse skin allograft survival after transplantation into the C57BL/6J (H-2b) strain of skin from BALB/c (H-2d) mice; and (v) a marked lymphopenia. Histological examination indicated lymphoid degeneration in the thymus, lymph nodes, and spleen with no alterations in other tissues including bone marrow, kidney, lung, gastrointestinal tract, and liver except for the occurrence of hepatitis. A decrease in the number of Thy-1-positive cells in both spleen and lymph nodes further supported the fact of cytotoxicity of DCF to T cells. Anorexia and weight loss were observed within 5 days of continuous DCF infusion at 0.4 mg/kg body weight per day. These data indicate that this method provides an experimental model for future studies on the biochemical mechanisms responsible for the genetically determined severe combined immunodeficiency disease in man.

Adenosine

Immune dysfunction in diabetes-prone BB rats. Interleukin 2 production and other mitogen-induced responses are suppressed by activated macrophages.

Spleen cells of diabetes-prone BB Wistar rats were found to generate excessively low proliferative responses, and interleukin 2 (IL-2) levels in response to T-dependent mitogens. This abnormality was not due solely to abnormal T cell numbers since: (a) addition of BB spleen cells of BB splenic macrophages to normal major histocompatibility complex (MHC)-matched Wistar Furth (WF) spleen cells resulted in severe suppression of concanavalin A (Con A)-, phytohemagglutinin (PHA)-, and pokeweed mitogen (PWM)-mediated proliferation, and IL-2 production; (b) macrophage depletion from BB spleen cells, but not B cell or T cell depletion, removed completely the suppressive effects of BB cells on WF cells; (c) macrophage depletion greatly enhanced the response of BB lymphocytes to T-dependent mitogens. Although suppressor macrophages could also be found in the spleen of WF control rats they were present in much smaller numbers than in the spleen of BB rats. The suppressive effect of BB macrophages was partially reduced by addition of the prostaglandin synthetase inhibitor indomethacin to cultures. Furthermore, indomethacin (but not catalase or PMA) considerably augmented IL-2 secretion of Con A-stimulated BB spleen cells, but had little effect on WF spleen cells. In contrast, prostaglandins E1 and E2 (PGE1 and PGE2) suppressed IL-2 production. While IL-2 secretion was severely depressed in BB rats unstimulated and lipopolysaccharide (LPS)-stimulated IL-1 secretion by splenic macrophages was normal. BB macrophages did not inactivate IL-2. Low IL-2 production and macrophage-mediated suppression were features of all BB rats tested.

Animals

Natural killer cytotoxicity in the diagnosis of immune dysfunction: criteria for a reproducible assay.

Current evidence indicates that natural killer (NK) cells, which are large granular lymphocytes that mediate non-major histocompatibility complex (MHC)-restricted cytotoxicity and antibody-dependent cytotoxicity and that are involved in multiple regulatory, developmental, and immunologic processes, are important in health. Immunodeficiency states presenting with low NK activity are often associated with malignancies, chronic viral infections, or autoimmune diseases. Monitoring of NK function appears to be indicated as an aid to diagnosis, prognosis, and follow-up after therapy. Reliable performance of NK assays in a clinical laboratory requires that uniform criteria be established and followed for the acceptability of results. Statistical analysis of daily variability can be of great assistance in identifying and tracking sources of error, but routine statistical adjustments are not generally advisable. The quality control program described here provides a degree of assurance that this cytotoxicity assay can be dependable whether performed at one time point or serially. The successful implementation of this program requires laboratory resources, biostatistical support, and interpretative skills, all of which are available in a modern clinical laboratory.

Cytotoxicity Tests, Immunologic

Variations in macrophage antigen phenotype: a correlation between Ia antigen reduction and immune dysfunction during tumor growth.

Variable Ia antigen expression by macrophages (M phi) was examined during tumor growth by measuring: Ia antigen masking and immunofluorescence by anti-Ia antibody, accessory cell function in concanavalin A (Con A) and mixed lymphocyte reaction (MLR)-induced T cell proliferation, and M phi stimulatory function in the MLR. Tumor-induced progressive loss of Ia antigen expression was shown by immunofluorescence and corroborated by anti-Ia blockade of MLR stimulatory activity of normal but not tumor-bearing hosts (TBH) splenic M phi. The TBH splenic M phi supported Con A-induced proliferation of syngeneic T cells (Ia antigen-independent) but did not support syngeneic T cell proliferation in the MLR (Ia antigen-dependent). Irrespective of tissue source, normal and TBH M phi differed in their MLR stimulatory capabilities. In general, splenic M phi preparations were better stimulators of allogeneic T cell blastogenesis in the MLR than thioglycollate-elicited peritoneal M phi. Kinetic studies with TBH M phi showed a significant progressive loss in MLR stimulatory activity, which was especially pronounced with peritoneal M phi. Expression of Ia antigens by normal but not TBH M phi were diminished by 24-h in vivo plating of the peritoneal M phi. Indomethacin treatment showed Prostaglandin E2 was not a direct in vitro factor in Ia antigen-mediated reduction of splenic M phi MLR stimulatory activity. Taken together, these data delineate a loss of M phi Ia antigen expression, resulting in a decrease in Ia antigen-mediated functional activities during tumor growth.

Animals

Integrated Multi-omics Profiling of 2,4-dinitrochlorobenzene (DNCB)-induced Atopic Dermatitis in Mice Reveals a Coordinated Network of Barrier Dysfunction, Immune Activation, and Metabolic Reprogramming.

Atopic dermatitis (AD) is caused by a combination of epidermal barrier defect and immune imbalance. However, the molecular networks between these structural abnormalities and metabolic variations are unclear. This study aim of this research was to examine the concurrent molecular alterations in skin barrier damage and metabolic disorders in an AD-like mouse model by a multi-omics strategy. A 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mouse model was established and the skin tissues were examined through the combination of transcriptomic, quantitative proteomic, and metabolomic analyses. Cross-omics correlation and network analyses were performed to identify consistently abnormal molecular pathways and crucial regulatory molecules. DNCB treatment caused severe epidermal hyperplasia, and prominent infiltration of CD3⁺ T cells, F4/80⁺ macrophages, and mast cells. Transcriptomic and proteomic analysis indicated significant disruption in keratinocyte differentiation, extracellular matrix organization, and cornified envelope formation pathways. Combined analysis detected 171 molecules which were simultaneously altered at both mRNA and protein levels, and network analysis identified FLG2 and KRT6B as central barrier-related molecules. Pathway enrichment analysis consistently showed the participation of AMPK and PPAR signaling pathways. Metabolomic analysis also revealed coordinated changes in lipid and amino acid metabolism which were closely associated with cornified envelope-associated genes and collagen-modifying enzymes. These findings indicate a close relationship between barrier, immune and metabolic regulation in DNCB-induced dermatitis and provide a multi-omics resource for future mechanistic studies of atopic skin inflammation.

Animals