Veterans and Agent Orange Update 2012 (2014) / Chapter Skim
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7 Immune-System Disorders
7 Immune-System Disorders
Pages 271-298
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The next section discusses factors that may lead the immune responses of animals exposed to the chemicals of interest (COIs) to be much more pronounced than any observed to date in humans.
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It is often difficult to diagnose such diseases, so they may or may not be medically categorized as immune disorders. Immune Suppression Suppression of immune responses can reduce resistance to infectious disease and increase the risk of cancer.
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However, unless the immune suppression is severe, it is often difficult to obtain clinical evidence that directly links chemically induced changes in immune function to increased infectious disease or cancer because many confounding factors can influence a person's ability to combat infection. Such confounders include age, vaccination status, the virulence of the pathogen, the presence of other diseases (such as diabetes)
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For example, the autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system; in Crohn's disease, the intestine is the target of attack; in type 1 diabetes mellitus, the i nsulin-producing cells of the pancreas are destroyed by the immune response; and rheumatoid arthritis arises from immune attack on the joints, but can also involve the lung, heart, and additional organs. More generalized forms of autoimmune diseases also occur.
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It is one component of the normal host response to infection and is mediated by innate immune cells. Inflammatory responses have evolved to speed the trafficking of macrophages, granulocytes, and some lymphocytes to the area of infection, where they produce toxic metabolites that kill pathogens.
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Participants in 1985 examination cycle, No change in surface markers for B and Wolfe et Operation Ranch Hand veterans vs T cells al., 1985 comparisons (morbidity and mortality) US CDC Vietnam Experience Study -- All COIs Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed Morbidity -- Deployed vs nondeployed No differences in infections, no changes CDC, in B and T cell-surface markers, WBC 1988b counts, or circulating serum Ig Mortality (1965–2000)
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From page 277... ...
; serum transforming growth factor alpha collected 30 yrs after exposure (TGF-α) IARC Phenoxy Herbicide Cohort -- Chlorophenoxy herbicides/Negative Saberi Dutch workers from 2 plants that correlation between TCDD exposure Hosnijeh produced and formulated chlorophenoxy and markers of humoral immunity, et al., herbicides (Plant A, n = 1,167; Plant B, except perhaps for C4 2012 n = 1,143)
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From page 278... ...
138 surviving workers from a larger TCDD: Among 14 immune measures; Ott et al., cohort of 254 exposed workers after regression analysis of TCDD 1994 an accident in a BASF TCP production concentration suggested marginal facility positive associations with IgG, IgA, C3, and C4; marginal reductions in some lymphocyte population were also reported IARC Phenoxy Herbicide Cohort -- Dioxins, 2,4,5-T; 2,5-DCP; 2,4,5-TCP German production workers at Boehringer-Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) Updated and expanded evaluation of TCDD (or "TCDD toxic equivalents" Neubert et 158 workers in a German chemical from PCDD/PCDF)
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1994 years after initial exposure 89 volunteers involved in TCDD (or equivalents via PCDD/PCDF Neubert et decontamination work at a chemical exposure) : Potentially complicated by al., 1993, plant in Hamburg, Germany; no control age differences among the compared 1994 population groups; only subtle, clinically nonsignificant changes were seen among immune-cell surface markers in a comparison of higher exposed vs low exposed to moderately exposed workers NIOSH Cohort (current and former Dioxins, phenoxy herbicides workers from chemical plants in New Jersey and Missouri, 2 of the 12 plants included in the NIOSH Mortality Study)
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but not with lower cumulative exposure Nested case-control study of rheumatoid No strong risk factors were identified De Roos et arthritis in agricultural families (57,000 for pesticide mixing or application or al., 2005b pesticide applicators and their spouses) for any specific class of pesticides in the AHS of rheumatoid arthritis Other Studies of Herbicide-Using Workers Longitudinal study of 10 farmers during 2,4-D and MCPA formulations: Faustini et 1994 within 7 days before and 1–12 Decreases in percentages of CD4, CD8, al., 1996 days and 50–70 days after exposure CTL, CD8-DR, and NK cells and in NK activity and mitogen-stimulated lymphoproliferation; CD4:CD8 ratio was unaltered; CD3 and CD8 percentages had recovered by the second assessment period; no significant correlations between immune changes and amount of pesticides applied
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Study of 101 chloracne cases vs 211 Persistent increase in TCDD in Baccarelli controls 20 years after the accident; chloracne cases; younger people seemed et al., relatively low statistical power was to be more susceptible; no major trends 2005b available because the study examined in disease occurrence the occurrence of individual diseases Study of 62 people from a highly Plasma concentration of TCDD was Baccarelli exposed zone and 53 from determined; multivariate regression et al., 2002 noncontaminated areas 20 years after analysis showed significant decrease the accident in plasma IgG with increasing TCDD concentration and no changes in IgM, IgA, or C3 45 children (3–7 years of age) living No differences in serum IG, mitogen Pocchiari in exposed areas vs 45 nonexposed responses of lymphocytes (PHA and et al., 1979 children as controls pokeweed)
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, and . only trends were noted Quail Run Mobile Home Park (MO)
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; TEQ values were increasing TEQ; IgE concentrations; al., 2002 calculated from serum dioxin-like PCB history of upper airway allergy, and concentrations and relationships with odds of a positive RAST test correlated immune measures were examined negatively with serum TEQ; IgA concentrations correlated positively with TEQ Germany -- Cross-sectional study of 221 Dioxin in wood preservatives, Wolf and teachers who worked in German day-care exposure primarily via inhalation: No Karmaus, centers treated with wood preservatives effects of inhaled dioxin were seen on 1995 vs 189 teachers who worked in untreated T4 or T8 cell numbers or on the ratio; facilities some evidence of a dose–response relationship was seen for risk of anergy (or hypoergy) in the DTH assay US (NHANES)
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-- telephone Chemical exposures, including Hardell et interviews concerning environmental and pesticides, and Agent Orange: No al., 1987 occupational chemical exposures were significant differences were reported in conducted with 50 AIDS patients (with a small study that generally lacked focus Kaposi sarcoma) and 50 homosexual men as controls NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; Con A, concanavalin A; DTH, delayed-type hypersensitivity; IFN-gamma, interferon-gamma; Ig, immunoglobulin; IL, interleukin; MCPA, methyl-4-chlorophenoxyacetic acid; MLR, mixed lymphocyte response; MO, Missouri; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; NK, natural killer; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines)
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in dioxin-exposed people. As seen in Table 7-1, some early studies of the Quail Run Mobile Home Park population exposures reported that dioxin exposure was associated with a reduced cell-mediated immune response, the delayed-type hypersensitivity (DTH)
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Prior VAO updates have concluded that human data were either insufficient or inconsistent with respect to an increased risk of immunosuppression, allergic disease, or autoimmune disease. UPDATE OF THE EPIDEMIOLOGIC LITERATURE AND HUMAN STUDIES Vietnam-Veteran and Case-Control Studies No new case-control studies or studies of Vietnam veterans exposed to the COIs and adverse immunologic conditions have been published since Update 2010.
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A new endogenous pathway, the tryptophan metabolic pathway, has recently been identified as affecting the aryl hydrocarbon receptor (AHR) and immune biology (Opitz et al., 2011)
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. It is consistent with its immunosuppressive effects that TCDD exposure suppresses the allergic immune response of odents; this in turn results in decreased r allergen-associated pathologic lung conditions and has recently been shown to suppress the development of experimental utoimmune disease Quintana et al., a ( 2008)
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Allergic and Autoimmune Diseases Epidemiologic studies have been inconsistent with regard to TCDD's influence on IgE production in humans. No human studies have specifically addressed the influence of TCDD on autoimmune disease, but several animal studies have shown that TCDD suppresses the development of autoimmune diseases.
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TRANSLATION BETWEEN ANIMAL AND HUMAN STUDIES Animal studies and in vitro studies with human cells and cell lines are important ways of trying to understand underlying biologic mechanisms associated with immunotoxic and other responses to xenobiotics, which are "foreign" substances that do not normally occur in biologic systems. However, as discussed above, despite the vast array of data supporting the immunotoxicity of TCDD in laboratory animals, little evidence from studies of Vietnam veterans or other human populations suggests that TCDD or the herbicides of concern produce immune alterations.
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Future studies should ensure that -- whether in animal models or in human studies -- gene-specific or sex-specific immune effects are able to be evaluated with sufficient statistical power to support distinctions. Stress Stress is a well-known modifier of human immune responses.
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2006. Depression and pesticide exposures in female spouses of licensed pesticide applicators in the Agricultural Health Study cohort.
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2011. Deletion of the aryl hydrocarbon receptor enhances the inflammatory response to leishmania major infection.
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2008. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters the dif ferentiation of alloreactive CD8+ T cells toward a regulatory T cell phenotype by a mechanism that is dependent on aryl hydrocarbon receptor in CD4+ T cells.
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2010. Dioxin and immune regulation: Emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells.
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2008. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor.
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2012. The aryl hydrocarbon receptor modulates acute and late mast cell responses.
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2011. Increased expression of aryl hydrocarbon receptor and interleukin 22 in patients with allergic asthma.
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