Immune responses to pollutant mixtures from indoor sources.

Indoor air pollution occurs as an undesirable consequence of urbanization, energy conservation, indoor bioaerosol contamination, and use of synthetic materials and new technologies, and has become a worldwide concern. It is important to comprehend not only the diversity of pollutant hazards but also to develop novel methods and approaches that establish dose-response relationships, cause-and-effect relationships, and clinical relevance. Coincident with heightened public concern over indoor air pollution and its health consequences, a revolution in immunology has occurred. The immune system is recognized as an essential defensive and homeostatic mechanism. Unfortunately, the immune apparatus is exquisitely sensitive to toxic damage. Equally important, among the disciplines available to assess the health impact of indoor air pollutants, immunology has the capability to provide sensitive and specific tools that may accurately measure relevant clinical effects at tissue, cellular, and molecular levels. Furthermore, exciting new insights into shared communications networks between the immune, endocrine, and central nervous systems may provide future explanations for the myriad human complaints associated with indoor air pollutants.

Indoor air pollution: an edifice complex.

The collision of escalating technological sophistication and surging environmental awareness has caused the reexamination of many societal paradigms. Horror stories about lethal chemical exposures involving isolated cases of ignorance, carelessness or greed have caused the public to demand constant vigilance to prevent exposure to potentially hazardous substances. Accordingly, much time and resource has been expanded by the U.S. government and citizens to abate and prevent air and water pollution. While these efforts have met with measurable success, there is increasing public concern about a new generation of pollution-related human illness in office, home and transportation environments. New instances of Sick Building Syndrome or Building Related Illness are reported daily by the popular press. Human health effects such as cancer, infectious disease, allergy and irritation have been ascribed to indoor air pollution. The clinical aspects of indoor air pollution are often discounted by consulting engineers and industrial hygienists involved in indoor air quality. Physicians and clinically-trained scientists have received a "Macedonian call" to sift clinical relevance from the emotional aspects of indoor air quality problems. Point sources of pollutants, associated human health effects, and problem solving approaches associated with indoor air pollution are described. Regulatory and litigational aspects of indoor air pollution are also discussed.

Nematospiroides dubius: two H-2-linked genes influence levels of resistance to infection in mice.

Strains of mice sharing common H-2 haplotypes but different genetic backgrounds, and H-2 congenic strains of mice differing only at H-2 genes were studied to assess the role of H-2 and non-H-2 genes in immunity to challenge infections with the nematode parasite Nematospiroides dubius. Strains of mice sharing the H-2k haplotype were uniformly more susceptible to challenge than strains expressing H-2q alleles, regardless of genetic background. However, in some cases strains of mice sharing the k or q haplotypes differed significantly in levels of resistance. Therefore, non-H-2 genes must influence the response observed. H-2 cogenic strains of mice differed markedly in their ability to resist challenge infections. Mice sharing the C57BL/10 background but expressing k alleles were very susceptible to challenge, while the H-2q, H-2f, and H-2s, haplotypes were associated with resistance. Studies of H-2 congenic recombinant strains of mice suggested that two H-2 genes influence the antiparasite response. One of these genes maps to the left of E alpha and the other to the D-end of the H-2 complex. It is concluded also that the unique configuration of H-2 genes in F1 hybrids contributes to increased resistance to challange.

Differential recovery of antibody production potential after sublethal, whole-body irradiation of mice.

Mice were given single injections of sheep erythrocytes (SE) or polyvinylpyrrolidone (PVP) at various times after sublethal, whole-body irradiation (550 rad 60CO) and direct, antigen-specific, plaque-forming cell (PFC) responses were quantified. Irradiated mice did not respond to SE or PVP when immunized 15 d postirradiation (PI); by day 30 PI, the responses by irradiated mice were 40-126% of normal to SE and 3-38% of normal to PVP. The impaired recovery after irradiation of immune responses to PVP was not due to altered antigen dose requirements or altered time of peak PFC response and occurred after irradiation of mice by doses as low as 200 rad. Both athymic and euthymic mice had impaired responses to PVP after whole-body irradiation. The impaired response of irradiated mice to PVP was repaired by adoptive transfer of normal bone marrow, fetal liver, or spleen cells and also by spleen cell preparations enriched in Ig+ cells but not by spleen cell preparations enriched in Thy.1+ or Ig- cells. With the aid of additional antigens it was observed that by day 30 PI, mice had recovered ability to respond to the T-cell-dependent antigen SE and the T-cell-independent type-1 antigens 2,4,6-trinitrophenyl-Brucella abortus and butanol-extracted bacterial lipopolysaccharide, but at that time they gave impaired responses to the T-cell-independent type-2 antigens PVP, type III pneumococcal polysaccharide, and phenol-extracted bacterial lipopolysaccharide; they had an immune response pattern similar to that of CBA/N mice having an X-linked immunodeficiency.

Genetic control of immunity to Trichinella spiralis infections of mice. Hypothesis to explain the role of H-2 genes in primary and challenge infections.

H-2 congenic strains of mice were compared for their ability to expel T. spiralis infections from the small intestine and for their ability to limit the reproduction of adult female worms. B10.M mice (H-2f) expelled both primary and challenge infections more quickly than did the strains B10.Q(H-2q) and B10.BR(H-2k). During a primary infection, expulsion of worms from B10.M mice began before Day 9 post-infection and worm counts differed significantly (P less than .05 Student's t-test) from counts in B10.BR mice on each of Days 12 and 15.B10.Q mice expelled worms more rapidly than B10.BR but worm counts did not differ significantly until Day 15. Whereas B10.M mice responded most quickly to expel worms from the gut, B10.Q mice were most effective in limiting worm reproduction. Female worms harvested from B10.Q mice and cultured for 24 hr in vitro produced significantly fewer newborn larvae than did worms from B10.M or B10.BR mice. Worms from B10.M mice were less fecund than worms from B10.BR, but this difference was not apparent before Day 9 post-infection, and worms from B10.M were always more fecund than worms from B10.Q. Challenge infections 21 days following a priming dose of 200 T. spiralis muscle larvae were rejected very quickly. B10.M mice expelled 65% of their worms during the first 24 h. By Day 6 after challenge, B10.M mice had expelled 84% of their worms; B10.Q and B10.BR expelled 75% and 37% respectively. These results suggest that a rapid expulsion response may be expressed in many different strains of mice depending on how the mice are immunized and the size of the infecting dose. Fecundity of female worms 6 days following a challenge infection was reduced for all strains tested when compared to primary infection controls; however, worms from B10.Q mice were less fecund than worms from B10.M or B10.BR. Results of these experiments demonstrate that H-2 genes play an important role in controlling the immune response which expels worms from the gut and the response which limits worm reproduction. These H-2-controlled differences are expressed during both primary and challenge infections. As the present results conflict somewhat with results published elsewhere, we have proposed a new hypothesis to explain the data collected in our laboratories thus far. According to this hypothesis, the anti-adult response, the anti-fecundity response, and the rapid expulsion response are under independent genetic control and influenced by the interacting products of both H-2 and non-H-2 genes.

A survey of susceptibility to infection with Trichinella spiralis of inbred mouse strains sharing common H-2 alleles but different genetic backgrounds.

Twenty-eight different inbred strains of mice representing five different H-2 haplotypes were compared for degree of susceptibility to a primary infection with Trichinella spiralis. Marked differences in susceptibility, measured by the average number of muscle larvae per host, were seen among strains of mice sharing common H-2 alleles. The genes controlling these differences must therefore map at loci outside the major histocompatibility complex. Strains of mice sharing the H-2k haplotype were generally more susceptible than strains expressing other haplotypes and strains expressing H-2q alleles were most resistant. Strains of mice were ranked in order of decreasing susceptibility. Knowledge of these ranking may be of value to researchers wishing to select strains of mice appropriate for studies on T. spiralis.

Immunosuppression in mouse trypanosomiasis: inhibition of secondary antibody responses is dependent on the time of antigen priming.

Trypanosoma musculi-induced immunosuppression was examined in both congenitally athymic (nude) mice and their phenotypically normal, euthymic littermates using T-independent (polyvinylpyrrolidone = PVP) and T-dependent (sheep erythrocyte = SE) antigens. T. musculi-infected nude mice had significantly diminished direct (IgM) plaque-forming cell (PFC) responses to PVP. In euthymic mice, T. musculi parasitemia significantly inhibited the direct PFC response to both PVP and SE. Trypanosoma musculi-infected euthymic mice had significantly diminished indirect (IgG) SE-specific PFC responses if priming occurred during parasitemia; however, T. musculi parasitemia did not significantly decrease indirect SE-specific PFC responses in euthymic mice if the mice were primed before infection.

A gene mapping between the S and D regions of the H-2 complex influences resistance to Trichinella spiralis infections of mice.

The strains B10.S(7R), B10.S(23R) and B10.S(24R), all thought to be genetically identical, differ in levels of susceptibility to infection with Trichinella spiralis. In a series of nine independent experiments, B10.S(7R) was shown to be more susceptible than the other two strains. In another series of seven experiments, the strain B10.A(18R) was shown to be more susceptible to infection with T. spiralis than the strains B10.S(21R) or B10.BAR-5, all of which were thought to share common H-2 alleles. These results indicate that a gene mapping between the S and D loci influences susceptibility to infection with T. spiralis. Typing of these strains for Qa and Tl loci rule out the possibility of a double crossover accounting for the differences observed. The new gene is designated Ts-2. Previously published data have also been reinterpreted and another gene Ts-1 is shown to be associated with The A beta locus. When the d allele is expressed at the Ts-2 locus, strains of mice expressing s, q, f or b alleles at Ts-1 are rendered more susceptible to infection.

Trichinella spiralis: role of non-H-2 genes in resistance to primary infection in mice.

Two strains of mice which share identical H-2 genes but differ in their genetic backgrounds were compared for their ability to resist infection with Trichinella spiralis. The two strains of mice, C3HeB/FeJ and AKR/J, share the H-2k haplotype which is associated with susceptibility to primary infection with T. spiralis in H-2 congenic strains of mice. AKR/J mice, infected with 150 infective muscle larvae, harbored significantly fewer muscle larvae 30 days postinfection than did mice of the strain C3HeB/FeJ. Approximately equal numbers of worms establish in the small intestine of AKR and C3H mice, but the AKR mice expelled adult worms from the gut more rapidly than did mice of the C3H strain. By Day 9 postinfection, 50% of the worms had been expelled by the AKR mice whereas expulsion of worms from C3H mice was delayed beyond Day 9 and occurred primarily between Days 10 and 12. Over this same experimental period (Days 6-12), fecundity of female worms from AKR mice, measured as the mean newborn larvae/female/hour, was approximately one-half that of worms taken from C3H mice. These results support the conclusion that genes outside of the mouse H-2 complex regulate expulsion of adult worms from the gut. These background genes also markedly influence the fecundity of female worms.

Immunity to Nematospiroides dubius: parasite stages responsible for and subject to resistance in high responder (LAF1/J) mice.

In the LAF1/J mouse strain, a single prior exposure to infective larvae of N. dubius given per os resulted in greater than 90% reduction of an homologous larval challenge; in contrast, a single larval sensitizing infection had no effect on adult worms introduced directly into the duodenum via laparotomy. The LAF1/J mice given a single sensitizing infection of adult worms via laparotomy did not exhibit resistance to homologous challenge of either infective larvae or adult worms. Because all sensitizing infections were removed chemotherapeutically before administration of challenge inocula, potential effects of "overcrowding" on establishment or development of challenge infections were precluded. Worm-specific antibody determinations indicated that adult worms introduced into the gut lumen did not prime the host for a secondary response to a challenge by larval or adult worms. However, a challenge with larvae of mice previously sensitized with an homologous larval infection, did stimulate an anamnestic antibody response. Collectively, the data indicated that in a highly responsive mouse strain (LAF1/J), larval stages were requisite in stimulation of host resistance to reinfection and a larval challenge was fully susceptible to the effects of that response. Mature adult worms apparently did not stimulate nor were they susceptible to the host's immune response.

Kinetics of immunoglobulin M and G responses of nude and normal mice to Trypanosoma musculi.

A sensitive and specific enzyme-linked immunosorbent assay was designed to measure the kinetics of Trypanosoma musculi-specific immunoglobulin M (IgM) and IgG responses in mice. Serum was obtained from congenitally athymic (nude) mice, their phenotypically normal, thymus-bearing littermates (NLM), and thymus cell-repaired nude mice (Nu-TC) at 6-day intervals throughout T. musculi parasitemia. NLM mice were shown to effect an antibody response to T. musculi that included an IgM to IgG shift and was correlated in time with reduction of parasite reproduction and stabilization of parasitemia. Nude mice were shown to effect a T. musculi-specific IgM response similar in onset and magnitude to that in NLM mice; this response was correlated in time with stabilization of parasitemia. Nu-TC mice were shown to effect IgM and IgG responses to T. musculi similar in time and magnitude to those in NLM mice. In marked contrast to NLM mice, Nu-TC mice did not exhibit suppression of T. musculi-specific IgM production after the IgM to IgG shift in response to this parasite.

Absorption of ablastic activity from mouse serum by using a Trypanosoma musculi population rich in dividing forms.

An in vivo assay of ablastin activity was developed by passive transfer of ablastic serum into nude mice. Preparations of Trypanosoma musculi that contained 35 to 50% dividing forms removed ablastic activity from mouse serum, but absorption of serum with a parasite preparation consisting of less than 5% dividing forms did not appreciably alter ablastic activity. These data suggest that ablastin is an antibody that can be absorbed onto homologous trypanosomes.