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Biomedical subjects

K M Garza

Publications and source records attributed to K M Garza.

16 recordsLinked to original sources
PubMed2006

Combustion-generated nanoparticulates in the El Paso, TX, USA / Juarez, Mexico Metroplex: their comparative characterization and potential for adverse health effects.

In this paper we report on the collection of fine (PM1) and ultrafine (PM0.1), or nanoparticulate, carbonaceous materials using thermophoretic precipitation onto silicon monoxide/formvar-coated 3 mm grids which were examined in the transmission electron microscope (TEM). We characterize and compare diesel particulate matter (DPM), tire particulate matter (TPM), wood burning particulate matter, and other soot (or black carbons (BC)) along with carbon nanotube and related fullerene nanoparticle aggregates in the outdoor air, as well as carbon nanotube aggregates in the indoor air; and with reference to specific gas combustion sources. These TEM investigations include detailed microstructural and microdiffraction observations and comparisons as they relate to the aggregate morphologies as well as their component (primary) nanoparticles. We have also conducted both clinical surveys regarding asthma incidence and the use of gas cooking stoves as well as random surveys by zip code throughout the city of El Paso. In addition, we report on short term (2 day) and longer term (2 week) in vitro assays for black carbon and a commercial multiwall carbon nanotube aggregate sample using a murine macrophage cell line, which demonstrate significant cytotoxicity; comparable to a chrysotile asbestos nanoparticulate reference. The multi-wall carbon nanotube aggregate material is identical to those collected in the indoor and outdoor air, and may serve as a surrogate. Taken together with the plethora of toxic responses reported for DPM, these findings prompt concerns for airborne carbonaceous nanoparticulates in general. The implications of these preliminary findings and their potential health effects, as well as directions for related studies addressing these complex issues, will also be examined.

Air Pollutants↗
PubMed2005

Cytotoxicity assessment of some carbon nanotubes and related carbon nanoparticle aggregates and the implications for anthropogenic carbon nanotube aggregates in the environment.

Nanotechnology and nanomaterials have become the new frontier world-wide over the past few years and prospects for the production and novel uses of large quantities of carbon nanotubes in particular are becoming an increasing reality. Correspondingly, the potential health risks for these and other nanoparticulate materials have been of considerable concern. Toxicological studies, while sparse, have been concerned with virtually uncharacterized, single wall carbon nanotubes, and the conclusions have been conflicting and uncertain. In this research we performed viability assays on a murine lung macrophage cell line to assess the comparative cytotoxicity of commercial, single wall carbon nanotubes (ropes) and two different multiwall carbon nanotube samples; utilizing chrysotile asbestos nanotubes and black carbon nanoaggregates as toxicity standards. These nanotube materials were completely characterized by transmission electron microscopy and observed to be aggregates ranging from 1 to 2 microm in mean diameter, with closed ends. The cytotoxicity data indicated a strong concentration relationship and toxicity for all the carbon nanotube materials relative to the asbestos nanotubes and black carbon. A commercial multiwall carbon nanotube aggregate exhibiting this significant cell response was observed to be identical in structure to multiwall carbon nanotube aggregates demonstrated to be ubiquitous in the environment, and especially in indoor environments, where natural gas or propane cooking stoves exist. Correspondingly, preliminary epidemiological data, although sparse, indicate a correlation between asthma incidence or classification, and exposure to gas stoves. These results suggest a number of novel epidemiological and etiological avenues for asthma triggers and related respiratory or other environmental health effects, especially since indoor number concentrations for multiwall carbon nanotube aggregates is at least 10 times the outdoor concentration, and virtually all gas combustion processes are variously effective sources. These results also raise concerns for manufactured carbon nanotube aggregates, and related fullerene nanoparticles.

Adolescent↗
PubMed2001

Intestinal parasitism terminates self tolerance and enhances neonatal induction of autoimmune disease and memory.

Genetic and environmental factors both influence autoimmune disease occurrence, but the identity and mechanism of action of environmental factors are poorly understood. Here we show that pinworm-infected neonatal but not adult mice, injected with an ovarian self peptide of the zona pellucida protein 3 (pZP3) in water and without adjuvant, develop Th2 responses and severe eosinophilic autoimmune ovarian disease. A strong Th2 memory response is recalled when, as adults, the mice are challenged with a regimen that elicits a strong Th1 response in naive adults. The strong Th2 autoimmune response included high levels of IL-4 and IL-5 production by pZP3-specific T cells, and an IgG1-biased autoantibody response. The Th2 response ended promptly upon pinworm eradication, and partially resurfaced upon re-infection. We conclude that the rodent pinworm is an environmental agent that modifies the neonatal response to a self peptide, resulting in termination of the tolerance state and induction of a strong Th2-associated autoimmune disease and T cell memory.

Animals↗
PubMed2001

Regulatory T-cell, endogenous antigen and neonatal environment in the prevention and induction of autoimmune disease.

Recent studies on autoimmune ovarian disease (AOD) induced by thymectomy on d3 (d3tx), and AOD induced by immunization with the ovary-specific zona pellucida 3 peptide (pZP3), have yielded the following results. First, female tolerance to pZP3 depends on the persistence of endogenous antigen (Ag). Second, following regulatory T-cell depletion, endogenous Ag in prepubertal d3tx mice triggers AOD and drives disease progression. Third, endogenous ZP3 from ovaries without AOD stimulates a diversified IgG autoantibody (autoAb) response that rapidly follows pZP3 T epitope immunization. Fourth, induction of AOD and autoimmune memory in neonatal female mice by pZP3 in incomplete Freund's adjuvant depends on endogenous Ag stimulation within the neonatal week. Fifth, in a rodent pinworm-positive environment, neonatal but not adult female mice injected with pZP3 in water develop Th2-mediated AOD and Th2 memory. Sixth, neonatal T cells transfer AOD to syngeneic athymic recipients, whereas adult T cells are non-pathogenic and in fact suppress AOD conferred by neonatal T cells. Therefore: 1) the continuous presence of physiologically-expressed autoAg is critical for both tolerance maintenance and autoimmune disease pathogenesis; the outcome is determined by the integrity of regulatory T cells; and 2) the neonatal mice, deficient in the regulatory T-cell function, are more responsive than adults to Ag and environmental stimuli that promote autoimmune disease and memory.

Animals↗
PubMed2001

A point mutation in CD28 distinguishes proliferative signals from survival signals.

Upon interaction with its ligand, B7, CD28 becomes phosphorylated on tyrosines. One tyrosine in particular (Y170 in mouse CD28, Y173 in human CD28) has received much attention. This is because it permits CD28 to recruit SH2-containing signaling molecules, including phosphoinositide 3 kinase, Grb2 and Gads. Using mice we employed a transgenic approach to express a tyrosine-->phenylalanine mutant form of CD28 that uncouples these SH2-mediated interactions from CD28. The CD28 mutant is unable to up-regulate expression of the prosurvival protein Bcl-xL, rendering the T cells more susceptible to radiation-induced death. Nonetheless, this mutated form of CD28 still prevents the induction of anergy and promotes T cell proliferation, interleukin 2 secretion and B cell help. Thus, we describe a single point mutation within the CD28 cytoplasmic domain that uncouples signals required for proliferation and survival.

Animals↗
PubMed2000

Role of antigen-presenting cells in mediating tolerance and autoimmunity.

The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic beta-islet cells together with T cells expressing an LCMV-gp-specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.

Animals↗
PubMed2000

Persistence of physiological self antigen is required for the regulation of self tolerance.

Endogenous Ag requirement for induction and maintenance of T cell tolerance has been extensively investigated in mice that express a transgenic Ag and/or its cognate transgenic TCR. In contrast, studies on tolerance for physiologically expressed self Ag and normal T cells are limited. Herein, we showed that the murine ovarian-specific ZP3 Ag is detectable from birth. Tolerance to ZP3 is detected in female relative to male mice. In comparison to males, 100-fold more ovarian peptide (pZP3) is required to elicit a comparable pathogenic response in females. Female tolerance to pZP3 was dependent on the presence of endogenous ovarian Ag, because neonatal ovariectomy converted the female response to that of males. Moreover, in female mice that were ovariectomized from the ages of 1-6 wk, the pZP3 responses were enhanced to the male level if ovaries were removed up to 7 days, but not 3 days, before adult challenge with pZP3. Thus, the physiologically expressed ZP3 Ag induces tolerance to pZP3, and the maintenance of tolerance is critically dependent on the continuous presence of the endogenous ovarian Ag. In contrast, exposure to endogenous ovarian Ag confined to the neonatal period is insufficient for the induction and maintenance of tolerance to ZP3.

Age Factors↗
PubMed2000

T cell tolerance and autoimmunity.

A functional immune system requires a T cell repertoire that is extremely diverse so as to allow for the elimination of all possible pathogens. However, the production of an immense T cell repertoire also increases the likelihood of generating autoreactive T cells. The immune system must therefore also incorporate a means of silencing or eliminating autoreactive T cells, while minimally sacrificing T cell diversity. The induction and maintenance of T cell unresponsiveness to self antigens is thus defined as T cell tolerance. This review provides an overview of the T cell tolerance mechanisms invoked in the thymus and in the periphery to prevent the induction of autoimmunity. Factors that can influence the induction of tolerance and autoimmunity are also discussed.

Animals↗
PubMed1998

Mechanism of ovarian autoimmunity: induction of T cell and antibody responses by T cell epitope mimicry and epitope spreading.

Autoimmune diseases are often manifested as organ inflammation with loss of function, and detectable autoreactive T cell and autoantibody responses. In the proper genetic context, we have shown that these parameters of autoimmunity can result from a single pivotal event: the induction of a strong and persistent T cell response for a foreign or unrelated self peptide that mimics the target self peptide. This may apply to organ-specific and systemic autoimmunity, independent of whether the tissue inflammation results from T cell immune mechanism or antibodies. T cell peptide mimicry, through sharing of critical residues or by a less defined mechanism, can result in autoimmune disease. Once triggered, the helper T cell response leads rapidly to a concomitant autoantibody response spreading to distant B cell determinants of the self protein antigen. Evidently, with T cell help, endogenous antigens can stimulate B cells to provoke a functional autoantibody response against conformational antigenic determinants. These findings are based on recent studies on a novel autoimmune ovarian disease model induced by a self peptide with well-defined T and B cell epitopes. However, studies reported on systemic lupus erythematosus models have shown that similar events may result in autoantibody response in systemic autoimmunity.

Animals↗
PubMed1997

Autoimmune ovarian disease: mechanism of disease induction and prevention.

Investigation of the versatile models for autoimmunity of the ovary and other selected organs has contributed to our understanding of the following aspects of autoimmunity: the mechanism of T cell molecular mimicry; T-->B epitope spreading, as a basis for autoantibody diversification, and as a link between organ-specific and systemic autoimmunity; the localization of genetic loci potentially influencing multiple autoimmune diseases; and the elucidation of regulatory T cells as a component of physiological self tolerance.

Animals↗
PubMed1997

Neonatal injection of an ovarian peptide induces autoimmune ovarian disease in female mice: requirement of endogenous neonatal ovaries.

Neonatal female mice injected with the self ZP3 peptide are not tolerant to the peptide; they develop autoimmune ovarian disease (AOD) and autoantibody response 5 weeks later. ZP3 challenge leads to severe AOD and ZP3-specific T cell and antibody responses. In contrast, neonatal tolerance to foreign ZP3 peptide is established in male mice: ZP3 peptide-specific T cell proliferative response is reduced and AOD is absent in ovarian grafts. Tolerance is associated with a Th2-dominant T cell cytokine and antibody isotype profiles. As controls, neonatal tolerance to foreign peptides, with Th2 deviation, was induced in both male and female mice. Endogenous ZP3 is important for the gender difference. Ablation of ovaries in female mice on days 2 and 5, but not on day 7 or 14, switches the ZP3 autoimmune response to a tolerogenic response with a concomitant change in cytokine profile. Thus, neonatal self ZP3 peptide, supported by endogenous ovaries within a neonatal time window, evokes a pathogenic autoimmune response.

Amino Acid Sequence↗
PubMed1996

Rapid induction of autoantibodies by endogenous ovarian antigens and activated T cells: implication in autoimmune disease pathogenesis and B cell tolerance.

Animals immunized with nuclear antigenic peptides produce autoantibodies to distant antigenic sites and neighboring Ags within a multimolecular complex. This has led to the hypothesis that induction of autoantibodies in systemic autoimmune diseases might be triggered by a T cell epitope. We have investigated the T to B epitope spreading phenomenon based on the murine autoimmune oophoritis model. Mice immunized with a ZP3 T cell peptide spontaneously produced amplified autoantibodies (amAb) against linear ZP3 B cell epitopes outside the peptide immunogen. Each ZP3 B cell peptide, chimerized to a foreign promiscuous T cell epitope, elicited Ab to the peptide within the native ZP3 molecule. Mice with amAb often had no oophoritis; but more importantly, bilateral ovariectomy 1 day before ZP3 T epitope injection inhibited the induction of the amAb response, whereas ovariectomy 2 to 4 days after immunization was not inhibitory. Because endogenous ovarian Ag depletion before detectable ZP3 T cell response (day 5) and oophoritis (day 7) failed to prevent the amAb response, the autoantibodies are likely stimulated by endogenous ZP3 Ags present outside the normal ovaries. AmAb, of only the IgG class, appeared on day 7; this was 2 to 3 days after detectable T cell response, and 5 to 6 days before A response to the T cell peptide immunogen. The rapid, class-switched amAb response indicates that B cells in female mice are not tolerant to self ovarian Ag and they may normally be primed by ZP3. As evidence for their pathogenic potentials, amAb were produced in response to oophoritogenic, nonovarian T cell peptides that mimic ZP3; moreover, an excellent correlation existed between amAb titers and fertility reduction.

Amino Acid Sequence↗
PubMed1995

Frequency of molecular mimicry among T cell peptides as the basis for autoimmune disease and autoantibody induction.

Experimental ovarian autoimmune disease is inducible by immunization with an ovarian peptide from zona pellucida (ZP) 3, a glycoprotein of the zona pellucida on mouse oocyte. The murine ZP3 peptide contains two nested T cell epitopes with slightly different critical residue motifs. To investigate the frequency of cross-reaction between nonovarian and ovarian peptides, we have chosen arbitrarily 16 nonovarian peptides with complete or partial homology to the critical residue motifs of the two T cell epitopes. Based on peptide induction of autoimmune oophoritis and T cell-dependent amplified autoantibody response to ovarian ZP, cross-reaction was documented for 7 (or 44%) of the 16 nonovarian peptides studied. Thus, molecular mimicry as a pathogenetic mechanism of autoimmunity should not be limited by the frequency of cross-reaction among self and nonself peptides. On the other hand, the sharing of critical residue motif per se is not sufficient for mimicry to occur, nor does it predict peptide cross-reaction.

Amino Acid Sequence↗
PubMed1993

Antigen mimicry in autoimmune disease sharing of amino acid residues critical for pathogenic T cell activation.

A nonamer peptide from murine nicotinic acetylcholine receptor delta chain (ACR delta), which shared four amino acid residues with a nonamer peptide of murine ovarian zona pellucida glycoprotein ZP3, induced murine autoimmune oophoritis and IgG autoantibody to the zona pellucida. Crossreaction between the ACR delta and ZP3 peptides was established by the response of a ZP3 peptide-specific, oophoritogenic T cell clone to both peptides in association with IA (alpha k beta b). By substituting the ZP3 peptides with a single alanine, four amino acids within the ZP3 peptide were found to be important for ovarian autoimmune disease, autoantibody response, and stimulation of the ZP3-specific T cell clone. Substitution with conservative amino acids of three residues also ablated activity, whereas the fourth, a phenylalanine, was replaceable by tyrosine without loss of activity. Of the four critical amino acids, three were shared between the ZP3 peptide and the ACR delta peptide. Moreover, polyalanine peptides with the four critical ZP3 amino acids or the four amino acids common to the ZP3 and ACR delta peptides induced immune response to ZP3 and elicited severe ovarian autoimmune disease. Thus, organ-specific autoimmune disease can occur through immune response against unrelated self (or foreign) peptides that share with a self-peptide sufficient common amino acid residues critical for activation of pathogenic, autoreactive T cells.

Amino Acid Sequence↗
PubMedDate not supplied

Autoimmune ovarian disease: mechanism of induction and prevention.

Research on murine autoimmune ovarian disease (AOD) models suggests that the following sequence of events operate in prevention and induction of AOD. Potentially pathogenic T cells for oocyte antigens that exist in normal mice are kept in check by regulatory CD25(+) T cells. Oocyte-specific pathogenic T cells are activated when the regulation is lost, as after day 3 thymectomy, or when T cells are stimulated through molecular mimicry. Activated, proinflammatory T cells induce interstitial ovarian inflammation without disruption in ovarian function. Activated T cells also help B cells that respond to endogenous oocyte antigens, to produce oocyte autoantibodies of diversified specificities. Autoantibodies, nonpathogenic in themselves, retarget T cell-mediated inflammation to ovarian follicles resulting in ovarian atrophy and ovarian failure. Future studies should determine the applicability of these findings to human ovarian autoimmunity.

Animals↗