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P Hultman

Publications and source records attributed to P Hultman.

At least 19 recordsLinked to original sources
PubMed1999

Methyl mercury-induced autoimmunity in mice.

Female SJL/N, A.SW, B10.S (H-2s), BALB/C, DBA/2 (H-2d), A.TL and B10. TL (H-2t1) mice were treated with sc injections of 1.0 mg CH3HgCl/kg body weight every third day for 4 weeks. Controls were given sterile, isotonic NaCl. CH3HgCl (MeHg) induced in SJL, A.SW and B10.S mice antinucleolar antibodies (ANoA) targeting the nucleolar 34-kDa protein fibrillarin. The susceptibility to develop ANoA in response to MeHg was linked to the mouse major histocompatibility complex (H-2), since H-2s but not H-2t1 mice sharing background (non-H-2) genes developed ANoA. However, the background genes decided the strength of the ANoA response in the susceptible H-2s mice, and the ANoA titer was in the order: A.SW > SJL > B10.S. Although MeHg as well as inorganic mercury induced ANoA, the two forms of mercury differed both quantitatively and qualitatively in their effect on the immune system. MeHg induced in H-2s mice a weaker general (polyclonal) and specific (ANoA) B-cell response than HgCl2, probably due to weaker activation of Th2 cells with lower IL-4 production, as indicated by the minimal increase in serum IgE. The A. TL strain with a susceptible genetic background, but a H-2 haplotype resistant to HgCl2, responded to MeHg with a modest polyclonal B-cell response dominated by Th1-associated Ig isotypes. H-2s mice treated with MeHg showed in contrast to HgCl2-treated mice no systemic immune-complex (IC) deposits, which may be due to the weaker immune activation after MeHg treatment. The increase in serum IgE concentration and ANoA titer 2-6 weeks after stopping treatment with MeHg is identical to reactions during the first 2-3 weeks of HgCl2 treatment. Therefore, demethylation of MeHg probably increased the concentration of inorganic mercury in the body sufficiently to reactivate the immune system. This reactivation indicated that genetically susceptible mice are not resistant to challenge with mercury, making them distinctly different from rats.

Animals↗
PubMed1999

In vitro lymphoproliferative assays with HgCl2 cannot identify patients with systemic symptoms attributed to dental amalgam.

Dental amalgam is suspected, by some exposed individuals, to cause various systemic psychological, sensory, and neurological symptoms. Since not all amalgam-bearers experience such reactions, an individual characteristic--for example, a susceptible immune system--might explain these conditions. In vitro lymphocyte proliferation is a valuable tool in the diagnosis of allergy. With HgCl2 as the antigen, however, the test is hampered, because Hg2+ can cause unspecific lymphocyte proliferation, optimal at 1.4 to 9.5 micrograms HgCl2/mL. Recently, the use of suboptimal HgCl2 concentrations (< or = 0.5 microgram/mL) has been suggested to circumvent these problems. The main aim of this study was to investigate whether patients with systemic symptoms alleged to result from the presence of dental amalgam differ from healthy controls, with reference to in vitro lymphoproliferative responses to HgCl2 < or = 0.5 microgram/mL. Three different test protocols--lymphocyte transformation test (LTT) in micro- and macro-cultures, and the memory lymphocyte immunostimulation assay (MELISA)--were used. Other immune parameters--such as a standard patch test for dental materials, the number of T- and B-lymphocytes, monocytes, granulocytes, and NK cells in peripheral blood, allergic symptoms, and predisposition--were also investigated. Twenty-three amalgam patients, 30 healthy blood donors with amalgam, ten healthy subjects without amalgam, and nine patients with oral lichen planus (OLP) adjacent to dental amalgam and a positive patch test to Hg0 were tested. None of the investigated immune parameters revealed any significant differences between amalgam patients and controls. The sensitivity of in vitro lymphocyte proliferation ranged from 33 to 67%, with the OLP patients as a positive control group, and the specificity from 0 to 70% for healthy controls with a negative patch test to Hg0. Thus, despite the use of HgCl2 < or = 0.5 microgram/mL, a high frequency of positive results was obtained among healthy subjects with or without dental amalgam. Consequently, in vitro lymphocyte proliferation with HgCl2 cannot be used as an objective marker for mercury allergy in dental amalgam-bearers.

Adjuvants, Immunologic↗
PubMed1999

Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity.

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL/lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl(2)-induced exacerbation of autoimmunity. Such genetic predisposition may have to be considered when assessing the immunotoxicity of xenobiotics. Additional comparative studies using autoimmune-prone and nonautoimmune mice strains with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations susceptible to autoimmune diseases.

Animals↗
PubMed1998

The prototypic Th2 autoimmunity induced by mercury is dependent on IFN-gamma and not Th1/Th2 imbalance.

Imbalances of Th1- and Th2-type responses have been postulated to be a predisposing factor for both humoral and cellular mediated autoimmune diseases. To further define their roles in systemic autoimmunity, IL-4 and IFN-gamma gene knockout mice were studied for susceptibility to the prototypic Th2-mediated mercury-induced autoimmunity. A predominant Th2-type response following HgCl2 treatment of wild-type B10.S mice was confirmed by the findings of a significant increase in splenic IL-4 and hypergammaglobulinemia primarily of the IgG1 isotype, without an increase in IFN-gamma levels. Paradoxically, IL-4-deficient mice developed the characteristic anti-nucleolar autoantibodies and tissue deposition of immune complexes, while IFN-gamma-deficient mice had very low autoantibody levels and essentially normal immunohistology. Studies to define defects in Ab responses of IFN-gamma-deficient mice, using the T-dependent Ag (4-hydroxy-3-nitrophenyl)acetyl, revealed an attenuated IgG response to low and to a lesser extent high doses of (4-hydroxy-3-nitrophenyl)acetyl-hemocyanin, but maintenance of affinity maturation. These results indicate that Th1/Th2 imbalance does not directly play a role in susceptibility to mercury-induced autoimmunity, and suggest that the dependence on Th1-type responses in certain autoimmune diseases is due to the requirement for IFN-gamma for Ab production to weakly antigenic self molecules.

Animals↗
PubMed1998

Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils.

Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inflammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms beta-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after approximately 25 days of inflammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inflammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA-amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloid-enhancing activity.

Amino Acid Sequence↗
PubMed1998

The effect of toxicokinetics on murine mercury-induced autoimmunity.

Mercury induces autoantibodies to the nucleolar protein fibrillarin (ANoA) in genetically susceptible (H-2AS) mouse strains. This study examines the importance of mercury toxicokinetics for the induction and strength (titer) of these autoantibodies. Female mice of the inbred strains A.SW and B10.S (H-2AS on the A and C57BL/10 genetic background, respectively) and A.TL and B10.TL (H-2Ak on the A and C57BL/10 background) were treated with 203HgCl2 in a dose of 1, 5, or 16 mg Hg/L drinking water for 56-70 days. Whole-body retention of 203Hg was monitored throughout the experimental period. Mercury accumulation in kidney, liver, heart, spleen, and brain was determined at end of the experiment when blood samples were also obtained for determination of ANoA. The drinking water consumption showed a limited variation between the strains and the dose groups. Therefore, intake of mercury did not vary much between the strains at a given dose level. The whole-body retention of mercury reached steady state after 4-5 weeks. In general, the B10.S and B10.TL strains showed a lower whole-body retention and deposition of mercury in the kidney and the liver, compared with the A.SW and A.TL strains given the same dose of mercury. The B10.S strain showed a threshold for induction of ANoA at 5 mg Hg/L, whereas ANoA were still seen in A.SW mice given 1 mg Hg/L. Taken together, this is compatible with a less efficient elimination of mercury in the A.SW and A.TL strains, which was also supported by the higher ratio between whole-body retention and intake of mercury in these strains. These findings indicate that genes residing outside the H-2 (MHC) complex play an important role for regulating mercury toxicokinetics, the A genes conferring higher accumulation of mercury in the body than the B10 genes. In mice congenic with regard to the susceptible H-2AS haplotype, a highly significant correlation (P<0.01) existed between on the one hand the whole-body retention and organ accumulation of mercury and on the other hand the titer of ANoA. We conclude that mercury toxicokinetics differs significantly among inbred mouse strains. The differences in toxicokinetics are regulated by non-H-2 genes and correlate with the autoimmune response in the genetically susceptible strains: quantitatively as the titer of the ANoA and qualitatively as different threshold doses for induction of ANoA by mercury.

Animals↗
PubMed1998

Strain dependence of steady-state retention and elimination of mercury in mice after prolonged exposure to mercury(II) chloride.

Previous studies have demonstrated that the toxicokinetics of a single oral dose of inorganic mercury in mice depends on the specific strain. The strain dependent kinetics were attributed primarily to differences in intestinal Hg2+ absorption. Elimination kinetics have been difficult to evaluate, however, as the majority of a single oral dose will pass through the gastrointestinal tract unabsorbed. Therefore, in contrast to previous studies, in this study exposure to inorganic mercury in drinking water for a prolonged time period was used in order to reach a steady state for whole-body retention of mercury. The exposure level (5 mg l-1) was sufficiently low to exclude gastrointestinal toxicity. The steady-state retention of mercury was established in four inbred mouse strains (B10.S, DBA, A.SW and SJL). The DBA strain reached the highest whole-body steady state level of mercury (19 micrograms Hg) whereas B10.S mice, when considering the drinking water consumption, had the lowest steady-state retention of mercury (15 micrograms Hg). Analysis of the whole-body elimination of mercury after 12 weeks of drinking water exposure indicated that variations in the elimination kinetics could explain a large fraction of the observed strain differences in the steady-state retention of mercury. Thus, the approximate half-time for elimination of aged mercury depots was longest in DBA mice (83 d) and shortest in B10.S mice (44 d). Further, the observed organ depositions indicated that differences in the transport of mercury from the liver to kidney might also explain some of the differences in the elimination kinetics.

Animals↗
PubMed1998

The genotype determines the B cell response in mercury-treated mice.

BACKGROUND: Mercury causes in mouse strains of the H-2s haplotype an autoimmune syndrome with antibodies to the nucleolar protein fibrillarin and systemic immune complex (IC) deposits. Other strains, like BALB/C (H-2d), develop only IC deposits, and most strains are resistant. However, mercury activates the murine immune system and causes lymphoproliferation in most strains: H-2s strains are high-responders also in this respect, while the relation between lymphoproliferation and autoimmune manifestations is unclear for other strains. We examined the B cell response to mercury in order to better understand the relation between lymphoproliferation and systemic autoimmunity, using the high-responder H-2s strains (A.SW and SJL), the intermediate responder strain BALB/C (H-2d), and the A. TL (H-2tl) and DBA/2 (H-2d) strains which are resistant to systemic autoimmunity. METHODS: During 4-7 weeks of subcutaneous mercuric chloride injections, the number of B cells and the expression of cell surface activation and proliferation markers was monitored by flow cytometry. The number of cytoplasmic Ig+ splenocytes was determined by direct immunofluorescence technique on slides, and serum Ig isotype levels as well anti-ssDNA and anti-DNP antibodies were determined by ELISA. Serum ANA were monitored weekly by indirect immunofluorescence technique. RESULTS: Mercury-treated A.SW and SJL mice (H-2s) developed an increased expression of the proliferation marker CD71 on B cells, an increased number of B cells in the spleen, and an early, strong, but transient increase in serum Ig concentrations of Th1- as well as Th2-regulated Ig isotypes. Mercury-treated H-2s mice rapidly developed a polyclonal B cell response including the IgM isotype, but also antinucleolar antibodies (ANoA) of the IgG isotype with a clumpy pattern, characteristic for antifibrillarin antibodies. The IgG ANoA response was of a long duration and high titer. The A.TL strain (H-2tl) showed only a slight, restricted B cell activation. The BALB/C strain developed a slight, transient B cell activation dominated by IgG1 and IgE, and antinuclear antibodies (ANA). The DBA/2 strain showed only a minimal B cell response without ANA. CONCLUSION: Mercury induces an early, transient, polyclonal B cell activation linked to the H-2A or H-2K locus in H-2s strains on the A background. This polyclonal response differs from the long-lasting, high-titered IgG autoantibody response to a nucleolar antigen with characteristics of fibrillarin in H-2s strains, which indicates that these responses arise from separate mechanisms. Another group of strains, exemplified by BALB/C (H-2d), responds to mercury with a slight, transient, Th2-dominated B cell response, a restricted antibody specificity targeting the cell nucleus, and systemic IC deposits. Another H-2d strain, DBA, is essentially resistant to mercury, illustrating the importance of non-H-2 genes for regulating the response to mercury.

Animals↗
PubMed1998

Activation of the immune system and systemic immune-complex deposits in Brown Norway rats with dental amalgam restorations.

Dental amalgam restorations are a significant source of mercury exposure in the human population, but their potential to cause systemic health effects is highly disputed. We examined effects on the immune system by giving genetically mercury-susceptible Brown Norway (BN) rats and mercury-resistant Lewis (LE) rats silver amalgam restorations in 4 molars of the upper jaw, causing a body burden similar to that described in human amalgam-bearers (from 250 to 375 mg amalgam/kg body weight). BN rats with amalgam restorations, compared with control rats given composite resinous restorations, developed a rapid activation of the immune system, with a maximum 12-fold increase of the plasma IgE concentration after 3 wks (p < 0.001; Mann-Whitney's test). LE rats receiving amalgam restorations showed no significant increase of plasma IgE (p > 0.05). After 12 wks, BN rats with amalgam restorations showed significantly increased (p < 0.05) titers of immune-complex (IC) deposits in the renal glomeruli and in the vessel walls of internal organs. These rats also showed a significant (p < 0.05), from six- to 130-fold, increase in tissue mercury concentration in the concentration order kidney > spleen > cerebrum occipital lobe > cerebellum > liver > thymus, and the tissue silver concentration was significantly (p < 0.05) increased from three- to 11-fold. Amalgam-implanted BN rats showed a significant (p < 0.05) increase in copper concentration in the kidney and spleen, and in kidney selenium concentration. We conclude that dental amalgam restorations release substantial amounts of their elements, which accumulate in the organs and which, in genetically susceptible rats, give rise to activation of the immune system and systemic IC deposits.

Analysis of Variance↗
PubMed1997

Effects of the murine genotype on T cell activation and cytokine production in murine mercury-induced autoimmunity.

Mercury induces a systemic autoimmune condition characterized by auto-antibodies to the nucleolar protein fibrillarin (AFA) and systemic immune-complex (IC) deposits in genetically susceptible mouse strains. This study examines T cell activation and cytokine production following mercury exposure in genetically susceptible and resistant strains. Mercury injected s.c., according to the protocol for induction of autoimmunity, caused an early T cell activation, measured as an increase of IL-2-producing cells, and increased expression of the IL-2-receptor proteins CD25 and CD122 and of the proliferation marker CD71 on days 2-4 in the susceptible A.SW and A. TH strains. This was followed by a long-lasting increase in the number of T cells, dominated by CD4(+) cells. Mice of the susceptible A.SW strain showed a modest increase of TNF-alpha-, IFN-gamma-, and IL-4-producing cells after 4-6 days, and a very distinct increase of IL-4-producing cells on days 8-10. The susceptible SJL strain (H-2(s)), severely deficient in Th2-promoting CD4(+), NK1.1(+) T cells, showed no increase of IL-4(+) cells on days 8-10. Instead, the number of IFN-gamma-producing cells was increased. Susceptible mice developed an increase of Ig-producing cells, AFA, and systemic IC-deposits. Genetically mercury-resistant A.TL mice showed a minimal increase of T cells, but no increase in cytokine-producing cells. We conclude that autoimmunogenic doses of HgCl2 induce an activation and proliferation of T cells in genetically susceptible mouse strains, as well as a broad increase of cytokine-producing cells, followed by a late predominance of the Th2-associated IL-4. One strain, severely deficient in Th2-promoting CD4(+), NK1.1(+) T cells, lacked the increase in IL-4(+) cells, indicating that a predominantly Th2-response is not necessary for induction of autoimmunity by mercury. However, a Th2-dominated response led to a faster and stronger B cell activation.

Animals↗
PubMed1997

A study of autoantibodies and circulating immune complexes in mercury-exposed chloralkali workers.

UNLABELLED: Inorganic mercury may cause immunologically mediated disease: e.g., glomerulonephritis, acrodynia, and contact allergy. Animal models have demonstrated the importance of genetic factors in determining susceptibility and resistance to autoimmunity, as well as the specific manifestation of the autoimmune response. Findings in groups of workers with occupational exposure to inorganic mercury have been inconsistent. OBJECTIVE: To investigate whether an immune response, caused by exposure to inorganic mercury (Hg), could be shown in occupationally exposed workers. METHODS: Immunoglobulin G (IgG), antinuclear autoantibodies, antibodies against thyroid, stomach or kidney antigens using indirect immunofluorescence, antibodies against glomerular basement membrane using ELISA, and circulating immune complexes in serum, and albumin in urine, were examined in Hg-exposed workers and controls. The two groups, 41 male chloralkali workers exposed to Hg vapour (mean exposure time 9 years) and 41 unexposed controls were age-matched and recruited from the same company. Hg concentrations in whole blood (B-Hg), plasma (P-Hg), and urine (U-Hg) were determined using cold vapor atomic spectrometry. DESIGN: Cross-sectional study. RESULTS: The mean B-Hg, P-Hg and U-Hg levels were 46 nmol/l, 37 nmol/l, and 27 micrograms/g creatinine in the exposed group, and 17 nmol/l, 6.9 nmol/l, and 3.4 micrograms/g creatinine in the referents. No statistically significant differences were found regarding IgG levels, urinary albumin excretion, prevalence of abnormal titers of autoantibodies or circulating immune complexes. There were no statistically significant associations between autoantibodies or immune complexes on the one hand and mercury exposure indices on the other. CONCLUSION: The results indicate that, if and when lasting autoimmune response occurs at the mercury exposure levels of the present study, it is uncommon. A small fraction of humans may, however, be susceptible to the development of autoimmunity, and there is also a possible "healthy worker" selection. Thus cross-sectional studies of moderate numbers of active workers will have low power to demonstrate autoimmune effects.

Adolescent↗
PubMed1997

Oral, perioral and systemic pathosis in HgCl2-induced autoimmunity in the BN rat.

Male BN rats were repeatedly skin-injected with HgCl2 solution and sacrificed after 6, 9, 14, 21, 28 or 24 days. Mononuclear cell infiltrates were observed in the oral mucosa and in lacrimal, salivary and thyroid glands from 6-9 days onwards, with a peak at 14-21 days. Immunohistochemistry identified these cells as predominantly T cells with some NK cells but very few B cells. Reversible parenchymal changes were observed but there was no obvious persistent tissue destruction. Serum titers of IgE, IgG1, anti-laminin and anti-DNP, but not IgG2a antibodies, were raised and peaked at 14-21 days. However, there was no correlation, within animals, between these titers and the extent of mononuclear cell infiltration. Mercury was histochemically detected within dendritic cells/macrophages in the connective tissue stroma of the glands and in the oral mucosa, but no correlation was found between the distribution of mercury and the degree of inflammation. We conclude that the accumulation of mononuclear cells in oral and perioral tissues of HgCl2-treated BN rats does not represent a local immune response to tissue-retained Hg. Instead, we propose that the extravasation represents an epiphenomenon that is not necessarily deleterious to the infiltrated organ.

Animals↗
PubMed1997

In vitro lymphocyte proliferation as compared to patch test using gold, palladium and nickel.

BACKGROUND: A conventional lymphocyte transformation test (LTT) was compared to the commercially available MELISA (memory lymphocyte immunostimulation assay), a lymphoproliferative assay that has been suggested to be a valuable instrument for the diagnosis of metal allergy. Sensitivity and specificity of the two assays were calculated using a patch test as a reference method. METHODS: 34 patients were patch-tested for gold sodium thiosulfate, palladium chloride and nickel sulfate, and the lymphocyte proliferation to these metals was tested in vitro using mononuclear cells from peripheral blood. RESULTS: No significant differences regarding sensitivity and specificity were found between MELISA and conventional LTT. The sensitivity varied between 55 and 95% and the specificity between 17 and 79%. CONCLUSIONS: The low specificity of the two in vitro assays suggests that they are not useful for diagnosis of contact allergy to the metals gold, palladium and nickel, since a large number of false-positive results will be obtained.

Adult↗
PubMed1997

Murine silver-induced autoimmunity: silver shares induction of antinucleolar antibodies with mercury, but causes less activation of the immune system.

BACKGROUND: Mercury and silver induce antinucleolar autoantibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin in susceptible mouse strains. Mercury has the ability to cause a general activation of the immune system, but antigen-specific mechanisms following direct or indirect interaction between mercury and fibrillarin are now believed to play a crucial role in the autoimmune pathogenesis. Our previous studies showed that silver neither induced the systemic immune complex deposits nor the increase of serum immunoglobulins seen after mercury treatment. The main objective of this study was to examine the relation between activation of the immune system and the induction of ANoA. METHODS: During 4 weeks of subcutaneous silver nitrate injections into mice of the susceptible A.SW and SJL strains and the resistant A.TL strain, the number of T and B cells as well as the expression of cell surface activation and proliferation markers were monitored by flow cytometry. The number of cytoplasmic Ig+ splenocytes was determined by direct immunofluorescence technique on slides, and serum Ig levels as well as anti-ssDNA anti anti-DNP antibodies were determined by ELISA. Serum ANoA were monitored by the indirect immunofluorescence technique. RESULTS: Silver caused in the susceptible strains a weaker and later activation and proliferation of T and B cells than mercury, and no significant polyclonal B cell activation. In contrast, the ANoA titer was not different from that seen in mercury-treated mice of the same strains. Silver-treated mice of the A.TL strain showed neither activation of the immune system nor ANoA. CONCLUSIONS: Despite being as effective as mercury inducing ANoA, silver caused only a slight activation of the immune system. This demonstrates that the massive activation of the immune system in mercury treatment is not necessary for the induction of ANoA, and indicates that (auto)antigen-specific mechanisms are likely to play a key role in mercury- and silver-induced murine autoimmunity.

Animals↗
PubMed1997

Allergic nephropathy associated with norfloxacin and ciprofloxacin therapy. Report of two cases and review of the literature.

Allergic nephropathy associated with quinolone antibiotics has been reported in an increasing number of cases. The mechanism might be a hypersensitivity reaction. Norfloxacin has been incriminated previously as a cause once only, with acute interstitial nephritis (AIN) as the histopathological finding. Ciprofloxacin-associated nephropathy has been reported in 28 cases, with AIN as the main histopathological finding. This report describes a second case of AIN associated with norfloxacin treatment and another ciprofloxacin-associated renal interstitial drug adverse reaction. Clinicians should be aware of quinolone-associated AIN, which is a rare but potentially dangerous renal complication.

Aged↗
PubMed1996

Murine genotype influences the specificity, magnitude and persistence of murine mercury-induced autoimmunity.

Genetic factors are major contributors in determining the susceptibility to systemic autoimmune diseases. We studied the influence of genotype on systemic autoimmunity by treating female mice of the H-2s strains SJL/N, SJL/J, A.SW, and B10.S with mercuric chloride (HgCl2) for 10 weeks and then following autoantibody and tissue immune deposits during the subsequent 12 months. All strains developed antinucleolar antibodies (ANoA) of the IgG class which reacted in immunoblotting with a 34-kDa nucleolar protein identified as fibrillarin. The titre of ANoA attained after 10 weeks' treatment varied from 1:1,280 to 1:20,480 in the order: A.SW > SJL > > B10.S. Following cessation of HgCl2 treatment ANoA and antifibrillarin antibodies (AFA) persisted for up to 12 months, although some B10.S mice showed pronounced reduction not only of their autoantibody titres, but also systemic immune deposits when compared to other H-2s strains. A second set of autoantibodies targeted chromatin and in some mice specifically histones, and were distinguished from the ANoA by a rapid decline after treatment and a susceptibility linked to the non-H-2 genes of the SJL. Tissue levels of mercury remained elevated above untreated controls throughout the study period, suggesting that the mercury detected in lymphoid tissues may provide stimulation of lymphoid cells specific for fibrillarin for a considerable period after exposure has ceased. We conclude that H-2 as well as non-H-2 genetic factors distinctly influence not only the susceptibility to induction of autoimmunity, but also the specificity and magnitude of the response.

Animals↗
PubMed1995

Genetic susceptibility to silver-induced anti-fibrillarin autoantibodies in mice.

Similar to mercuric chloride, silver nitrate has recently been shown to induce IgG autoantibodies targeting the nucleolar 34-kDa protein fibrillarin i SJL (H-2s) mice. In the present study we show that the autoimmunogenic effect of silver is dependent on intact T-cell function since SJL/N mice homozygous for the nude mutation (athymic), in contrast to the functionally T-cell-intact SJL/N-nu/+ littermates, did not develop anti-nucleolar/anti-fibrillarin autoantibodies (ANoA/AFA). The genetic susceptibility for silver-induced AFA was localized to the H-2A locus using congenic and intra-H-2-recombinant strains. However, background (non-H-2) genetic factors substantially influenced both the response rate and the titer of ANoA/AFA attained. Strains bearing H-2As on the SJL and A backgrounds (SJL, A.SW, A.TH) showed 100% response rate and high ANoA titers (3750 +/- 246, mean reciprocal titer +/- SEM), whereas H-2As mice on the B10 background (B10.S) showed 60% response rate and significantly lower ANoA titers (1170 +/- 305) in the responding mice. Expression of H-2E [B10.S(9R) mice] further reduced the response rate (22%) and the ANoA titer (640 +/- 0). A suppressive effect on the B10 background has previously been observed in mercury treatment, but the effect was stronger in silver-treated mice. Two major differences were noted between silver- and mercury-induced murine autoimmunity. First, silver-treated mice did not show elevated titers of other autoantibody specificities, specifically not of antichromatin and anti-histone antibodies, which develop in mercury-treated SJL mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗