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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MRL/Mp-lpr/lpr mice develop a spontaneous lupus syndrome, including hypergammaglobulinemia, autoantibodies, glomerulonephritis, and lymphadenopathy. To investigate the role of lymphocytes subsets in the pathogenesis of disease, lupus-prone MRL mice deficient in alpha beta T cells, gamma delta T cells, or both were generated. Mice deficient in alpha beta T cells developed a partially penetrant lupus syndrome, characterized by lymphadenopathy, elevated levels of class-switched immunoglobulins, an increased incidence of antinuclear antibodies, and immune deposits in kidneys which progressed to renal insufficiency over time. In comparison to wild type animals, gamma delta T cell-deficient animals developed an accelerated and exacerbated disease phenotype, characterized by accelerated hypergammaglobulinemia and enhanced autoantibody production and mortality. Repertoire analysis of these latter animals identified polyclonal expansion (V beta) of alpha beta CD4+ B220-cells. Mice lacking both alpha beta and gamma delta T cells failed to generate class-switched autoantibodies and immune complex renal disease. First, these findings demonstrate that murine lupus in the setting of Fas-deficiency does not absolutely require the presence of alpha beta T cells, and they also suggest that a significant basis for MRL/lpr disease, including renal disease, involves alpha beta T cell-independent, gamma delta T cell dependent, polyreactive B cell autoimmunity, upon which alpha beta T cell-dependent mechanisms aggravate specific autoimmune responses. Second, these data indicate that gamma delta T cells partake in the regulation of systemic autoimmunity, presumably via their effects on alpha beta CD4+ B220-T cells that provide B cell help. Finally, these results demonstrate that MRL/lpr B cells, despite their intrinsic abnormalities, cannot per se cause tissue injury without T cell help.
Mol Biol Rep 1996
PMID:T cells in murine lupus: propagation and regulation of disease. 911 36

Following administration of certain chemicals (heavy metals or lupus-inducing drugs), H-2s mice produce autoantibodies reacting with various nuclear antigens such as fibrillarin in the nucleolus and histones in chromatin. In the present study, we have immunized A.SW (H-2s) mice and their congenic counterparts A.BY (H-2b) mice with bovine thymus nuclei in Freund's adjuvant. As was previously observed with lupus-prone mice, such active immunization did not elicit antinuclear antibodies in any of the experimental groups. Surprisingly, the A.SW immunized with nuclei in adjuvant developed high titers of IgG antibodies that reacted exclusively with synthetic polycations. We obtained several monoclonal IgG antibodies from these mice and verified that these polycation-reactive antibodies were not directed against a specific nuclear antigen. The genetic analysis of the monoclonal antibodies further confirmed their clonal diversity. The mechanisms leading to the appearance of antibodies reactive with highly basic molecules in A.SW mice may be related to their predisposition to produce autoantibodies to cationic nuclear antigens (fibrillarin, histones) during chemically-induced autoimmunity.
Mol Immunol 1997 Jan
PMID:Induction of anti-polycation antibodies in H-2s mice by immunization with nuclear antigens. 918 75

Since dual specificity at the antibody active-site level involves new principles relative to monospecific antigen-antibody interactions and may be a general property of autoantibodies, it was important to further characterize such antibodies. Four lupus derived autoantibodies were studied to understand parameters and mechanisms involved in the participation of dual-specific antibody molecules in the formation of highly stable immune complexes. Because the dual-specific binding properties of selected lupus-related murine autoantibodies had been previously described using a solid-phase polystyrene-based ELISA, a conformational sensitive membrane based assay (CSI) was used on a comparative basis to further characterize NZB/NZW F1 murine monoclonal anti-DNA autoantibodies BV 04-01 (anti-ssDNA), BV 16-19 (anti-ssDNA), BV 17-45 (anti-dsDNA), and BV 16-13 (anti-dsDNA). All four monoclonal autoantibodies exhibited anti-IgG binding in the solid-phase ELISA. However in the CSI assay, only anti-dsDNA monoclonal autoantibodies BV 17-45 and BV 16-13 demonstrated anti-IgG binding, while anti-ssDNA autoantibodies BV 04-01 and BV 16-19 did not. Upon subjection to time-dependent thermal denaturation, with and without thiol reduction at 100 degrees C in the CSI, the self-binding activities of BV 17-45 and BV 16-13 were abrogated demonstrating that the recognized IgG autoepitope(s) possessed conformational or discontinuous three-dimensional properties. The immunological implications of dual specificity are discussed on a structure-function basis and its correlation with formation of pathogenic immune complexes.
J Mol Recognit
PMID:Dual specificity and the formation of stable autoimmune complexes. 958 72

Autoantibodies target a diverse group of tissue antigens in human and experimental autoimmune nephritis. The proximal events that generate and regulate these various pathogenic Ab remain obscure. To examine the origins and fate in normal mice of autoantibodies reactive with renal basement membrane antigen, we established mice transgenic for an IgM H chain encoding an unmutated nephrotropic V region, termed LamH, derived from an MRL/lpr mouse and directed against basement membrane laminin. We previously demonstrated that in vitro transfectants combining LamH-Cmu with unmutated L chains generate distinct nephrotropic autoantibodies. Herein we report in vivo reconstruction of diverse pathogenic autoreactivity by association of LamH-Cmu with endogenous L chains. Progeny of one founder, termed M7, express a distinct phenotype characterized by minimal B cell mIgM and spontaneous production of LamH-Cmu autoreactivity. Similar Ab were not recovered from two phenotypically distinct transgenic lines expressing abundant transgene mIgM. The results suggest that lupus-like autoantibodies are readily generated in the normal genetic background by random recombinatorial events in the absence of mutation and that these Ab may contribute to disease if normal regulation is disturbed.
Mol Immunol 1998 Feb
PMID:Lupus-like nephrotropic autoantibodies in non-autoimmune mice harboring an anti-basement membrane/anti-DNA Ig heavy chain transgene. 968 54

Cardiac chamber enlargement and hypertrophy are normal physiologic responses to repetitive endurance exercise activity in human beings and domestic dogs. Whether similar changes occur in wild animals as a consequence of increased activity is unknown. We found that free-ranging gray wolves (Canis lupus, n = 11), the archetypical endurance athlete, have electrocardiographic evidence of cardiac chamber enlargement and hypertrophy relative to sedentary captive gray wolves (n = 20), as demonstrated by significant increases in QRS duration, QT interval, and QT interval corrected for heart rate, a tendency towards increased Q, R, and S wave voltages in all leads, and a significant decrease in heart rate. We conclude that exercise activity level and therefore lifestyle affects physiologic variables in wild animals. An immediate consequence of this finding is that physiologic measurements obtained from a captive wild-animal population with reduced exercise activity level may not accurately reflect the normal physiologic state for free-ranging members of the same species.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jul
PMID:Electrocardiographic consequences of a peripatetic lifestyle in gray wolves (Canis lupus). 978 34

Genetic data suggest that red wolves (Canis rufus) resulted from a hybridization between coyotes (C. latrans) and grey wolves (C. lupus). The data of the hybridization, however, is uncertain. According to one hypothesis, the two species came into contact as coyotes increased their geographical range in conjunction with the advance of European settlers and as grey wolves were extirpated from the American south. Alternatively, the red wolves could have originated tens of thousands of years ago as a result of climate and habitat changes that disturbed the ecology of the two parent species. To obtain an upper limit on the date of hybridization that would help to distinguish the two scenarios, we compared microsatellite allele length distributions from red wolves, coyotes and grey wolves. Subject to the assumptions of our analysis, we conclude that the red wolves originated as a result of hybridizations that occurred during the past 12,800 years, and probably during the past 2500 years.
Mol Ecol 1999 Jan
PMID:Genetic evidence for a recent origin by hybridization of red wolves. 991 3

Systemic lupus erythematosus (SLE) is the prototype of human autoimmune diseases. Its genetic component has been suggested by familial aggregation (lambdas = 20) and twin studies. We have screened the human genome to localize genetic intervals that may contain lupus susceptibility loci in a sample of 188 lupus patients belonging to 80 lupus families with two or more affected relatives per family using the ABI Prism linkage mapping set which includes 350 polymorphic markers with an average spacing of 12 cM. Non-parametric multipoint linkage analysis suggests evidence for predisposing loci on chromosomes 1 and 18. However, no single locus with overwhelming evidence for linkage was found, suggesting that there are no 'major' susceptibility genes segregating in families with SLE, and that the genetic etiology is more likely to result from the action of several genes of moderate effect. Furthermore, the support for a gene in the 1q44 region as well as in the 1p36 region is clearly found only in the Mexican American families with SLE but not in families of Caucasian ethnicity, suggesting that consideration of each ethnic group separately is crucial.
Hum Mol Genet 1999 Apr
PMID:Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. 1007 32

We have used single and multiple site-directed mutagenesis, and molecular modeling, to identify critical residues in the DNA binding site of MAb 2C10, an IgG anti-dsDNA autoantibody from an MRL/lpr lupus mouse. Simultaneous replacement of four Arg residues in the CDR3H abolished binding activity. With one exception, replacement of any one of these Arg residues reduced the activity to 20-50% of the unmutated scFv activity. Arg to Asp replacements had a slightly greater effect than Arg to Ala replacements. In the one exceptional case, replacement of Arg99 with Ala actually increased DNA binding five-fold and replacement by Asp had little effect. Mutation of Phe32 and Asn35 to A1a in CDRIH decreased DNA binding, whereas replacement of Arg31 with A1a had negligible effect. Ala substitution of any one of a cluster of Asp residues in CDR1L increased DNA binding three to six-fold, confirming previous findings that the L-chain of MAb 2C10 is not favorable for DNA binding. The L-chain does participate in shaping the selectivity of antigen binding, and mutation of CDR3L residue Asp92 or Asn93 caused a decrease in DNA binding activity. Directed mutagenesis, consistent with a molecular model, indicates that: several CDR amino acids contribute to DNA binding, without one residue dominating; both VH and VL CDR3 domains contribute to specificity of binding whereas the CDR1L hinders DNA binding. The results suggest a significant role for electrostatics in the interaction of DNA with MAb 2C10.
Mol Immunol 1998 Dec
PMID:The structural basis for DNA binding by an anti-DNA autoantibody. 1019 94

Fibroblast growth factors (FGFs) have been implicated in the pathobiology of autoimmune inflammation on the basis of their angiogenic properties, as well as their increased expression at inflammatory sites. In order to better evaluate the role of FGF-1 in the renal disease of mice that develop spontaneous lupus-like clinical features, we examined the expression of FGF-1 mRNA and protein in the kidneys of the murine MRL lpr/lpr strain. Both Northern and Western blot analyses demonstrated that FGF-1 levels do not increase in the kidneys of this particular autoimmune mouse strain as a function of renal disease. These results suggest that FGF-1 may not be involved in the pathogenesis of autoimmune nephritis in MRL lpr/lpr mice.
Res Commun Mol Pathol Pharmacol 1999 Jan
PMID:Lack of FGF-1 overexpression during autoimmune nephritis in the kidneys of MRL lpr/lpr mice. 1044 May 69

The grey wolf (Canis lupus) and coyote (C. latrans) are highly mobile carnivores that disperse over great distances in search of territories and mates. Previous genetic studies have shown little geographical structure in either species. However, population genetic structure is also influenced by past isolation events and population fluctuations during glacial periods. In this study, control region sequence data from a worldwide sample of grey wolves and a more limited sample of coyotes were analysed. The results suggest that fluctuating population sizes during the late Pleistocene have left a genetic signature on levels of variation in both species. Genealogical measures of nucleotide diversity suggest that historical population sizes were much larger in both species and grey wolves were more numerous than coyotes. Currently, about 300 000 wolves and 7 million coyotes exist. In grey wolves, genetic diversity is greater than that predicted from census population size, reflecting recent historical population declines. By contrast, nucleotide diversity in coyotes is smaller than that predicted by census population size, reflecting a recent population expansion following the extirpation of wolves from much of North America. Both species show little partitioning of haplotypes on continental or regional scales. However, a statistical parsimony analysis indicates local genetic structure that suggests recent restricted gene flow.
Mol Ecol 1999 Dec
PMID:Mitochondrial DNA phylogeography and population history of the grey wolf canis lupus 1063 60


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