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Biomedical subjects

A Cooke

Publications and source records attributed to A Cooke.

At least 109 records · Page 6Linked to original sources
PubMed1992

The implications of the failure to generate autoantibody-producing hybridomas from rat erythrocyte-immunized mice.

Injection of mice with rat erythrocytes (RRBC) has long been thought to provide an experimental model in which suppressor T cells (Ts) control autoimmunity. The basis of this is that whilst mice immunized with RRBC produce an antibody response, of which a proportion cross-reacts with autologous red cells, the RRBC-immunized recipients of RRBC-primed spleen cells make no, or little, autoantibody, and secondly because the transfer of this autoantibody-specific suppression can be abrogated by T-cell depletion of transferred spleen cells. Here an alternative explanation of these phenomena is described.

Animals↗
PubMed1992

Adjuvant composition determines the induction of type II collagen-induced arthritis.

In this study we have investigated the influence of adjuvant composition on the development of collagen-induced arthritis and of anti-collagen type II specific B- and T-cell responses following immunization with type II collagen. DBA/l mice immunized with bovine collagen type II emulsified in complete Freund's adjuvant (CFA) containing Mycobacterium tuberculosis strain H37Ra developed footpad swelling indicative of arthritis. Animals immunized with collagen type II plus CFA containing Mycobacterium butyricum, or incomplete Freund's adjuvant showed no significant increase in footpad width. Induction of anti-CII specific T-cell proliferation was also dependent upon immunization with CII plus CFA containing M. tb H37RA. In contrast, ovalbumin-reactive T-cell proliferation was unaffected by the species of mycobacteria, indicating that the difference in adjuvant activity of the mycobacterial species is specific for anti-collagen type II T-cell responses. Antibody response to collagen type II, unlike T-cell responses, was not significantly different using the two adjuvants. This study therefore demonstrates that murine collagen-induced arthritis requires immunization with collagen type II together with complete Freund's adjuvant containing Mycobacterium tuberculosis H37RA. Since only this combination of antigen and adjuvant induces detectable arthritis and T-cell responses against collagen type II, while antibody synthesis does not have such stringent adjuvant requirements, this suggests that the development of the full pattern of the collagen-induced arthritis disease requires synergistic activation of both humoral and cell-mediated responses.

Adjuvants, Immunologic↗
PubMed1992

The influence of adjuvants on the generation of autoantibody and specific suppression in rat erythrocyte-immunized mice.

A number of adjuvants were investigated for their ability to modulate either the autoimmune response induced in mice by immunization with rat erythrocytes (RRBC) or the ability of RRBC-primed spleen cells to suppress the induction of anti-red cell autoimmunity in recipient mice. The inability of the agents used to do so is discussed on the background of models used to explain the generation of suppression in this system.

Adjuvants, Immunologic↗
PubMed1992

The influence of I-E on the generation of autoantibody and specific suppression in rat erythrocyte-immunized mice.

A proportion of the antibodies produced by mice in response to the injection of rat erythrocytes (RRBC) cross-react with autologous red cells. When spleen cells from mice so immunized are transferred to naive syngeneic recipients, the recipient mice produce high anti-RRBC antibody titres but little or no autoantibody. This phenomenon has been attributed to the action of suppressor T cells. To date, the only mouse strain which consistently fails to demonstrate specific suppression of the autoantibody response is the SJL, which lacks the I-E molecules suggested to be important in the generation of suppressor T cells. The results presented here show that some, but not all, I-E negative strains of mice are capable of exhibiting transferable suppression of RRBC-induced antibodies.

Animals↗
PubMed1991

Identification of a thyroxine-containing self-epitope of thyroglobulin which triggers thyroid autoreactive T cells.

Although thyroglobulin (Tg), the thyroid prohormone, is well known as a T cell dependent autoantigen in human and experimental autoimmune thyroid disease, very little is known about the molecular basis of Tg recognition by T cells. In this paper, we have characterized the epitopes recognized by two clonotypically distinct, murine Tg autoreactive T cell hybridomas, CH9 and ADA2. In vitro iodination of a Tg preparation which was deficient in in vivo organified iodine was first used to confirm our previous observation that these T cells recognize iodination-related epitopes in the Tg molecule. Affinity chromatography of tryptic peptides derived from normally iodinated human Tg revealed that these epitopes were exclusively located in thyroxine (T4) containing peptides. Through the use of synthetic T4-containing peptides, representing the four major hormonogenic sites in Tg, we demonstrated that both CH9 and ADA2 recognize an epitope containing the T4 at position 2553 in human Tg. Sets of overlapping 5mer to 12mer peptides around this T4 showed that the most potent peptide was a 9mer beginning at Asp 2551. The T4 was shown to be a critical residue, since its replacement with any of the 20 naturally occurring amino acids produced only nonstimulatory peptides. Since the T cell hybridomas could also be stimulated by major histocompatibility complex class II positive (interferon-gamma-treated) thyroid epithelial cells in vitro, and their parent T cell lines can induce thyroiditis on adoptive transfer, the T4-containing Tg sequence described here is implicated as a pathogenic epitope in murine thyroid autoimmunity.

Amino Acid Sequence↗
PubMed1991

Characterization of pancreatic islet cell infiltrates in NOD mice: effect of cell transfer and transgene expression.

Insulin-dependent diabetes mellitus can be transferred into young irradiated non-obese diabetic (NOD) mice by spleen cells from a diabetic NOD donor. T cells (both L3T4+ and Ly-2+) enter the pancreas 2 weeks following transfer. They are present initially at peri-islet locations but progressively infiltrate the islet with accompanying beta cell destruction. The infiltrate is heterogeneous with respect to V beta usage. Inflammatory macrophages (Mac-1+, F4/80+) can be detected at peri-islet locations at 1 week after transfer and continue to be recruited during the disease process. Their presence at the initiation of disease suggests that their primary function may be autoantigen presentation. Increased expression of major histocompatibility complex (MHC) class I molecules is observed on both endocrine and exocrine tissue in areas of intra-islet infiltration. MHC class II and ICAM-1 expression was restricted to the cells constituting the inflammatory infiltrate. Expression of these molecules was not observed on beta cells implying that presentation of autoantigen by the beta cell itself does not play a role in the beta cell destruction in NOD mice.

Animals↗
PubMed1991

Estimating the risk of a fetal autosomal trisomy at mid-trimester using maternal serum alpha-fetoprotein and age: a retrospective study of 142 pregnancies.

Risks appropriate for mid-trimester prenatal screening for autosomal trisomies have been estimated from a combination of maternal age and maternal serum (MS) alpha-fetoprotein (AFP) levels at 16-20 weeks gestation. Published data on the frequency of Down's syndrome births relative to maternal age were modified to include the additional age-related frequency of trisomy 18 and trisomy 13 cases to provide an overall risk for an autosomal trisomy at mid-trimester. MSAFP results from a retrospective study of 142 affected (114 trisomy 21, 19 trisomy 18, and 9 trisomy 13) and 113,000 unaffected pregnancies were converted to multiples of the appropriate gestational median (MOM). The AFP levels in the autosomal trisomy pregnancies were found to be significantly reduced at 0.72 MOM of the unaffected pregnancies. Risks (likelihood ratios) were derived from the overlapping log Gaussian distributions for affected and unaffected pregnancies and combined with maternal age risks to give the overall odds of an affected pregnancy. A mid-trimester cut-off risk of 1:280 gave an estimated 37 per cent detection rate for autosomal trisomies in the west of Scotland population for a follow-up (false-positive) rate of 6.6 per cent. These figures compare with a 30 per cent detection and 6.7 per cent false-positive rate if age 35 years and over is used as the sole criterion for selection of at-risk pregnancies.

Adolescent↗
PubMed1991

Expression and function of Qa-2 major histocompatibility complex class I molecules in transgenic mice.

Qa-2 molecules are weak transplantation antigens encoded by class I genes of the major histocompatibility complex. When expressed in transgenic CBA mice, Qa-2 molecules provoke rapid rejection of skin grafts and strong, Qa-2 specific, cytotoxic T-cell responses. Efficient rejection of skin grafts from Qa-2 transgenic mice takes place when Qa-2 molecules are attached to the cell membrane with a glycophosphatidyl anchor or by a transmembrane protein domain, except that rejection times are slightly longer in the former case. These results demonstrate that Qa-2 molecules can behave as major transplantation antigens, as do closely related H-2 molecules. Failure of Qa-2 molecules to provoke strong T-cell responses in non-transgenic mice is probably due to the very low level of expression of Qa-2 molecules in skin keratinocytes from such mice since these cells express increased levels of Qa-2 molecules in all Qa-2 transgenic mice.

Animals↗
PubMed1991

In vitro regulation of thyroglobulin (Tg) autoantibody production by Tg-specific T-cell lines and hybridomas.

To define the interactions between self thyroglobulin (Tg)-reactive T and B we co-cultured enriched B cells taken from rat or mouse Tg-primed mice with major histocompatibility complex (MHC) class II-restricted T-cell lines specific for iodinated determinants on self-Tg, or hybridomas derived from those lines. Using two clonally distinct T-cell hybridomas, ADA2 and CH9, in vitro help for Tg autoantibody responses was observed using mouse (M)Tg-primed B cells and a 100 ng/ml MTg challenge. Using rat Tg-primed B cells and the same conditions, only CH9 provided help, indicating that the fine specificity of B cells influences their ability to interact with specific anti-Tg T-cell clones. In contrast to T-cell hybridomas, their parent T-cell lines MTg9B3 and MTg12B suppressed Tg autoantibody responses in vitro, although they augmented bystander proliferation of unprimed B cells. The MTg12B cells also (i) diminished the survival of Tg-primed B cells, and (ii) inhibited the proliferation of an antigen-presenting B-cell hybridoma (LK35.2) in a cytostasis assay. These findings together support the view that their suppressive activity is mediated through cytotoxicity. While the role of class II-restricted cytotoxic cells in thyroid autoimmunity is unknown, the results suggest that such cells may act to suppress autoantibody responses as well as to mediate tissue damage to class II-expressing thyroid cells.

Animals↗
PubMed1990

Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages.

Insulin-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The non-obese diabetic mouse is a good spontaneous animal model of the human disease, with IDDM developing in 50-80% of female mice by the age of 6 months. The disease can be transferred by splenic T cells from diabetic donors and is prevented by T-cell depletion. The mechanism(s) by which the beta cell is specifically destroyed is not known, but T cells and macrophages have both been implicated, based on the presence of macrophages in the infiltrated islet and the ability of chronic silica treatment to prevent disease. The monoclonal antibody 5C6 is specific for the myelomonocytic adhesion-promoting type-3 complement receptor (CR3 or CD11b/CD18) and does not bind to T cells. Here we show that blockade of macrophage CR3 in vivo prevents intra-islet infiltration by both macrophages and T cells and inhibits development of IDDM. We conclude that both T cells and macrophages have an essential role in the onset of IDDM.

Animals↗
PubMed1990

Glycosylation of IgG, immune complexes and IgG subclasses in the MRL-lpr/lpr mouse model of rheumatoid arthritis.

The MRL-lpr/lpr (MRL/lpr) mouse spontaneously develops a disease syndrome which, in many respects, is similar to human rheumatoid arthritis. These mice developed joint inflammation, circulating rheumatoid factors and immune complexes. We now show that the parallel with human disease extends to a glycosylation defect which is observed on IgG from rheumatoid arthritis patients. Using the lectins ricin and Bandeiraea simplicifolia II we have found that terminal N-acetylglucosamine is clearly raised in MRL/lpr IgG. Increased exposure of galactose was also detected, indicating that a second glycosylation site must be present on these molecules. Polyethylene glycol-precipitated IgG complexes bound significantly more of each lectin than did free IgG, indicating that the changes in glycosylation were associated with complex formation. The sugar abnormality was most marked in the IgG2a/IgG3 fraction from protein A IgG subclass chromatography. Our results suggest that the IgG glycosylation defect seen in rheumatoid arthritis is apparent in the MRL/lpr mouse and may contribute, through complex formation, to the pathological processes in the rheumatoid syndrome.

Acetylglucosamine↗
PubMed1990

Investigation of three patients with the "ring syndrome", including familial transmission of ring 5, and estimation of reproductive risks.

We report three cases of ring chromosome 5 [r(5)], two familial (mother and daughter) and one sporadic. The phenotype resembled that of the "ring syndrome" with prenatal onset of short stature, growth retardation, mild facial dysmorphism and normal psychomotor development. Extended metaphase and prometaphase chromosome preparations using G-, R- and Q-banding and scanning electron microscopy (SEM) failed to demonstrate deletion in the ring 5. Flow karyotype using the FACS cell sorter and peak area analysis showed the r(5) to be in the same position as the normal chromosome 5. The deletion that is presumably associated with ring formation appears to involve less that one megabase of DNA. In the "complex" rings, high resolution SEM showed fragile sites at the 5q34 and 5q35 region with frequent deletions at that site. A literature survey suggests that when a parent carries a ring chromosome about 80% of recognised pregnancies result in live birth. Of these, about half have a normal phenotype and karyotype, and half inherit the parental ring; about half of those acquiring the ring (20%) show significant mental retardation.

Adult↗
PubMed1990

Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination.

Clinical, chromosomal and molecular studies of a group of 15 XX males confirm the presence of two main groups. A Y + ve group of ten patients exhibit sex reversal as the result of transfer of the distal end of the short arm of the Y chromosome, including testis determining factors, to the short arm of one X-chromosome, presumably by accidental crossing-over in paternal meiosis. The ten patients have Klinefelter's syndrome but differ from XXY cases in that they are short and shown no impairment of intelligence. The four Y-ve XX males have no demonstrable Y sequences and differ from Y + ve cases in abnormality of the external genitalia and invariable gynaecomastia; in this, they more closely resemble XX true hermaphrodites than XY males. These observations on Y - ve XX males and an additional exceptional Y + patients suggest that the ZFY locus is not essential for male differentiation and is not the primary testis determining factor. Male sex determination in sporadic, and familial Y-ve XX males and true hermaphrodites is likely to be the result of mutation in an X-linked TDF gene and its consequent escape from the constraints of X-inactivation. It seems premature to abandon the dosage model of sex determination on the recent evidence that ZFX does not show dosage compensation.

Genotype↗