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Biomedical subjects

I R Mackay

Publications and source records attributed to I R Mackay.

At least 163 records · Page 9Linked to original sources
PubMed1989

HLA A1, B8, DR3 extended haplotypes in autoimmune chronic hepatitis.

Genetic determinants of the autoimmune type of chronic active hepatitis include the major histocompatibility complex alleles HLA-B8 and HLA-DR3, which are usually present as the haplotype A1, B8, DR3. In certain other autoimmune diseases, an extended haplotype including complement alleles confers a greater relative risk than does B8, DR3. Hence, extended haplotypes were ascertained in autoimmune chronic active hepatitis by typing for HLA, complement alleles C4A, C4B, and Bf, and glyoxalase type 1 or 2. Eight of the 10 B8, DR3 haplotypes were A1, B8, DR3. Of the 8, 7 had the extended haplotype A1, B8, C4AQ0, C4B1, BfS, DR3, but this haplotype occurred in four instances with glyoxalase 2 and in three with glyoxalase 1. Thus, we find that in autoimmune chronic active hepatitis there is a high frequency of null alleles for complement but an extended haplotype does not cause any greater risk for disease than B8, DR3 alone.

Alleles↗
PubMed1989

Molecular basis of mitochondrial autoreactivity in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC), styled as a model autoimmune disease, has a very close association with antibodies to mitochondrial antigens. The cloning of cDNAs for mitochondrial antigens led to their identification as the three enzymes of the 2-oxo-acid dehydrogenase family which includes pyruvate dehydrogenase (PDH). The autoantigen is associated with the E2 subunit of these enzymes. PDH is the 70-74 kDa antigen previously identified by immunoblotting. An immunodominant site (autoepitope) can be mapped to a sequence of PDH-E2 which is the site of attachment of the functionally important lipoic acid prosthetic group. Here, Ian Mackay and Eric Gershwin discuss how autoantigen identification and epitope mapping has now proceeded further in PBC than in other autoimmune diseases, and will allow access to critically important questions on pathogenesis of PBC in particular and autoimmunity in general.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1989

Primary biliary cirrhosis: current knowledge, perspectives, and future directions.

These perspectives from the first International Symposium on Primary Biliary Cirrhosis review recent advances and single out some areas for further enquiry. The latter include frequency and type of associated autoimmune diseases, the existence of clinical subsets of PBC, immunohistochemical analysis of lymphoid infiltrates in the liver, effects of immunosuppressive and other treatment regimens, and models for predicting the optimal time for liver transplantation. The M2 autoantigens have been identified as mitochondrial 2-oxo-acid dehydrogenase enzymes. These include pyruvate dehydrogenase (70-74 kd antigen) and branched chain 2-oxo-acid dehydrogenase and 2-oxo-acid glutaric dehydrogenase (45-52 kd antigens). Each of these enzymes has three subunits, E1 to E3. For PDH, an autoepitope has been identified as a decapeptide containing the attachment site of lipoic acid, an essential cofactor for enzyme activity. Current questions include the degree to which antibodies to PDH, and related enzymes, account for the mitochondrial reactivity defined by immunofluorescence or other procedures, the cell-surface expression of M2 autoantigens, and the significance of the occurrence of nonmitochondrial (such as centromeric) autoantibodies in PBC. The unknown T lymphocyte contribution to the autoimmune response in PBC may involve inducer and effector components. A postulated T-cell autoepitope may be presented, in association with MHC class I or class II molecules, on the surface of biliary epithelial cells. T cell lines from PBC livers removed during transplantation could provide data on the T-lymphocyte contribution to the pathogenesis of PBC.

Humans↗
PubMed1989

Lack of informative HLA restriction fragment length polymorphisms in autoimmune chronic active hepatitis.

Autoimmune chronic active hepatitis (CAH) is strongly associated with HLA-B8, DR3. Accordingly, DNA was isolated from 10 HLA-B8, DR3 control subjects and 11 patients with autoimmune CAH and analyzed for informative restriction fragment length polymorphisms using HLA-DQ beta and DR beta probes, and six enzymes, Hinc II, Bgl II, Bam HI, Rsa I, Taq I and Msp I. None of the polymorphic fragments demonstrable was discriminatory for autoimmune CAH. A genetic polymorphism in the HLA-B8, DR3 region predisposing to autoimmune CAH may not have been detecting owing to an insufficient number of probes or enzymes used, or alternatively HLA-DR3 is predisposing by an effect on immune regulation or suppression.

Adult↗
PubMed1989

Alpha 1-antitrypsin phenotypes in homosexual men.

The alpha 1-antitrypsin (AAT) phenotype was determined by isoelectric focusing in 215 male homosexuals and compared with those in 208 male heterosexuals. The incidence of abnormal phenotypes was 16.3% in the homosexual group which was significantly different (p less than 0.03) than the 8.7% in the heterosexual group. There was no difference in the phenotype distribution between homosexuals who were anti-human immunodeficiency virus reactive and those who were non-reactive. It suggests that investigation into the interplay of factors associated with homosexuality could include genetic as well as psychological and social factors.

HIV Seropositivity↗
PubMed1989

The association of the autoantigens of primary biliary cirrhosis with the mitochondrial H+-ATPase--a reassessment.

The claimed association between the M2 autoantigens of primary biliary cirrhosis (PBC) and the mitochondrial H+-ATPase has been re-examined in view of the recent reports that PBC autoantibodies react specifically with the lipoate acetyl transferases of 2-oxo acid dehydrogenases. Study of F0F1-ATPase purified from human and yeast mitochondria, and the comparison between immunoprecipitates obtained with antibodies against the H+-ATPase beta subunit and anti-M2 antibodies of PBC, established that the M2 antigens are not associated with the H+-ATPase complex. The M2 antigens did copurify with a crude bovine heart F1-ATPase preparation, but not with F1-ATPase from yeast, human heart or human liver.

Autoantigens↗
PubMed1988

High-affinity interleukin-2 receptors on blood lymphocytes are decreased during active rheumatoid arthritis.

The expression of receptors for interleukin-2 (IL-2R) was examined in patients with active or inactive rheumatoid arthritis (RA) and in control subjects. Unstimulated blood lymphocytes from patients with active RA had increased levels of total IL-2R, as measured by Tac-positive cells, compared with the levels found in the other 2 groups. Mitogen-stimulated cells from patients with active RA expressed less IL-2R per cell, but the most striking feature was the failure to express high-affinity IL-2R. These changes could reflect persistent antigenic stimulation and explain the defective cell-mediated immunity in RA patients.

Adult↗
PubMed1988

Interferons in rheumatoid arthritis: alterations in production and response related to disease activity.

Various markers associated with the production of and response to interferons (IFNs) were studied in patients with either inactive rheumatoid arthritis (RA) or active RA, and in healthy subjects. The IFN markers assessed were serum and synovial fluid (SF) levels, the activity in peripheral blood leukocytes (PBL) of (2'-5') oligoadenylate synthetase (OAS), and the production in vitro by PBL of IFN-alpha/beta in response to Sendai virus or Poly(I):Poly(C) as inducers, and of IFN-gamma using PHA or Con A as inducers. IFN activity, tested by antiviral assays using two different cell lines, was not demonstrable in the serum of any patient with RA. The activity of (2'-5') OAS in PBL, which may indirectly indicate exposure of leukocytes to IFN, was increased in RA compared with healthy subjects, more so in patients with inactive RA. The production of IFN-alpha/beta by PBL in response to Sendai virus was low in active RA but high in inactive RA, relative to production in healthy subjects. The production of IFN-gamma by PBL in RA was lower than in healthy subjects, more so in active RA. Thus inactive RA (remission status) is marked by evidence of PBL having been influenced by interferon and being a state of augmented inducibility to an IFN-alpha/beta stimulus, whereas active RA is associated with low inducibility of PBL to an IFN stimulus, but no evidence of IFN production in vivo. Our findings underscore the relevance of interferon to remission/activity in rheumatoid arthritis.

2',5'-Oligoadenylate Synthetase↗
PubMed1988

Premises for immune interventional therapy in rheumatoid arthritis.

Consideration of rheumatoid arthritis (RA) as an autoimmune disease includes initiating event(s), genetic predisposition, immune regulatory derangements, and effector cycles of articular damage. The initiating event is still unknown. Collagen type 2 has good claims as a rheumatogenic autoantigen which perpetuates disease. The association of HLA DR4 with rheumatoid arthritis is in part explainable by the affinity of binding of the rheumatogenic antigen to a hypervariable portion of MHC Class II molecules with selective presentation of this complex to T cell receptors. Immune regulatory derangements include lymphokine-induced aberrant expression of MHC Class II molecules on synovial tissues, the presence of a 'resistant' subset of B cells (CD5 + ve), failure of anti-idiotypic control of autoantibodies (not well established as yet in rheumatoid arthritis), and defective immune suppression, revealed by low counts in synovial fluids of a suppressor-inducer subset of CD4 + ve T cells. The many possibilities for therapeutic immune intervention would include polyclonal or monoclonal antibody to block (a) receptors for antigen on B or T lymphocytes (but this would require knowledge of the rheumatoid arthritis-inducing antigen), (b) the CD4 complex on helper T lymphocytes, (c) MHC Class II (Ia) molecules, for which there are excellent prototypes in experimental immunopathology, or (d) lymphokines or their receptors. Induction of suppression by 'tolerogenic vaccines' is experimentally validated, but only for diseases for which an autoantigen can be identified.

Arthritis, Rheumatoid↗
PubMed1988

Activated killer cell lymphoma: an erythrophagocytic syndrome simulating histiocytic medullary histiocytosis.

We report a detailed analysis of a lymphoma-induced erythrophagocytic syndrome mimicking histiocytic medullary reticulosis. Phenotypic analysis of cell surface molecules demonstrated a T cell-like phenotype. However, more extensive analysis showed that this phenotype was not typical of any element of the normal T cell lineage. The markers were consistent with a subset of natural killer cells, the lymphokine-activated killer (LAK) cell. The lymphoma cells, like normal LAK cells, were shown to be capable of non-specific cytotoxicity. Moreover, consistent with the reported regulatory effects of certain non-specific killer cells on hemopoiesis, the lymphoma cells were able to suppress in-vitro hemopoiesis, especially maturation of erythroid precursors, although a soluble factor could not be directly demonstrated. Both of these activities were blocked by a monoclonal antibody (9.IC3) which inhibits NK cell function. These findings imply that this tumour is a neoplastic counterpart of the cell identifiable in vitro as an LAK cell.

Antibodies, Monoclonal↗
PubMed1988

Characterization of a 95,000 molecule on sheep leucocytes homologous to murine Pgp-1 and human CD44.

The phagocyte glycoprotein-1 (Pgp-1) antigen of mice is a 94,000 MW molecule with a wide tissue distribution, but no attributed function. We produced a monoclonal antibody (mAb) termed 25-32 which recognizes the Pgp-1 molecule of numerous mammalian species, including humans and sheep. Preclearing experiments with I42/5, a rat anti-mouse Pgp-1 mAb that cross-reacts with human Pgp-1, established the specificity of 25-32 for human and sheep Pgp-1. Moreover, an antibody recognizing human CD44, termed F10-44-2, also reacted with the same molecule as that recognized by 25-32 and I42/5, so establishing the co-identity of CD44 and Pgp-1. Within the sheep thymus, Pgp-1 was expressed most strongly by medullary thymocytes and stromal cells, and by small numbers of cells at the subcapsular cortex. Pgp-1 was expressed early in thymic ontogeny; all 35-40-day gestation fetal sheep thymocytes were intensely Pgp-1+, but by 80 days the number of reactive thymocytes had decreased to adult levels. The expression of Pgp-1 on lymphocytes was markedly increased after stimulation with mitogens, or with phorbol esters and ionomycin. The highly conserved nature of Pgp-1 through evolution, its expression on virtually all cell types within the body, and its increased expression on rapidly dividing cells indicate that this molecule mediates an important function, possibly serving as a hormone or metabolite receptor.

Animals↗
PubMed1988

Plasma exchange in dermatomyositis/polymyositis: beneficial effects in three cases.

We describe ameliorative effects of plasmapheresis in three patients with dermatomyositis-polymyositis resistant to other therapy, particularly prednisolone. Serologically, the cases were marked, respectively, by a weakly-reactive speckled-type ANA; a strongly reactive speckled-type ANA and an unidentifiable precipitin line by CIEP; and an antibody to cytoplasm and to Jo1. The remission induced by plasmapheresis was temporary in one case and lasting, with low doses of prednisolone, in two. The nuclear autoantibody in case two became undemonstrable after plasmapheresis but recurred during a subsequent relapse. This experience with plasmapheresis in myositis supplements a substantial reported experience of benefit from this therapy.

Adult↗
PubMed1988

Interleukin 2 inhibitor in synovial fluid.

Since evidence for the presence of IL-2 activity in rheumatoid synovial fluid is conflicting, we have assayed IL-2 activity in synovial fluid from patients with rheumatoid arthritis (RA) and other articular diseases (OAD). Using the IL-2-dependent murine T cell line CTLL, IL-2 activity was not demonstrable in synovial fluid tested at concentrations ranging from 50% to 0.02%. There was an inhibitory effect on IL-2 activity in the bioassay of synovial fluid from 16 of the 22 patients with RA and 15 of the 16 with OAD. This inhibitory activity was heat-labile, precipitable by ammonium sulphate, reversible with excess IL-2 and was not significantly altered by preincubation of synovial fluid with CTLL. The mean inhibitory activity of synovial fluid from patients with RA was significantly reduced in comparison with that of synovial fluid from patients with OAD. Sera also had an inhibitory effect on IL-2 activity; however sera from patients with RA were less inhibitory than control sera but were more inhibitory than sera from patients with systemic lupus erythematosus. The deficiency in synovial fluid of an inhibitor of IL-2 activity may be relevant to the pathogenesis of RA.

Adult↗
PubMed1988

Murine monoclonal antibody to mitochondria reacts with the 72 kD antigen of primary biliary cirrhosis.

BALB/c mice were immunized with canine gastric mucosal cells enriched to 70% for parietal cells, to produce monoclonal antibodies (MoAb). Three MoAb, FMM-4C5, FMM-4C9 and FMM-2B2, were obtained which reacted by indirect immunofluorescence with gastric parietal cells and kidney tubules, predominantly distal kidney tubules, with a pattern similar to that of the M2 autoantibodies of primary biliary cirrhosis (PBC). The antibodies also reacted with tissues from rabbit, rat, pig, human and with rod-shaped structures in acetone-fixed monolayer cultures of human fibroblasts and HEp 2 cells. FMM-4C9 and FMM-2B2 reacted with tissues from BALB/c mice but FMM-4C5 did not. Immunoblots of FMM-4C5 with mitochondrial fractions showed that the antibody recognized a 63 kD antigen from dog stomach, rat kidney and rat liver, and a 72 kD antigen from human placenta; mouse preparations were not reactive. The antigen co-migrated with that recognized by serum from cases of PBC and some cases of progressive systemic sclerosis. Absorption of the mitochondrial fraction with PBC sera removed reactivity by immunoblotting with the murine autoantibody and vice versa. Two dimension immunoblots showed that the murine and human antibodies recognized an identical series of paired 'spots'. FMM-4C5 also reacted by immunoblotting with a rat recombinant mitochondrial polypeptide which has disease-specific reactivity with PBC sera. Absorption with recombinant polypeptide removed anti-mitochondrial activity by immunoblotting and immunofluorescence. These observations suggest that the MoAb FMM-4C5 recognizes part of the same 72 kD molecule recognized by human PBC sera. The murine monoclonal antibodies should be useful probes for further studies of the structure, function and possible pathogenicity of the 72 kD autoantigen.

Animals↗
PubMed1988

Collagen antibodies in juvenile arthritis and adult rheumatoid arthritis: differences in levels and type-specificity.

Antibodies to both native and denatured type II collagen were measured in the serum of 63 patients with juvenile onset arthritis (JA) and in 67 patients with adult onset rheumatoid arthritis (RA). Levels of antibodies in the 2 groups were compared with antibody levels in 30 healthy adult controls, and in 20 children with nonrheumatic diseases. Antibodies to denatured and native collagen were increased in RA but not in JA. There was no apparent difference between the collagen antibody levels in any of the 3 subgroups of JA, pauciarticular, polyarticular or systemic onset disease. Antibodies to denatured collagen were not type specific, and reacted similarly with type I and type II collagens, but antibodies to native collagen were much more specific, and most reacted more strongly on type II collagen than on type I collagen. Our results, unlike those in previous reports, imply that antibodies to collagen are infrequent in JA and hence cannot be implicated in the pathogenesis of that disease, which is in contrast to adult onset RA.

Adolescent↗