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Biomedical subjects

J G Knight

Publications and source records attributed to J G Knight.

At least 19 recordsLinked to original sources
PubMed1990

Autoantibodies against brain septal region antigens specific to unmedicated schizophrenia?

Health et al. (1989) reported that serum from 96% of unmedicated schizophrenic patients contained IgG autoantibodies specific for the septal region of rhesus monkey brain, compared with 0% of nonschizophrenic control subjects and 6% of schizophrenic patients who were on neuroleptic medication. Using the same technique of crossed immunoelectrophoresis, we have tried to replicate this finding. In contrast to the original report, we observed "positive" precipitin arcs with IgG concentrates from all 14 serum samples tested. The failure of immunoelectrophoretic methods to provide convincing evidence of pathogenic autoantibodies in schizophrenia in no way detracts from the hypothesis that autoimmune processes are involved in some forms of schizophrenia. Such methods have not proved useful in established autoimmune diseases such as Graves' disease and myasthenia gravis in which the pathogenic autoantibodies against cell-surface receptors can only be detected by assays which measure functional interactions with such receptors.

Adolescent↗
PubMed1989

Influenza viruses induce autoantibodies to a brain-specific 37-kDa protein in rabbit.

Immunization of rabbits with certain H1N1 influenza viruses, including the neurotropic strains NWS/33 and WSN/33 and the New Jersey/76 strain, resulted in the production of autoantibodies to a brain-specific protein of 37 kDa that is present in various species, including humans. Autoantibodies were produced to brain only; various other tissues tested were negative. These antibodies were not elicited by other influenza A or B viruses, including closely related recombinant strains, but were elicited by the isolated hemagglutinin of A/Bellamy/42 strain and by formaldehyde-fixed WSN virus--demonstrating that infection was not essential for the induction of autoantibodies. In histological studies, reaction with anti-viral antisera was specific to gray matter and was confined to sera that recognized the 37-kDa protein. Antibody binding was prominent in regions comprised of neuronal cell bodies in cellular layers of the dentate gyrus, hippocampus, cerebral cortex, and cerebellum and was undetectable in myelin-rich regions, such as the corpus callosum. The 37-kDa protein, therefore, appears to be a neuronal antigen. Antibodies directed against this protein may be involved in the pathogenesis of one or more of the neuropsychiatric disorders that occur after infection with influenza.

Animals↗
PubMed1988

Scenarios for a viral etiology of schizophrenia.

Recent discoveries in the field of virus receptors have revolutionized our concepts of viral pathogenesis. The lysis of cells resulting from virus infection or immune recognition of infected cells is seen as merely one facet of a spectrum of pathogenic mechanisms which may be subtle and complex. This is particularly relevant to the central nervous and immune systems which share cell-surface receptors for various neuropeptides and neurotransmitters. A number of viruses are now known to share receptors for such endogenous ligands; indeed, some viruses (e.g., human immunodeficiency virus and vaccinia) may themselves be structural analogs of these ligands. There is, therefore, considerable scope for interference by viruses in the normal functioning of the brain and neuroendocrine systems. Brief reactive psychoses are occasionally reported as acute sequels to viral infections, but generally these are regarded as unrelated to schizophrenia. An opposite viewpoint is presented in the article: i.e., that the only reason these reactive psychoses do not progress to schizophrenia is that the majority of individuals affected are not predisposed genetically to schizophrenia. Conceivably, therefore, the genetic predisposition to schizophrenia may be attributable to genes which determine idiosyncratic differences in immune responsiveness to common viral pathogens.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Autoantibodies to acetylcholine receptor in myasthenia gravis: light chains.

We studied the light chain type of autoantibodies to acetylcholine receptor (AChR) by affinity chromatography with monoclonal anti-kappa and anti-lambda antibodies. The autoantibodies in four of eight myasthenic patients were of a single light chain type; the others comprised both types. In Graves' disease and cold-reactive hemolytic anemia, the pathogenic autoantibodies are confined to a single light chain type in individual patients, and in other diseases, doubtfully pathogenic autoantibodies are invariably mixtures of both light chain types. AChR antibodies may comprise both pathogenic and nonpathogenic types of autoantibody.

Aged↗
PubMed1984

A solution to the genetic and environmental puzzles of insulin-dependent diabetes mellitus.

Studies of the segregation of heterozygous immunoglobulin allotypes in families with several cases of insulin-dependent diabetes mellitus (IDDM) show that germline heavy-chain V (variable region) genes are not major genetic determinants for IDDM, but data for IDDM and Graves' disease together suggest involvement of kappa light-chain V genes. Absence of IDDM at birth, the semi-random age of onset, and the 50% discordance of identical twins suggest that somatic mutation of germline V genes is involved in the development of the pathogenetic anti-beta-cell clones. The effect of histocompatibility and other alloantigens on the prevalence of IDDM is readily accounted for by the effect of the "holes" they induce, by natural tolerance, in the immune response repertoire; these alterations apparently affect the chance of emergence of anti-beta-cell clones by the somatic mutations and network of interclonal deletions that constantly change the fringes of the repertoire. Histocompatibility antigens can also influence repertoire development by changing the specificity of conjoint presentation of foreign antigens by macrophages. Antigenic stimulation by particular environmental microorganisms is probably essential to the repertoire development necessary for the occurrence of IDDM. Additionally, beta-cell damage by local infection may play a part by facilitating autoantigen presentation to the immune system.

Antigens, Viral↗
PubMed1984

Is schizophrenia an autoimmune disease? A review.

Autoimmunity has been shown to be the basis of an ever-increasing number of human diseases. Schizophrenia shares a number of genetic features with these autoimmune diseases and therefore could be an autoimmune disease itself. Several lines of evidence suggest that overactivity of dopaminergic pathways in some areas of the brain are involved in schizophrenia, but the apparent absence of an increase in dopamine turnover suggests that this hyperactivity could be mediated by a dopamine agonist rather than by dopamine itself. Schizophrenia is reviewed in the light of precedents from the field of autoimmune diseases in which autoantibodies have been shown to be able to interact with, and sometimes stimulate hormone receptors, thereby causing disease.

Arthritis, Rheumatoid↗
PubMed1982

Dopamine-receptor-stimulating autoantibodies: a possible cause of schizophrenia.

Schizophrenia shares several genetic features with diseases known to be autoimmune and could therefore be an autoimmune disease itself. Antipsychotic drugs, which are effective in treating the psychotic symptoms of schizophrenia, have one property in common--they block dopamine receptors in the central nervous system. This observation has led to the hypothesis that overactivity of dopaminergic pathways is the cause of the psychotic symptoms, but a seeming anomaly is that the turnover of dopamine is not increased in schizophrenia. Dopamine-receptor-stimulating autoantibodies are postulated to cause the dopaminergic hyperactivity, thereby accounting for the anomaly.

Amphetamine↗
PubMed1982

The genetic basis of autoimmune disease.

The genetic predisposition to autoimmune disease in man is largely specific for each disease, indicating that these diseases are based not on a generalized breakdown of a tolerance mechanism, but on highly specific abnormalities of immune responsiveness which are subject to genetic transmission. In the presence of particular antigens encoded in the major histocompatibility complex (MHC) the relative risk of certain autoimmune diseases is increased, or in some cases decreased, and the increased risk has been widely attributed to linkage disequilibrium with unidentified disease-causing genes. Our studies on the inheritance of spontaneous autoimmune diseases in New Zealand mice have revealed that small numbers of dominant genes, some associated with the MHC but the remainder elsewhere in the genome, determine susceptibility to these diseases. That MHC-linked genes are not of paramount importance casts doubt on the linkage disequilibrium hypothesis. An alternative possibility is that major and minor histocompatibility antigens themselves predispose to the development of autoimmune diseases by altering the immune response repertoire through the effect of their clonal deletions on the network of paratope-idiotope clonal interactions. Such alterations could influence the chances of emergence, by somatic mutation, of pathogenic forbidden clones.

Anemia, Hemolytic↗
PubMed1980

H gene theory of inherited autoimmune disease.

Autoimmune disease in inbred mice is probably determined by co-dominant genes associated with both the major and minor histocompatibility loci. It is postulated that the genes involved are histocompatibility-antigen (H) genes themselves, which delete complementary clones in fetal life, in accord with Burnet's theory of clonal selection. Such deletions cause perturbations in the paratope-idiotope network reactions envisaged by Jerne. As well as having negative effects on immune-response capacity, the perturbations have positive effects, because the deletion of clones with specificity for the idiotopes of other clones permists immune responses which would otherwise be absent. Such perturbations can influence the chance of emergence of a forbidden clone by somatic mutations occurring in the V genes of dividing immunocytes and so can provide a genetic predisposition to autoimmune disease.

Animals↗
PubMed1978

Three genes for lupus nephritis in NZB x NZW mice.

The occurrence of early severe lupus nephritis in (NZB x NZW)F1 mice must depend on the action of at least two dominant or codominant genes (at least one gene from each parent) as neither of the inbred parental strains shows the disorder. Identifying affected animals by antemortem determinations of renal function, we have studied the incidence of the renal disease in 230 (NZB x NZW) x NZW backcross mice (an earlier study) and, in this study, in 150 (NZB x NZW) x NZB backcross mice. The data indicate that the NZB strain contributes only one gene and the NZW strain contributes two genes, or clusters of closely linked genes, to the renal disorder of the F1 hybrid. One of the NZW genes was found to be linked to the H-2 complex. All three genes must be dominant or codominant, as their effect is expressed in the heterozygous state.

Animals↗
PubMed1977

The genetic contribution of the NZB mouse to the renal disease of the NZB x NZW hybrid.

The occurrence of lupus nephritis in (NZB x NZW)F1 mice appears to depend on the action of at least two dominant or co-dominant genes (at least one gene from each parent) as neither of the inbred parental strains shows the disorder. Identifying affected animals by antemortem determinations of renal function, using improved methods of measuring proteinuria and renal clearance, we have studied the incidence of the renal disease in 230 (NZB x NZW)F1 x NZW backcross mice. The incidence was 49-6% which indicates that NZB strain contributes only one gene, or cluster of closely linked genes, to the renal disorder of the F1 hybrid. The gene(s) must be dominant or co-dominant, as it expresses its effect in the heterozygous state. Study of the H-2 status of the backcross mice showed a loose linkage of the NZB renal disease gene(s) to the D end of the H-2 complex, the crossover frequency being 32-6+/-3-1%.

Aging↗
PubMed1976

Histocompatibility antigens in Graves' disease.

Histocompatibility antigen typing was undertaken in 100 Caucasian patients with Graves' disease (autoimmune thyrotoxicosis) and in 100 healthy Caucasian blood donors. Standard lymphocyte microcytotoxicity methods were used to tests for the presence of 22 HL-A antigens in all subjects. There was a significant difference between the groups in respect of the HL-A 8 antigen which was present in 40 patients and in 25 controls (P less than 0-0023). There was no significant difference between the patients and controls with respect to the frequency of occurrence of any of the other HL-A antigens tested.

Adult↗
PubMedDate not supplied

On the nature of the genes influencing the prevalence of Graves' disease.

Burnet's theory that Graves' and other autoimmune diseases are caused by forbidden clones of immunocytes, reactive against host antigens and emerging in post-natal life due to somatic events (somatic mutations of V genes and inter-clonal deletions), remains the most comprehensive and likely concept of the pathogenesis. The MHC antigens, B8 and D/DR3, have a predisposing influence of X 2.5 and X 3.7 respectively, whilst male sex has a protective influence, divided by 6. Family studies testing for associated inheritance of Graves' disease and immunoglobulin allotypes (Gm and Km), by observation of the segregation of known heterozygous allotypes and also by Penrose's sibling pair method, have failed to show involvement of immunoglobulin genes. The H gene theory, prompted by studies on the inheritance of autoimmune diseases in the New Zealand mice, postulates that germline genes influencing the prevalence of Graves' and other autoimmune diseases code for major and minor histocompatibility or other alloantigens. By deleting complementary clones, alloantigens alter the immune response repertoire of each individual and this could alter the chance of emergence of a forbidden clone by the somatic mutations and the inter-clonal deletions envisaged by Burnet and Jerne. The H gene theory is superior to the linkage disequilibrium theory in that it accounts for all the known genetic features of Graves' disease, including the female sex preponderance, which is ascribed to the effect of clonal deletions imposed by the H-Y antigen.

Animals↗