The autoimmune model of schizophrenia.

Schizophrenia is of mysterious causation. It is not infectious, not congenital, but shows familial aggregation, the Mendelian genetics indicating involvement of multiple codominant genes with incomplete penetrance. This is the pattern for autoimmune diseases, such as Graves' disease of the thyroid, where forbidden clones of B lymphocytes develop, and cause thyrotoxicosis by secreting autoantibodies that react with the thyroid gland's receptor for thyroid-stimulating hormone from the pituitary gland. In 1982, Knight postulated that autoantibodies affecting the function of neurons in the limbic region of the brain are a possible cause of schizophrenia. Today, this is even more probable, with genes predisposing to schizophrenia having being found to be immune response genes, one in the MHC and two for antibody light chain V genes. Immune response genes govern the immune repertoire, dictating the genetic risk of autoimmune diseases. The simplest test for an autoimmune basis of schizophrenia would be trial of immunosuppression with prednisone in acute cases. The urgent research need is to find the microbial trigger, as done by Ebringer for rheumatoid arthritis and for ankylosing spondylitis. This could lead to prophylaxis of schizophrenia by vaccination against the triggering microbe.

The great cholesterol myth; unfortunate consequences of Brown and Goldstein's mistake.

Following their Nobel Prize-winning discovery of the defective gene causing familial hypercholesterolaemia, Brown and Goldstein misunderstood the mechanism involved in the pathogenesis of the associated arterial disease. They ascribed this to an effect of the high levels of cholesterol circulating in the blood. In reality, the accelerated arterial damage is likely to be a consequence of more brittle arterial cell walls, as biochemists know cholesterol to be a component of them which modulates their fluidity, conferring flexibility and hence resistance to damage from the ordinary hydrodynamic blood forces. In the absence of efficient receptors for LDL cholesterol, cells will be unable to use this component adequately for the manufacture of normally resilient arterial cell walls, resulting in accelerated arteriosclerosis. Eating cholesterol is harmless, shown by its failure to produce vascular accidents in laboratory animals, but its avoidance causes human malnutrition from lack of fat-soluble vitamins, especially vitamin D.

Why the histocompatibility system exists and how transplant surgeons can xenograft without rejection.

The histocompatibility system is responsible for the rejection of allografts. The system exists to counter the explosive speed of viral replication by directing the defensive immune attack by cytotoxic T cells on to histocompatibility antigens on the infected cell's surface. This enables destruction of the virus factories before the cytotoxic T cells are swamped by the myriad numbers of new virions, a thousand coming from each infected cell every 10 h. The immunity system mistakes alloantigens for virus-infected host cells that need swift destruction. For transplantation, Sykes has improved Kaplan's technique by adding recipient bone marrow cells to the donor ones injected for reconstitution of the recipient after immune ablation. This technique should enable the use of xenografts from pigs.

Rationale for a trial of immunosuppressive therapy in acute schizophrenia.

Schizophrenia is a debilitating, costly, socially disruptive, life-threatening disease in which available treatments are largely palliative and empirical, and produce significant short- and long-term side effects. Therefore, a strong case can made for exploring alternative treatments with a rational basis for use in this disease. Considerable evidence indicates that autoimmune processes may be involved in some forms of schizophrenia, including altered risk of certain autoimmune diseases in patients and their relatives, shared epidemiological features, and apparent involvement of genes known to influence the immune response repertoire. Attempts to provide direct evidence for autoimmune processes have proven elusive, possibly due to the technical difficulty inherent in accessing autoantibodies with high affinity for brain cell-surface receptors. In view of this impasse, we argue for a well-designed trial in schizophrenia of immunosuppressive therapy, which is now the mainstay of therapy for many autoimmune diseases. Analysis of disease states in which immunosuppression has been effectively used over many decades provides guidelines necessary for a meaningful trial.

An informative case of Graves' disease with implications for schizophrenia.

The aetiology of schizophrenia and the other psychoses is not yet established. The Knight model, based on genetic and other evidence, proposes that schizophrenia is an autoimmune disease, caused by the development of forbidden clones of B lymphocytes that secrete autoantibodies that accidentally stimulate cell surface receptors on certain neurons, affecting the limbic system of the brain. An unusual defect in a Maori man with Graves' disease rendered him unresponsive to the usually effective antithyroid drugs, prompting his being treated with prednisone, a non-specific immunosuppressant agent. This was highly successful, reducing the blood level of the causative thyroid-stimulating autoantibodies with reduction of thyroid hormone levels and thyroid gland size. Unfortunately, high dosage prednisone can be used for only a month, because of steroid toxicity. A research pathway to effective therapy of receptor-mediated autoimmune diseases, which probably include the psychoses, is now apparent. It involves finding the autoantibodies, then cloning of their antigenic targets, as has been done for Graves' disease. This will provide knowledge of the peptide sequences necessary for constructing therapeutic agents for selectively destroying the pathogenic forbidden clones. Meanwhile, usage of short-term therapy with prednisone could be helpful in the management of schizophrenia and should be explored.

Principles of autoimmune disease: pathogenesis, genetics and specific immunotherapy.

The immunity system has the daunting task of producing lymphocyte clones able to react with any pathogenic microbe, new or old, to defend against infectious disease. It cannot do this without occasionally producing a forbidden clone, Burnet's apt name for the pathogenic lymphocyte clones that cause the autoimmune diseases by accidentally reacting with a host antigen instead of an antigen on an invading microbe. Unfortunately, Burnet's insight has been lost by immunologists, for four decades. V genes code for the specificity of receptors for antigen on B and T lymphocytes. They change by the DNA sequence copying errors (somatic mutations) that create new clones during the lymphocyte cell divisions that occur in an immune response to microbial infection. These mutations are necessary for achievement of the higher affinity, between a lymphocyte clone and the microbe, that enables recovery from infectious disease. H genes code for histocompatibility antigens, major, minor and HY. These are peptides, which, unlike V gene products, are invariant throughout life. H genes dictate the immune repertoire by constantly deleting any nascent lymphocyte clone reactive with them. This protects, with imperfect success, against autoimmune disease arising from the V gene changes that produce forbidden clones. Microbial triggers cause an autoimmune disease by initiating a cascade of clonal development that produces a forbidden clone by unlucky somatic mutations in lymphocyte V genes, exemplified by group A streptococci triggering rheumatic fever and measles triggering encephalomyelitis. Specific immunotherapy will come from finding and targeting forbidden clones.

Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo.

The mechanisms controlling neural stem cell proliferation are poorly understood. Here we demonstrate that the PTEN tumor suppressor plays an important role in regulating neural stem/progenitor cells in vivo and in vitro. Mice lacking PTEN exhibited enlarged, histoarchitecturally abnormal brains, which resulted from increased cell proliferation, decreased cell death, and enlarged cell size. Neurosphere cultures revealed a greater proliferation capacity for tripotent Pten-/- central nervous system stem/progenitor cells, which can be attributed, at least in part, to a shortened cell cycle. However, cell fate commitments of the progenitors were largely undisturbed. Our results suggest that PTEN negatively regulates neural stem cell proliferation.

HIV-1 actively replicates in naive CD4(+) T cells residing within human lymphoid tissues.

Although HIV-1 gene expression is detected in naive, resting T cells in vivo, such cells are resistant to productive infection in vitro. However, we found that the endogenous microenvironment of human lymphoid tissues supports de novo infection and depletion of this population. Cell cycle analysis and DNA labeling experiments established that these cells were definitively quiescent and thus infected de novo. Quantitation of the "burst size" within naive cells further demonstrated that these cells were productively infected and contributed to the local viral burden. These findings demonstrate that lymphoid tissues support active HIV-1 replication in resting, naive T cells. Moreover, these cells are not solely reservoirs of latent virus but are permissive hosts for viral replication that likely targets them for elimination.

Generation of HIV latency during thymopoiesis.

The use of combination antiretroviral therapy results in a substantial reduction in viremia, a rebound of CD4+ T cells and increased survival for HIV-infected individuals. However, this treatment does not result in the total eradication of HIV. Rather, the virus is thought to remain latent in a subset of cells, where it avoids elimination by the immune system. In this state the virus is capable of reactivation of productive infection following cessation of therapy. These latently infected cells are very few in number and it has thus been difficult to determine their origin and to study the molecular nature of the latent viral genome. HIV replication is linked to cellular gene transcription and requires target cell activation. Therefore, should an activated, infected cell become transcriptionally inactive prior to cytopathic effects, the viral genome might be maintained in a latent state. We used the SCID-hu (Thy/Liv) mouse model to establish that activation-inducible HIV can be generated at high frequency during thymopoiesis, a process where previously activated cells mature towards quiescence. Moreover, we showed that these cells can be exported into the periphery where the virus remains latent until T-cell receptor stimulation, indicating that the thymus might be a source of latent HIV in humans.

A mouse genetic locus with death clock and life clock features.

A senility syndrome, with weight loss and priapism, occurs in CBAT6/T6 mice, an exceptionally long-lived strain. Instead of dying at the expected time, these mice get senile weight loss and priapism and go on living. We have postulated that a mutant death clock kills the wrong neurons. Crosses with the NZW and C57BL/6 strains show causation by a single genetic locus (Priap1), with a pronounced gene dosage effect on timing. We report here that various cancers were the cause of death in 31 of 32 NZW mice, compared to only five of 22 CBAT6/T6 mice, a highly significant difference (P<0.001). The longevity of (CBAT6/T6xNZW)F1 hybrids, and the segregation of longevity with priapism and senile weight loss in (CBAT6/T6xNZW) F2 hybrids, indicates that Priap1, or a linked gene, inhibits the cancers that usually shorten the lives of NZW mice. If a timer gene is involved, the cancer resistance action could be because the locus impedes the normal mid-life regression of anti-cancer defence. The priapism suggests loss of the medullary reticular formation neurons which normally inhibit male spinal sexual reflexes. In this region of the medulla there are also the respiratory and cardiac control centres, where apoptotic neuron destruction by the wild-type locus could govern maximal life-span. The CBAT6/T6 locus may be a mutant life-stage control clock. Its discovery could be the revelation of a new, major class of aetiology of disease.

Generation of functional thymocytes in the human adult.

Reconstituting the immune response will be critical for the survival of HIV-infected individuals once viral load is brought under control. While the adult thymus was previously thought to be relatively inactive, new data suggest it may play a role in T cell reconstitution. We examined thymopoiesis in adults up to 56 years of age and found active T cell receptor (TCR) rearrangement, generating a diverse TCR Vbeta repertoire. The resulting thymocytes are functional and are capable of responding to costimulatory signals. These data demonstrate that the adult thymus remains active late in life and contributes functional T cells to the peripheral lymphoid pool.

A monogenic senility syndrome segregating with longevity in mice.

We have found that around 2 years of age all surviving CBA T6/T6 mice develop hyperactivity and progressive weight loss, terminating in death, which is preceded in the males by priapism, persistent penile erection. As there is no genital lesion, the priapism is presumably of neurogenic origin, providing an invaluably specific sign of development of a neurological lesion. A loss of neurons, somewhere in the brain stem, not detectable without computerised, automated microscopy, not yet applied, is at present the best explanation for the occurrence of the syndrome. In maternally-derived F2 hybrids with the NZW and C57 BL/6 strains, the syndrome occurs exactly as in the CBAs, with a frequency of 25%, indicative of mediation by a single gene or gene cluster. The syndrome also occurs in the F1 hybrids, but with a 34-week delay, suggesting a delaying effect of either a halved CBA gene dosage, or of non-CBA genes. In NZW F2 hybrids the syndrome segregates with longevity (P < 0.001). The phenomenon provides an animal model for study of mechanisms of ageing and their relationship to senile neuropathies, such as Alzheimer's disease.

Three theories which explain the occurrence and inheritance of the autoimmune diseases.

The immunity system uses random processes. In B lymphocytes these are antigen-driven somatic gene mutations which tighten antibody affinity for invading microbes to enable recovery from and prevention of infectious diseases. In T lymphocytes, randomized gene segment combinations continually provide new clones, needed to counter continually-changing microbial parasites. Because these B and T cell processes are random, they entail risk of producing forbidden (self-antigen-reactive) clones, a minority of which cause autoimmune diseases, as envisaged by Burnet in his forbidden clone theory. A corollary of the forbidden clone theory is the V gene theory, postulating that the specificities of the germline variable (V) genes coding for antigen receptors influence the risks of autoimmune diseases. The H gene theory, postulates that the main defense against autoimmune disease is mediated by the permanent, unbreakable tolerances imposed on the clonal repertoire by the histocompatibility (H) antigens, major, minor and H-Y. Recent work shows that the last two act as peptides which modify MHC antigens by occupying their Bjorkman grooves. The absolute absence of autoimmunity to histocompatibility, ABO and H-Y antigens shows that nascent clones with high affinity for these white cell antigens are continually eliminated. Application of molecular biological techniques has shown that H antigen tolerance impositions profoundly alter the clonal repertoire and hence the risks of development of the forbidden clones which cause the autoimmune diseases. Precise basic theory is crucially important for effective application of molecular biology and microbiology to the eminently achievable therapeutic and prophylactic conquest of the ubiquitous autoimmune diseases.

A computer interface for psychophysical and speech research with the Nucleus cochlear implant.

A computer interface has been designed and implemented that allows presentation of biphasic pulse stimuli to patients with the Nucleus Ltd./Cochlear Corporation cochlear implant. The one version of the interface connects to a standard parallel output port of a PC or AT compatible computer, and another version plugs directly into a standard PC/XT bus slot. The host computer sends a stream of bytes to the parallel port that specifies the configuration of the desired output pulses. Upon receipt of the data, the interface generates the appropriate burst sequence that is delivered to the patient's external transmitter coil. The coded information is interpreted by the internal receiver that delivers the pulse to the specified electrodes at the specified amplitude and pulse width. This interface makes it possible to interleave pulses on two or more electrode pairs, to modulate the amplitude or timing of a pulse sequence, or to sweep a stimulus across the electrode array. Investigators can achieve stimulus control with this interface that allows them to conduct psychophysical, electrophysiological, and speech experiments not possible through the patient's speech processor or with available clinical interfaces.

Genetic evidence favouring cytotoxic T cell forbidden clones as the cause of insulin-dependent diabetes mellitus.

Recent evidence indicates that immunoglobulin light chain variable region genes are genetic determinants for Graves' disease, which is caused by autoantibodies which stimulate the thyroid gland. We have tested whether germline immunoglobulin kappa light chain variable region (V kappa) genes contribute to the genetic predisposition for IDDM. Status for the kappa light chain constant region (C kappa) allotype, Km(1), was determined in members of suitable multiplex IDDM families. Such families had two or more siblings with IDDM, together with one parent negative for Km(1) and the other heterozygous, so that each sibling had a 50% chance of receiving the kappa light chain marker. Twenty-one families of this type were found. Of the siblings, disregarding disease status, 31 were concordant with the diabetic proband for Km(1) and 29 were discordant, this close approximation to equality confirming the validity of the methodology. Of the diabetic siblings of the probands, 14 were concordant and 15 discordant. Of the non-diabetic siblings, 17 were concordant and 14 discordant. This similarity shows that V kappa genes, which are closely linked to C kappa genes, are not genetic determinants for IDDM. The contrast with Graves' disease favours the possibility that the islet beta cell destruction of IDDM is mediated by forbidden clones of cytotoxic T cells, rather than of B cells.

Studies on the enzymes of Sarcocystis suicanis: purification and characterization of an acid phosphatase.

Percoll density gradient centrifugation was used for isolating large quantities of bradyzoites of Sarcocystis suicanis, which were used for enzymatic analysis. Crude extracts of bradyzoites contained activities suggestive of several acid hydrolases. Levels of acid and alkaline phosphatase were higher than those of beta-N-acetylhexosaminidase and beta-galactosidase. Acid phosphatase was purified 156-fold with an overall recovery of 54% using DEAE-Sepharose 4B and Sephadex G-200 chromatography. The partially purified enzyme was not a glycoprotein and had a molecular weight of approximately 170,000. The enzyme was markedly inhibited by Cu++, Hg++, and iodoacetamide, suggesting the presence of a sulfhydryl group. Sodium tartrate caused strong inhibition of the enzyme. The acid phosphatase of S. suicanis appears to be a unique enzyme that cannot be classified under high or low molecular weight acid phosphatases of widely diverse origin.

Protection from autoimmune disease as the third function of the major histocompatibility gene complex.

The collection of genes known as the major histocompatibility gene complex (MHC) appears to subserve three functions. Firstly, its class I genes, coding for antigens on all nucleated cells, assist clones of cytotoxic T cells to kill virus-infected cells quickly, without being muffled by the myriad numbers of free virus particles. Secondly, the absence of autoimmunity to both class I and class II MHC antigens shows that they impose unbreakable tolerances on the immune repertoire. The class II antigens, which are confined to B lymphocytes (if their apparent occurrence on other dividing cells is a cross-reaction), may have the sole function of tolerance induction, supplementing this activity of the class I antigens. Both sets of MHC antigens serve to diversify immunity-repertoire gaps among individuals of a population, thus hampering epidemic spread of infection and providing a diversity of immunoreactivity that favours survival of at least some members of a population in the face of pestilence. Thirdly, the permanence of the MHC tolerance inductions affords a powerful, adaptable mechanism for curtailment of reproductively disadvantageous autoimmune disease liable to arise through somatic mutations in lymphocytes multiplying under drive from a microbial antigenic stimulus.