Duncan D. Adams

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.

How the immune system works and why it causes autoimmune diseases.

Abstract The immune system has evolved to defend the host against infectious disease. Here, Duncan Adams outlines the historic developments that have led to our current understanding of how the immune system works, why it causes autoimmune diseases and how these could be cured or prevented.

Graves’ Disease a Paradigm For Autoimmunity

The presence of iodine atoms in thyroid hormone has proved to be fortunate for man in enabling him to understand great principles of the diseases which plague him. Dietary deficiency of iodine, leading to spectacular goitres, drew attention to the thyroid and the success of surgeons in extirpating goitres founded the study of endocrinology by showing that the thyroid secretes a product which is necessary for health and readily available from simple preparations of animal tissue 1.

Autoimmune destruction of pericytes as the cause of diabetic retinopathy

In diabetic retinopathy, collapse of the retinal vasculature is associated with loss of the pericytes. These are contractile cells that together with endothelial cells form the terminal arterioles of the retina. The cause of the loss of pericytes is not known. Recently, it has been discovered that type 1 diabetes is caused by forbidden clones of cytotoxic T lymphocytes, which destroy the insulin-making cells with exquisite specificity. In the light of this, I postulate that an antigenically-related forbidden clone of cytotoxic T lymphocytes selectively destroys the pericytes and that this is the cause of the vascular collapse of diabetic retinopathy. If this is so, the therapeutic implications are immense, involving a switch from ineffectual tight glycemic control to immunotherapy. This is already used as immunosuppression to prevent organ transplant rejection, and as the immune ablation and autologous bone marrow cell reconstitution that has saved the lives of patients with lethally-severe scleroderma. Once the pericyte surface auto-antigen for the T lymphocytes has been isolated, selective destruction of the pathogenic T lymphocytes would be possible by manufacture and use of cytotoxic auto-antigen complexes, which arrests progression of the retinopathy.

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.

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.

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 Alzheimers disease.