Robert H. Kelly

Clinical and Laboratory Evidence of Autoimmunity in Acute Schizophrenia

A number of assays were performed to assess immunologic function in 28 patients with clinically well-defined schizophrenia. Our data provide laboratory evidence that patients with schizophrenia have characteristics consistent with an autoimmune process, directed to components of the brain, which may participate in either the pathogenesis or etiology of schizophrenia. One-third of our patients had a clinically evident autoimmune syndrome unrelated to their psychiatric illness. Of the nine patients with an autoimmune disease, two had one autoantibody in their serum and five had more than one autoantibodies. Twelve of eighteen patients without clinical evidence of autoimmune disease had no detectable autoantibodies. Mitogenic responses to PHA and PWM were significantly reduced in the patient population when compared to controls. Fifty percent of the patients had an increased percentage (greater than 5%) of blood-borne HLA-DR (+) OKT4 (+) T-helper lymphocytes. Immune reactivity toward brain antigens was sought by measuring lymphocyte transformation to a saline extract of frontal lobe, and by immunoblotting of antigens extracted from frontal lobe, cingulate gyrus, interventricular septum, and hippocampus. Lymphocyte transformation did not reveal differences between patient and control groups. Normal sera were found to contain antibody to some of these brain antigens. However, patients with schizophrenia had antibody to antigens of the hippocampus, septal region and cingulate gyrus which were not encountered during analysis of normal sera.

Sources of Error in Use of Beta-2 Transferrin Analysis for Diagnosing Perilymphatic and Cerebral Spinal Fluid Leaks

Beta-2 Transferrin Is A Protein Found In Cerebral Spinal Fluid And Inner Ear Perilymph, But Not In Blood, Nasal, Or Ear Secretions. The Clinical Use Of This Test Has Been Previously Demonstrated, But Sources Of Test Error Have Not Been Addressed. The Purpose Of This Study Was To Evaluate Sources Of Error Related To This Test In Order To Improve Its Clinical Use. We Reviewed The Specimens Submitted For Beta-2 Analysis Over The First 12 Months Of Test Availability At Our Institution To Identify Potential Factors Leading To Test Error. Sources Of Error Were Categorized Into The Following Groups: Sample Collection, Delivery, And Extraction Factors; Assay Factors; Physician-Related Factors; And Patient-Related Factors. The Test For Beta-2 Transferrin Is A Valuable Diagnostic Tool For The Management Of Difficult Clinical Problems, Provided The Physician Is Aware Of Potential Factors That Can Lead To Test Error And Clinical Mismanagement.

Antibody to discrete areas of the brain in normal individuals and patients with schizophrenia

Autoimmune syndromes are frequently associated with the presence of serum antibodies that bind to autoantigens of the involved tissue (Botazzo et al. 1974). Reports of antibrain antibody in patients with schizophrenia have produced conflicting results (Kuznetsova and Semenov 196 1; Fessel 1963; Rubin 1965; Heath and Krupp 1967; Whittingham et al. 1968; Logan and Deodhar 1970; DeLisi et al. 1985; Pandey et al. 1981). In the work reported here, an enzymelinked immunoabsorbent assay (ELISA) was used, with antigen extracted from discrete areas of the brain, to look for serum autoantibodies in patients with schizophrenia.

Cerebrospinal fluid immune complexes in systemic lupus erythematosus involving the central nervous system

C ENTRAL nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is a commonly encountered situation in which diagnostic certainty is lacking.‘,’ The clinical manifestations are diverse, ranging from mild affective disorders to profound encephalopathy, transverse myelopathy, and stroke.3’4 Other conditions capable of causing neuropsychiatric disease, such as hypertension and corticosteroidinduced mental syndromes, frequently coexist in patients with SLE. Furthermore, no laboratory test has been reported that is both sensitive and specific in establishing the diagnosis of CNS lupus.*~5~’ Immunoglobulin abnormalities of cerebrospinal fluid (CSF) are found in several neurologic diseases where immune mechanisms are thought to be involved in pathogenesis.‘-” Recent advances in the technology of zone electrophoresis, particularly the adoption of agarose gel as a separation medium,” have led to the description of specific qualitative immunoglobulin abnormalities, including oligoclonal patterns (i.e., two or more homogeneous restricted bands of protein, each representing intact immunoglobulin secreted by individual clones of phlsma cells)‘2m’4 and more recently, identification of immune complexes.‘5 The present study applied this method to the search for immunoglobulins and immune complexes in the CSF tif patients with systemic lupus erythematosus involving the central nervous system.

β2-Transferrin Confirms Perilymphatic Fistula in Children

β2-Transferrin is a protein that is unique to the cerebrospinal fluid and aqueous humor. on the basis of this Information and a recent study from our Institution that demonstrated that β2-transferrin was also unique to human perilymph, a prospective, double-blind study to evaluate perilymphatic fistula in children was performed. Attending otolaryngologists at Childrens Hospital of Pittsburgh evaluated and recommended surgery for 10 children (10 ears) who were suspected of having a congenital perilymphatic fistula. During the operation, the surgeon decided whether a perilymphatic fistula existed, on the basis of otomicroscopic findings, and then separate pieces of gelatin sponge were placed on the oval and round windows, respectively, and sent to the immunopathology laboratory where they were analyzed for β2-transferrin. Ten patients (10 ears) undergoing tympanoplasty or tympanomastoidectomy were used as controls and tested in a similar fashion. During the study, both the surgeons and patients were blinded from the results of the test. of the 10 control patients, none was observed to have a perilymphatic fistula, and all were negative for β2-transferrin. of the 10 patients undergoing exploratory tympanotomy for perilymphatic fistula, 1 ear was thought to be negative for perilymphatic fistula on microscopic visual examination, whereas 9 were considered to be positive for perilymphatic fistula. No β2-transferrin was identified from the ear that was considered not to have a perilymphatic fistula, whereas six of the nine ears that were thought to have perilymphatic fistula tested positive for β2-transferrin. β2-Transferrin, an objective test for perilymphatic fistula, agreed with the microscopic visual determinations in 66.7% of ears noted to have a perilymphatic fistula. This study confirms the existence of congenital perilymphatic fistula in children. Further investigation is needed to determine the true sensitivity and specificity of this new laboratory test for perilymphatic fistula.

Lash’s: A bitter medicine: Biochemical analysis of an historical proprietary medicine

Patent medicines were widely used during the late 1800s and early 1900s. Bitters were one important subtype of patent medicines that were typically made from extracts of bitter tasting herbs. Lash’s Bitters was a popular patent medicine that was advertised as an extract of the bark of the buckthorn tree, Rhamnus purshiana, and was sold as a laxative. Analysis of the contents of an undisturbed bottle of Lashs Bitters, ca. 1918, revealed an ethanol content of 19.2% by volume as well as trace amounts of methanol. Potentially toxic concentrations of lead, 295 mg/dl, were also found. Interestingly, the medicine contained none of the active ingredient found in Rhamnus purshiana.

Anti-Estrogen Antibodies in Systemic Lupus Erythematosus: A Quantitative Evaluation of Serum Levels

We measured the beta-estradiol binding capacity of serum gamma-globulins in four subject groups; 1) normal men, 2) normal women who had never taken oral contraceptives, 3) normal women who had a history of oral contraceptive use and, 4) patients with systemic lupus erythematosus (SLE). We used dextran-coated charcoal to strip endogenous estradiol from serum proteins, added 3H-estradiol, and measured its association with proteins in various electrophoretic fractions following zone separation on agarose gels. Most of the bound radioactivity was present in the albumin, beta and gamma-globulin fractions. Binding to gamma-globulins was elevated in SLE patients, and normal controls who had taken oral contraceptives, as opposed to other controls (p less than 0.005). Gamma-region radioactivity could be removed by protein-G adsorption prior to zone electrophoresis. Isoelectric focusing revealed a pattern of tritiated-E2 binding consistent with polyclonal B-cell activation in all groups. There was no correlation between the extent of gamma-region binding and the total serum immunoglobulin level for any of the groups studied, nor was there a correlation between E2 binding and anti-DNA titers in the SLE group. The average anti-estradiol antibody concentrations in SLE sera (assuming equimolar binding) was 105 ng/ml (95% CL = 92-118), whereas their average anti-DNA antibody concentration was in the microgram/ml range. Thus, quantitatively, the level of anti-estradiol antibodies is at least an order of magnitude lower than the anti-DNA antibodies characteristic of this disease.

CSF α2-macroglobulin and C-reactive protein as aids to rapid diagnosis of acute bacterial meningitis

alpha 2-Macroglobulin (AMG) and C-reactive protein (CRP) levels in cerebrospinal fluid (CSF) of patients with bacterial and aseptic meningitis have been analyzed by a rate nephelometric method to determine if these acute phase proteins can aid in differentiation of bacterial from aseptic meningitis. The mean CSF concentrations of AMG and CRP were 15 and 3.5 times greater, respectively, in the bacterial compared to the aseptic meningitis group. Also, the range of AMG levels showed minimal overlap between the two groups. The elevated levels of the proteins persisted after CSF cultures became negative. Quantitation of specific acute phase proteins in CSF may assist the differentiation of bacterial from aseptic meningitis.

Early Recipient-Donor Switch of the Complement Type after Liver Xenotransplantation

Liver transplantation is an immunological peculiarity with respect to the resistance of the graft to humoral rejection. We undertook a kinetic analysis of molecules involved in humoral rejection for a period of one week following xenografting in the hamster to rat model system. A complement-dependent lymphocytotoxicity test (CDC) was used to detect anti-donor antibodies in the recipient rats. Complement was studied by two methods. Function of the classical complement pathway was evaluated with a hemolytic assay, and C3 was measured by radial immunodiffusion. Conversion of the major plasma proteins from recipient to donor profile was studied by zone electrophoresis on agarose. CDC showed antibody titers rose during the first week post-transplantation, and they were of complement-activating isotypes. Zone electrophoresis showed almost complete replacement of rat C3 by hamster C3 within 72 hours. Hemolytic assay of complement on day 6 post-transplant showed serum of the xenograft recipients could lyse erythrocytes sensitized with rat antibody with 80% of efficiency of normal rat serum. Our data show the effector molecules for humoral rejection, rat antibodies with anti-hamster specificity and a functional complement cascade, were present within the first week following transplantation. Rapid conversion of serum complement to hamster proteins maintains compatibility with the species-specific membrane inhibitors of complement activation expressed by the xenografted hepatocytes, and could limit complement-mediated damage.

Functional cooperation of xenoproteins after hamster-to-rat liver transplantation: With particular reference to hamster C3 and secretory component for rat IgA

Abstract: Long‐term survival after hamster‐to‐rat liver xenotransplantation has provided the opportunity to study the posttransplantation source of major serum proteins and the functional consequences of several different receptor‐ligand interactions, where one or the other is a xenogeneic protein. We report here that serum albumin, α‐1‐antitrypsin, complement component 3, and other acute phase reactants switch from recipient to donor origin during the first week after transplantation while serum immunoglobulins remain largely that of recipient. Despite the disparate source of complement (hamster) and immunoglobulins (rat), these two proteins were able to cooperate effectively to produce lysis of sheep red blood cells. Moreover, rat IgA was successfully processed by hamster hepatocytes and biliary epithelial cells, being present in the bile of successful liver xenograft recipients within one day after transplantation. The ability of these liver xenograft recipients to survive long‐term in conventional and viral‐free animal facilities without grossly obvious morbidity or unusual susceptibility to stress, suggests that xenogeneic proteins are able to successfully interact with several different physiologic I systems in the hamster‐to‐rat combination.