Schizophrenic psychoses and HLA antigens. Personal data and review of the literature

Genetic factors play probably an important part in the development of schizophrenic psychoses. As a consequence the use of a genetic marker as the HLA system appears to be interesting in determining the disease susceptibility gene of these psychoses. Methods and results of an investigation about the frequencies of 33 HLA alleles observed in 51 patients considered as paranoid schizophrenics are presented. The frequency of HLA-A 29 was diminished while the one of HLA-B 15 was increased but the differences were no longer significant when p was corrected. However when all the results published from 1974 to 1980 were pooled in a combined statistical analysis, some associations became significant. It seems that schizophrenia as a whole, once paranoid and hebephrenic sub-types have to be distinguished. It may be concluded from these data that correlations between schizophrenia and HLA antigens which remain doubtful could be explained with a biological genetic heterogeneity of schizophrenic disorders. Review of literature concerning the identification of HLA haplotypes in schizophrenics pedigrees and about the HLA system as a genetic marker for the clinical response to neuroleptics in schizophrenic patients or in vitro, is also discussed.     

Guillain-Barré and Fisher's syndromes subsequent to Campylobacter jejuni enteritis are associated with HLA-B54 and Cw1 independent of anti-ganglioside antibodies

The frequencies of human leukocyte antigens (HLA)-class I (A, B and Cw) were determined serologically and those of HLA-class II (DRB1 and DQB1) at the genomic level in 35 Japanese patients with Guillain-Barré syndrome (GBS), 58 with Fisher's syndrome (FS), and 112 healthy controls. HLA-B54 and -Cw1 antigens were found in GBS and FS patients from whom Campylobacter jejuni had been isolated more often than found in the healthy controls. No HLA types were related to GBS or FS as a whole, except for the B54 antigen which often was significant in the entire GBS group. This relation, however, may depend on the high population of C. jejuni-isolate patients in our GBS group. There were no relationships between the frequencies of HLA types and the presence of serum IgG antibodies to GM1, GQ1b, GD1a, or GalNAc-GD1a. Our findings suggest that HLA types are associated with the onset of GBS and FS after C. jejuni enteritis and that the HLA types in distinct GBS and FS subgroups of a single etiological origin need to be examined.     

The HLA system and diabetes mellitus

There is a significant positive association between insulin dependent diabetes, irrespective of age of onset, and the HLA system, whereas there is no association of HLA antigens with non-insulin dependent diabetes. There is a significant concordance value for HLA antigen frequencies in insulin dependent diabetics from three different centres, indicating that the genes (s) conferring susceptibility to this type of diabetes is possibly present in all "juvenile-onset" diabetics and is in linkage disequilibrium with all the B locus alleles.     

The etiologic heterogeneity of schizophrenia

Evidence is increasing in support of the etiologic heterogeneity of schizophrenia. Five distinct diseases/disorders are suggested in this paper, and the relevant studies are reviewed. Familial forms of the disorder include a dopamine psychosis (supported by research documenting both altered dopamine activity and early neuroleptic response among some schizophrenic patients), a neurodegenerative psychosis (supported by investigations that document ongoing change in ventricular brain ratio, elevation of products of cell membrane catabolism within the central nervous system, and age-progressive third ventricle enlargement accompanied by delayed response to neuroleptics), and a neurodevelopmental psychosis (supported by evidence of static enlarged ventricles in some schizophrenic patients and neurological soft signs in high-risk offspring of schizophrenic individuals). Nonfamilial forms include a neurodevelopmental psychosis (supported by evidence of neurodevelopmental abnormalities triggered by neurotropic viruses, radiation, or anoxia) and a lithium-responsive psychosis (supported by evidence of a subgroup of psychotic patients who have low risk of either psychosis or mania in their pedigrees and respond to lithium).     

Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data

OBJECTIVE: An excess of obstetric complications in the histories of schizophrenic patients is a well-replicated finding, but less consistent results have been found concerning the relationships between obstetric complications and family history of schizophrenia, age at onset of schizophrenia, and gender. Small sample size limited the power of previous studies that attempted to assess such relationships. The aim of this study was to use data on individual patients from all available studies to examine the links between a history of obstetric complications and family history of schizophrenia, age at onset, and gender. METHOD: Raw data from 854 schizophrenic patients concerning history of obstetric complications rated according to the Lewis and Murray scale were obtained from 11 different research groups. Weighted average estimates were calculated with the use of regression techniques. RESULTS: A significant association was found between age at onset of schizophrenia and obstetric complications: the earlier the age at onset, the more likely the history of obstetric complications. Subjects with onset of schizophrenia before age 22 were 2.7 times more likely than those with onset at a later age to have had a history of abnormal presentation at birth and 10 times more likely to have had a history of complicated Cesarean birth. No association was found between obstetric complications and family history of schizophrenia or gender. CONCLUSIONS: The association between obstetric complications and early age at onset of schizophrenia indicates that the pathophysiology of early-onset schizophrenia involves neurodevelopmental impairment.     

Neurodevelopmental schizophrenia: the concept of developmental origins of certain forms of schizophrenia

This article presents the concept of neurodevelopmental schizophrenia and reviews the studies that contributed to its formulation. According to this concept some forms of schizophrenia (early onset, with predominating negative symptoms) are conditioned by distorted CNS development, probably in prenatal period. Such pathogenesis of certain forms of the disease is suggested by the following results of the studies on the CNS structure and function in schizophrenia: 1) structural abnormalities on in vivo brain imaging and postmortem studies 2) cytoarchitectural distortions in some brain regions, suggestive of disruption of cell migration during the CNS developmental processes 3) co-occurrence of the CNS congenital anomalies, minor physical anomalies and schizophrenia 4) neurological defects and psychosocial childhood dysfunction in individuals with adult onset schizophrenia. Genetical conditions, viral infections in prenatal period, obstetric complications or combination of the mentioned factors are considered as the factors disturbing the CNS developmental processes.     

Is immunogenetic susceptibility to neuropsychiatric systemic lupus erythematosus (SLE) different from non-neuropsychiatric SLE?

OBJECTIVES: To analyse frequency of HLA class II antigens (DR and DQ) and lymphocytotoxic autoantibodies in patients with systemic lupus erythematosus (SLE) and subsets with or without neuropsychiatric involvement. METHODS: Ninety three patients with SLE (42 with neuropsychiatric features) were typed for HLA class II antigens and investigated for the presence of lymphocytotoxic autoantibodies by a complement dependent microlymphocytotoxicity assay. A total of 191 controls of similar ethnic background were also typed for HLA antigens. RESULTS: HLA-DR3 antigen was increased in the total group of patients with SLE (p = 0.003) and in the neuropsychiatric group (p = 0.002). HLA-DR4 antigen frequency was increased in non-neuropsychiatric patients (p = 0.001) and decreased in patients with neuropsychiatric SLE (p = 0.0005). Comparisons of HLA frequencies between subgroups of patients showed decreased HLA-DR4 (p < 0.0001) and increased HLA-DR9 and HLA-DQ2 antigens (p = 0.0008 and 0.005 respectively) in the neuropsychiatric group. The frequency of lymphocytotoxic autoantibodies was increased in neuropsychiatric patients with SLE having HLA-DR9 specificity (p = 0.04). CONCLUSION: HLA-DR4 may have a protective specificity for the development of neuropsychiatric features of SLE and HLA-DR9, in addition to HLA-DR3, and the presence of lymphocytotoxic auto-antibodies may predispose to neuropsychiatric abnormalities.     

Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis

BACKGROUND: Rheumatoid arthritis frequently remits during pregnancy, for unknown reasons. Since an immune response to paternally inherited fetal HLA can occur during normal pregnancy and since rheumatoid arthritis is an autoimmune disorder with a known HLA class II antigen association, we tested the hypothesis that maternal-fetal disparity in HLA alloantigens might be associated with the pregnancy-induced remission of rheumatoid arthritis. METHODS: We studied 57 pregnancies of 41 women with rheumatoid arthritis, 18 prospectively and 39 retrospectively. Serologic and DNA techniques were used to study HLA class I and II antigens. For newborns, typing was performed from cord-blood samples obtained at delivery. For four young children, typing was performed from DNA extracted from hair samples. RESULTS: We found significantly more maternal-fetal disparity in HLA-DR and DQ antigens in pregnancies characterized by the remission or improvement of rheumatoid arthritis than in pregnancies characterized by active disease. Further studies using DNA-typing techniques to define allelic variants of HLA-DR and DQ antigens confirmed this observation. Maternal-fetal disparity in alleles of HLA- DRB1, DQA, and DQB occurred in 26 of 34 pregnancies characterized by remission or improvement (76 percent), as compared with 3 of 12 pregnancies characterized by active arthritis (25 percent) (odds ratio, 9.7; P = 0.003). The difference between the two groups was most marked for alleles of HLA-DQA. CONCLUSIONS: Amelioration of rheumatoid arthritis during pregnancy is associated with a disparity in HLA class II antigens between mother and fetus. These findings suggest that the maternal immune response to paternal HLA antigens may have a role in the pregnancy-induced remission of rheumatoid arthritis.     

Distribution of HLA antigens in idiopathic pulmonary fibrosis

Divergent observations suggest that genetic factors contribute to the susceptibility to or clinical course of idiopathic pulmonary fibrosis. To determine whether there is an association between the major histocompatibility (HLA) system and idiopathic pulmonary fibrosis, the distribution of 35 antigens of HLA loci A and B was determined among 33 white patients with idiopathic pulmonary fibrosis and 329 healthy white control subjects. Although certain antigens tended to be more prevalent among patients with idiopathic pulmonary fibrosis compared with control subjects, there were no significant differences in the phenotype frequencies of the HLA-A and HLA-B antigens between these 2 groups. Thus, although subtle associations may exist between the HLA loci and idiopathic pulmonary fibrosis, these results indicate that antigens of the HLA-A and HLA-B loci are not linked with major risk factors in this disease.     

Neuroimaging in child and adolescent neuropsychiatric disorders

OBJECTIVE: To review the major findings and pathophysiological implications of imaging studies of neuropsychiatric disorders that onset in childhood or adolescence. METHOD: More than 200 neuroimaging studies were selected for review from Medline searches if the studies concerned developmental neuropsychiatric disorders such as autism, fragile X syndrome, Down syndrome, schizophrenia, obsessive-compulsive disorder, Tourette's syndrome, attention-deficit hyperactivity disorder, and dyslexia. RESULTS: Disordered central nervous system development may produce evidence of cortical neuronal migration abnormalities in autism, smaller cortical structures in Down syndrome, frontal lobe deficits and larger basal ganglia in schizophrenia, hypoplastic basal ganglia in Tourette's syndrome, aberrancies of the planum temporale in dyslexia, and hypoplastic cerebellar structures in numerous developmental disorders. Normal cerebral asymmetries appear to be disrupted in a number of disorders, including schizophrenia, Tourette's syndrome, attention deficit disorder, and dyslexia. CONCLUSIONS: Neuroimaging data regarding pathological central nervous system development in childhood are still sparse, and many of the findings in developmental disorders of childhood onset concern the study of adult subjects with those disorders. Nevertheless, imaging modalities previously used only in adults are with increasing frequency being applied to the study of children, which will likely continue to contribute to the understanding of pathological brain structure and function throughout childhood and to the improved treatment of these disorders.     

Gender differences in general practice consultations: methodological challenges in epidemiological research

The present study is an analysis of the frequencies of HFE mutations in patients with different forms of iron overload compared with the frequencies found in healthy subjects from the same region. The frequencies of HLA-A and -B antigens and HLA haplotypes were also analyzed in the same subjects. The study population included: 71 healthy individuals; 39 genetically and clinically well-characterized patients with genetic hemochromatosis (HH); and 25 patients with non-classical forms of iron overload (NCH), excluding secondary hemochromatosis. All subjects were HLA-typed and HFE-genotyped by the oligonucleotide ligation assay (OLA). The gene frequencies found for the C282Y and H63D mutations of HFE were respectively: 0.03 and 0.23 in healthy individuals, 0.86 and 0.04 in HH patients, and 0.08 and 0.48 in NCH patients. An expected significant association between HH and HLA-A3 was observed, which was found to be in linkage disequilibrium with the C282Y mutation. A new association was seen, however, between HLA-A29 and NCH, in linkage disequilibrium with the H63D mutation. Again as expected, the HLA-B antigen B7 was associated with HH in linkage disequilibrium with HLA-A3. In addition, the HLA-B antigen B44 was found to be associated with NCH but not in linkage disequilibrium with either A29 or the H63D mutation. In conclusion, a new association of the HFE H63D mutation with forms of hemochromatosis other than HH and a new association between the HLA phenotype A29 and the HFE H63D mutation were found in the same patients. These findings reinforce evidence for the involvement of the major histocompatibility class I in iron metabolism, supporting the notion of a physiological role for the immunological system in the regulation of iron load.     

Activin B: detection by an immunoenzymometric assay in human serum during ovarian stimulation and late pregnancy

Cerebral 1H MR spectra were recorded in 13 children and adolescents with schizophrenia and 12 healthy children and adolescents. Stimulated echo acquisition mode (STEAM) sequence was used to localize an 8-ml voxel bilaterally in the frontal gray matter. The frontal gray matter metabolite ratios for NAA/Cr, Ch/Cr, Glx/Cr, and mI/Cr in schizophrenic children and adolescents were 1.08 +/- .28, .64 +/- .23, 1.09 +/- .30, and .60 +/- .24, respectively. In comparison, these ratios were 1.59 +/- .35, .74 +/- .27, 1.23 +/- .36, and .58 +/- .29 in healthy children and adolescents. Decrease in the frontal lobe NAA/Cr of schizophrenic children and adolescents was statistically significant (P < .001). In contrast, the MR spectra localized bilaterally in the occipital gray matter (8 ml) showed no significant changes between the patients and the controls. In the occipital gray matter, the metabolite ratios were 1.21 +/- .26,.52 +/- .08, 1.00 +/- .11, and.55 +/- .12 inpatients versus 1.30 +/- .23, .45 +/- .10, 1.15 +/- .20, and .48 +/- .19 in controls. Our preliminary finding of reduced NAA/Cr ratio in the frontal gray matter is consistent with the neurodevelopmental models emphasizing dysfunction of frontal lobe areas in patients with schizophrenia.     

Effects of selective contracting on hospital efficiency, costs and accessibility

Many retrospective studies, and an increasing number of prospective studies, have identified subtle abnormalities in preschizophrenics from as early as the first year of life. Premorbid characteristics include development delays, cognitive deficits, and abnormal social interactions. Schizoid personality traits have been a particularly well documented finding, and show some specificity in their association with schizophrenia. Information about the premorbid characteristics of schizophrenia has played a major role in the reorientation of the field, from regarding schizophrenia as an adult onset degenerative disorder, to considering it, at least in part, as a neurodevelopmental condition. However, whether the childhood personality traits are a reflection of an underlying brain lesion, or whether they are independent risk factors for the disorder, is uncertain. In the future, the identification of childhood characteristics may enable us to predict those who are at high risk of developing schizophrenia, and may even be useful in formulating preventive policies. However, at present, the powers of prediction are inadequate for such purposes.     

Radiation therapy for stage I-II non-small cell lung cancer in patients aged 75 years and older

Vaccination with peptides that induce a specific immune response is a potential prophylactic or therapeutic strategy against viral infections and tumors. Because of the extensive polymorphism of the HLA loci, synthetic peptide vaccines must consist of a cocktail of peptides that bind specifically to different HLA molecules. Such cocktails should be optimized for the target population as each population has its specific HLA gene frequencies. To achieve maximum population coverage with a minimum number of peptides, information is needed on the ranking of the most frequent HLA phenotypes. We introduce the minimal phenotype panel, which is the smallest combination of HLA antigens selected so that the proportion of individuals in a population that express at least one of the antigens in the panel exceeds a desired minimum value. We developed a method for assembling minimal phenotype panels based on known HLA class I gene frequencies. We give an example based on a set of 2446 well-defined HLA-typed, random, healthy, unrelated, Dutch Caucasoid individuals. In addition, we discuss the possibility of assembling minimal phenotype panels based on two-locus haplotypes, which enables the assembly of phenotype panels from the antigens of both loci.     

HLA genes in patients with pulmonary tuberculosis in the Kirghiz population]

The immunogenetic features of the HLA system were studied in 116 Kirghiz patients with pulmonary tuberculosis and 120 apparently healthy individuals of the same nationality (a control group). HLA antigen typing was made by the routine microlymphocytotoxic test. The antigens Bw53, Bw62(15), DR2 and DR7 which should be regarded as markers of the disease were more commonly found in the HLA phenotype in Kirghiz patients with tuberculosis than in healthy individuals. The risk for tuberculosis increased in carriers having HLA haplotypes with the DR allele.     

Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients

Some evidence points towards a possible autoimmune role in the aetiology of schizophrenia. Experimental findings provide contradictory results regarding abnormalities in cytokine production in this disorder. In the present study we tested the production of cytokines in CSF and serum in 16 schizophrenic patients and 10 healthy controls (tumor necrosis factor alpha - TNF alpha; interleukins IL-1 beta, IL-2, IL-6, soluble IL-2 receptor). Cytokine levels were evaluated by radioactively-labeled antibodies (IL-1 beta, IL-2, IL-6), by enzyme-linked immunoassay (TNF) and by a sandwich enzyme immunoassay (soluble IL-2 receptor). No significant differences were found in either CSF fluid or serum levels of TNF and IL-2 or IL-6. Interleukin-1 beta was significantly decreased in patients' CSF and serum as compared to controls. Soluble interleukin-2 receptor levels were decreased in CSF of patients, but highly increased in their serum in comparison with controls. Changes in various cytokine levels in CSF fluid and serum of schizophrenic patients probably reflect interrelated process of growth, degeneration or neuroimmunological abnormalities, which may all play a role in the pathophysiology of schizophrenia. The present study supports evidence for change in immune activation, probably of peripheral origin, in schizophrenic patients.     

External radiotherapy plus intracavitary brachytherapy for recurrent chordoma of the nasopharynx

Soluble HLA class I (sHLA-I) and soluble HLA class II (sHLA-II) antigen levels during different stages of disease were investigated in paired serum and cerebrospinal fluid (CSF) samples from 37 patients with multiple sclerosis (MS) using ELISA and Western blot analysis. Soluble HLA-II antigens in the serum of untreated patients with the relapsing-remitting type of MS (RRMS) were found to be significantly elevated in acute relapse as compared to values obtained from patients under steroid treatment, in remission or healthy controls. No significant differences in circulating sHLA-I levels could be detected. In contrast, a trend towards increased intrathecal production of sHLA-I molecules in the CSF was observed in untreated RRMS patients in acute relapse, whereas the levels of soluble HLA-II antigens in the CSF were below the detection limit of the ELISA method. Our observations underline the presence of systemic immune activation in MS patients, as reflected in elevated serum sHLA-II antigen levels, and reveal a dichotomy between sHLA class I and II antigen production in the peripheral blood versus CSF in acute MS. Serial measurements of sHLA-II antigen levels might represent a non-invasive method to assess disease activity in MS patients.     

Medical manpower and public policy: a short history of P.L. 94-484

Twenty-three HLA antigens were investigated in 121 patients with clinical cancer as well as 188 male and 212 female controls. Patients with cervical carcinoma showed significant differences in some HLA frequencies from that of controls. Patients with cervical carcinoma showed significant differences in some HLA frequencies from that of controls. In the localized form of the neophasia HLA-A3 was decreased, HLA-A9 and B 12 were increased. In the disseminated form of cervical carcinoma HLA-A 1 were found decreased and AW 32 and B 12 increased. HLA antigens could be factors, together with others yet unknown, i.e. immune response genes, HSV-2-infection, which produce an increased susceptibility to the disease.     

Value of beat-to-beat blood pressure changes, detected by pulse transit time, in the management of the obstructive sleep apnoea/hypopnoea syndrome

BACKGROUND: Previous studies of oculomotor dysfunction in schizophrenia have tended to concentrate on abnormalities of smooth pursuit eye tracking in chronic medicated patients. We report the results of a study of smooth pursuit, reflexive and antisaccade performance in drug naive and antipsychotic treated first-episode schizophrenic patients. METHODS: Smooth pursuit and saccadic eye movements were recorded in 36 first-episode schizophrenic patients and 36 controls matched for age and estimated IQ. The schizophrenic patients were divided into drug-naive (N = 17) and antipsychotic treated groups (N = 19). RESULTS: Smooth pursuit velocity gain was significantly lower than controls only in the drug-naive patients. The treated patients did not differ significantly from either the controls or the untreated group. In an antisaccade paradigm both treated and drug-naive schizophrenic patients demonstrated an increased number of errors, but only drug-naive patients also demonstrated an increased latency in initiating correct antisaccades. CONCLUSIONS: These impairments are unlikely to be due to a generalized deficit in oculomotor function in the schizophrenic groups, as there were no differences between the groups in saccadic metrics on a reflexive saccade task. The results show that both smooth pursuit and saccadic abnormalities are present at the onset of schizophrenia and are integral to the disorder.     

Conversational repair in schizophrenic and normal children

OBJECTIVE: Children acquire the skills to monitor the adequacy of their spoken message and to self-initiate repair strategies that modify the message during early, middle, and late childhood. To characterize further the communication deficits of childhood-onset schizophrenia, this study compared self-initiated repair strategies in schizophrenic and normal children and their relationship with formal thought disorder, discourse deficits, and distractibility. METHOD: Measures of self-initiated repair, formal thought disorder, and cohesion were coded in 32 schizophrenic and 47 normal children, aged 5.6 to 12.4 years, from speech samples elicited with the Story Game. RESULTS: The schizophrenic children used some repair strategies (false starts, fillers, referential revision) more infrequently than the normal children. Within the schizophrenic group, the children who were receiving neuroleptic medication underutilized repair and had more discourse deficits than the unmedicated patients. Loose associations and distractibility were associated with increased use of false starts but not fillers. CONCLUSIONS: In addition to formal thought disorder and discourse deficits, schizophrenic children underutilize self-initiated repair when presenting their thoughts to the listener, particularly if they are being treated with neuroleptics, a potential sign of increased clinical morbidity. Impoverished communication skills might reflect negative signs in childhood-onset schizophrenia.