Paradoxical downregulation of HLA-A expression by IFNγ associated with schizophrenia and noncoding genes.

Neuronal MHC/HLA regulates the synapses of the central nervous system (CNS). The expression of MHC/HLA is, in turn, regulated by immune cytokines. We were therefore interested in the regulation of schizophrenia-associated HLA antigens, specifically their regulation of expression by interferons. We had previously observed a moderately increased frequency of HLA-A10 expression in schizophrenic patients. While searching for the "true" disease gene near the HLA-A gene, we discovered that homozygosity of the HLA-J M80469 pseudogene allele, in combination with HLA-A10 or HLA-A9, was associated with a high risk of schizophrenia (HLA-A10 relative risk = 29.33, p = 0.00019, patients N = 77, controls N = 214). The allele HLA-J M80468, which codes for interferon-inducible mRNA, conferred protection on carriers of HLA-A9 and HLA-A10 (HLA-A10 relative risk = 0.022, p = 0.00017). Functional analysis revealed that interferon γ (IFNγ) downregulated the expression of HLA-A9 and HLA-A10 in monocytes from HLA-J M80469 homozygous patients but not from carriers of the HLA-J M80468 allele. This is the first demonstration of an inverse effect of IFNγ on HLA expression that is associated with non-coding gene variants and schizophrenia. Our findings suggest that the interferons secreted during acute and chronic infections may interfere in synaptic regulation via neuronal HLA and that this disturbance in synaptic regulation may induce the symptoms of mental illness.

Responsiveness of a patient in a persistent vegetative state after a coma to weekly injections of autologous activated immune cells: a case report.

INTRODUCTION: An 82-year-old Caucasian woman had remained in a persistent vegetative state after a coma of seven months duration, which occurred after a stroke with hemiplegia, nine years previously. The persistent vegetative state could be reversed in part by weekly injections with activated immune cells. After therapy, our patient responded to commands in addition to regaining spontaneous movements of both arms and the ability to swallow. This is the first report on the treatment with activated immune cells of a patient in a persistent vegetative state after a coma. CASE PRESENTATION: An 82-year-old Caucasian woman presented with a persistent vegetative state subsequent to a coma. She retained respiratory and autonomic functions. As contact was not possible, physiotherapy was passive. Her skin was yellowish, and our patient did not move by herself. Vomiting repeatedly resulted from tube feeding. After a once-weekly treatment with activated immune cells sampled from our patient's blood and activated in vitro, several of her functions gradually returned. Our patient opened her eyes in the requested direction and turned her head toward people entering the room. She 'supported' nursing efforts, as the nurse noted a loss of spastic motions. The strength in both her arms returned, and she spontaneously moved her arm on the side experiencing hemiplegia. After three months, our patient could stick out her tongue upon demand. Finally, the swallow reflexes of our patient started to return. However, tube feeding was continued, and our patient died after aspiration of vomit following a feeding. CONCLUSION: The success of treatment with autologous activated immune cells in this patient may have resulted from the production of neuroactive substances, such as neurotrophin-3 and brain-derived neurotrophic factor, by activated immune cells. The deterioration of our patient could be reversed, as demonstrated by the restoration of motor strength in her hemiplegic side. In addition, our patient was able to induce motor responses upon request. It seems reasonable to conclude that activated immune cells may improve the chronic vegetative state in some patients.

The LMP7-K allele of the immunoproteasome exhibits reduced transcript stability and predicts high risk of colon cancer.

Destruction of cancer cells by cytotoxic T lymphocytes depends on immunogenic tumor peptides generated by proteasomes and presented by human leukocyte antigen (HLA) molecules. Functional differences arising from alleles of immunoproteasome subunits have not been recognized so far. We analyzed the genetic polymorphism of the immunoproteasome subunits LMP2 and LMP7 and of the transporters associated with antigen processing (TAP1 and TAP2) in two independently collected panels of colorectal carcinoma patients (N(1) = 112, N(2) = 62; controls, N = 165). High risk of colon cancer was associated with the LMP7-K/Q genotype (OR = 8.10, P = 1.10 × 10(-11)) and low risk with the LMP7-Q/Q genotype (OR = 0.10, P = 5.97 × 10(-13)). The basis for these distinct associations of LMP7 genotypes was functionally assessed by IFN-γ stimulation of colon carcinoma cell lines (N = 10), followed by analyses of mRNA expression of HLA class I, TAP1, TAP2, and LMP7, with real-time PCR. Whereas induction of HLA-B, TAP1, and TAP2 was comparable in all cell lines, transcript amounts of LMP7-Q increased 10-fold, but of LMP7-K only 3.8-fold. This correlated with a reduced transcript stability of LMP7-K (t(1/2) ≈ 7 minutes) compared with LMP7-Q (t(1/2) ≈ 33 minutes). In addition, LMP7-Q/Q colon carcinoma cells increased (the peptide based) HLA class I surface expression significantly after IFN-γ stimulation, whereas LMP7-Q/K and LMP7-K/K carcinoma cells showed minimal (<20%) changes. These results suggest that the presence of LMP7-K can reduce the formation of immunoproteasomes and thus peptide processing, followed by reduced peptide-HLA presentation, a crucial factor in the immune response against cancer.

Increased prevalence of Chlamydophila DNA in post-mortem brain frontal cortex from patients with schizophrenia.

Infection can initiate symptoms of mental illness. It has been shown previously that Chlamydophila DNA is present six times more often in the blood of patients with schizophrenia than in the blood of control individuals. Monocytes, the main targets of Chlamydiaceae infection, are microglia precursors. We identified Chlamydiaceae infection using blinded brain DNA samples derived from the frontal cortex. Using PCR and sequence analysis, we found Chlamydophila DNA to be four times greater in patients with schizophrenia than in controls (schizophrenia: N=34, microbial DNA frequency 23.5%; controls: N=35, microbial DNA frequency 5.7%; P=0.045, OR=5.08). Persistent Chlamydophila-infected microglia or neuronal cells may impair neuronal circuits and thus be a mechanism for causing psychiatric illness in these patients.

Transporter associated with antigen processing and the chaperone tapasin: are non-classical HLA genes keys to the pathogenesis of schizophrenia?

Schizophrenia is a mind-destructive disease. Family and twin studies have indicated an equal contribution of genetic endowment and environmental factors in the pathogenesis of schizophrenia. Recently Chlamydiaceae species has been identified as a major factor in the pathogenesis of schizophrenia, suggesting defective immune responses of schizophrenic patients against this environmental factor. Immune responses against Chlamydiaceae species are controlled by immunogenetic factors. Successful responses against microbes depend on the presentation of immunogenic peptides by HLA molecules, which are encoded by a highly polymorphic gene system. Until now several HLA alleles or HLA antigens have been found associated with schizophrenia by some researchers but not by others. This could be explained by failing immune responses against different microbes or different immune responses against the same microbe. Another explanation, not contradictory rather supplementary, is the participation of non-classical HLA genes in the immune response and thus in the disease development. Variants of these genes, i.e. alleles, which control transportation and loading of microbial peptides onto HLA molecules, could prevent clearing of immune cell infection by selection of non-immunogenic peptides for HLA presentation. To generate support for our hypothesis we determined in a small group of schizophrenic patients and control individuals allele frequencies of the transporter proteins TAP1/TAP2, which select the immunoproteasome-tailored peptides for transportation. We determined also frequencies of TAPASIN alleles, which encode chaperons and also may select peptides for loading on MHC molecules. Our pilot study included 20 patients and 162 control individuals. We found significant associations between schizophrenia and TAP1 allele frequencies (P=9.95x10(-3), chi(2)=12.36) as well as TAPASIN allele frequencies (P=2.8x10(-2), chi(2)=5.3). This suggests that variants of these two genetic systems could influence the disease process of schizophrenia. Furthermore, these genes belong to the family of ABC transporter proteins and may also influence the efficiency of drugs and thus of therapeutic modalities. Our investigations require certainly larger patient panels to prove our hypothesis and our results to be correct.

Xrs2 facilitates crossovers during DNA double-strand gap repair in yeast.

Xrs2 is a member of the MRX complex (Mre11/Rad50/Xrs2) in Saccharomyces cerevisiae. In this study we demonstrate the important role of the MRX complex and in more detail of Xrs2 for the repair of radiation-induced chromosomal double-strand breaks by pulsed field gel electrophoresis. By using a newly designed in vivo plasmid-chromosome recombination system, we could show that gap repair efficiency and the association with crossovers were reduced in the MRX null mutants, but repair accuracy was unaffected. For these processes, an intact Mre11-binding domain of Xrs2 is crucial, whereas the FHA- and BRCT-domains as well as the Tel1-binding domain of Xrs2 are dispensable. Obviously, the Mre11-binding domain of the Xrs2 protein is crucial for the analysed functions and our results suggest a new role of the MRX complex for the formation of crossovers. Analysis of double mutants showed that the phenotype of the Deltaxrs2 null mutant concerning the crossover frequency is dominant over the phenotypes of Deltasrs2 and Deltasgs1 null mutants. Thus, the complex seems to be involved in early steps of double-strand break and gap repair, and we propose that it has a regulatory role for the selection of homologous recombination pathways.

High risk of schizophrenia and other mental disorders associated with chlamydial infections: hypothesis to combine drug treatment and adoptive immunotherapy.

Many microbial factors have been implicated as pathogenic factors in mental disorders. Occurrence of such microbial factors also in the mentally unaffected population raised skepticism against such findings, although each microbial factor may cause mental problems only in some individuals, depending on the individual's immunogenetic disposition. Skepticism against the role of infection in schizophrenia was also fostered by the low impact of antiinfections treatment on the course of disease progression in schizophrenia. We discovered previously that neurotrophins like neurotrophin3 (NT-3) and brain-derived neurotrophic factor (BDNF), involved in processes of neuroplasticity, are also secreted by immune cells, but only by subpopulations of immune cells. Therefore, infection of the immune cell subpopulation, specialized in secreting BDNF, or of another subpopulation, specialized in secreting NT-3, could distort communication of immune cells with the central nervous system (CNS). Chlamydiaceae could cause disbalancement of immune cell sub-populations and, in some individuals with a vulnerable disposition, symptoms of mental illness. Based on previous observations of persisting IgA titers in some patients with mental illness we hypothesize that the intracellular parasites Chlamydiaceae are main pathogenic factors in schizophrenia. We hypothesize furthermore that antiinfectious treatment has to be accompanied by adoptive immunotherapy because antibiotics alone will not restore the balance of immune subpopulations. Our hypothesis is supported by examination of patients with schizophrenia and other mental disorders. Using nested PCR we found a significant prevalence of the intracellular parasites Chlamydophila psittaci, C. pneumoniae and Chlamydia trachomatis (9/18, 50%), as compared to controls (8/115, 6.97%) (chi(2)=25.86, Fisher's exact p two-tailed=5x10(-5)). Treatment with in vitro-activated immune cells together with antibiotic modalities showed sustained mental improvements in patients that did not depend on treatment with antipsychotic drugs. Future controlled studies including sham treatment of patients have to be carried out to prove our hypotheses.