Immunology, Autoimmunity, and Autoantibodies in Parkinson’s Disease

Recent revelations of immune alterations in Parkinson??s disease have led to the convergence that an autoimmune mechanism may play a role in the etiopathogenesis of this neurodegenerative disease. In the current study, 77 Parkinson??s disease patients and 77 matched healthy controls were analyzed for the presence of seven autoantibodies previously found to be associated with central nervous system manifestations namely: antineuronal-cells, anti-brain lysate, anti-dsDNA, anti-phosphatidylserine, anti-cardiolipin, anti-serotonin, and anti-melanocytes antibodies. Patients underwent systematic assessments of demographics, clinical, and biochemical manifestations. Three autoantibodies were found to be more prevalent among Parkinson??s disease patients (antineuronal cells10.3% vs. 1.3%, p?=?0.017; anti-brain lysate 9.1% vs. 1.3%, p?=?0.032; anti-dsDNA 10.3% vs. 2.6%, p?=?0.049). Clinical manifestations of Parkinson??s disease, particularly dyskinesia and depression, were found to be associated with the presence of these autoantibodies.     

Regression-based identification of behavior-encoding neurons during large-scale optical imaging of neural activity at cellular resolution

The advent of methods for optical imaging of large-scale neural activity at cellular resolution in behaving animals presents the problem of identifying behavior-encoding cells within the resulting image time series. Rapid and precise identification of cells with particular neural encoding would facilitate targeted activity measurements and perturbations useful in characterizing the operating principles of neural circuits. Here we report a regression-based approach to semiautomatically identify neurons that is based on the correlation of fluorescence time series with quantitative measurements of behavior. The approach is illustrated with a novel preparation allowing synchronous eye tracking and two-photon laser scanning fluorescence imaging of calcium changes in populations of hindbrain neurons during spontaneous eye movement in the larval zebrafish. Putative velocity-to-position oculomotor integrator neurons were identified that showed a broad spatial distribution and diversity of encoding. Optical identification of integrator neurons was confirmed with targeted loose-patch electrical recording and laser ablation. The general regression-based approach we demonstrate should be widely applicable to calcium imaging time series in behaving animals.     

Infectome: A platform to trace infectious triggers of autoimmunity

The “exposome” is a term recently used to describe all environmental factors, both exogenous and endogenous, which we are exposed to in a lifetime. It represents an important tool in the study of autoimmunity, complementing classical immunological research tools and cutting-edge genome wide association studies (GWAS). Recently, environmental wide association studies (EWAS) investigated the effect of environment in the development of diseases. Environmental triggers are largely subdivided into infectious and non-infectious agents. In this review, we introduce the concept of the “infectome”, which is the part of the exposome referring to the collection of an individual's exposures to infectious agents. The infectome directly relates to geoepidemiological, serological and molecular evidence of the co-occurrence of several infectious agents associated with autoimmune diseases that may provide hints for the triggering factors responsible for the pathogenesis of autoimmunity. We discuss the implications that the investigation of the infectome may have for the understanding of microbial/host interactions in autoimmune diseases with long, pre-clinical phases. It may also contribute to the concept of the human body as a superorganism where the microbiome is part of the whole organism, as can be seen with mitochondria which existed as microbes prior to becoming organelles in eukaryotic cells of multicellular organisms over time. A similar argument can now be made in regard to normal intestinal flora, living in symbiosis within the host. We also provide practical examples as to how we can characterise and measure the totality of a disease-specific infectome, based on the experimental approaches employed from the “immunome” and “microbiome” projects.     

Tracing environmental markers of autoimmunity: introducing the infectome

We recently introduced the concept of the infectome as a means of studying all infectious factors which contribute to the development of autoimmune disease. It forms the infectious part of the exposome, which collates all environmental factors contributing to the development of disease and studies the sum total of burden which leads to the loss of adaptive mechanisms in the body. These studies complement genome-wide association studies, which establish the genetic predisposition to disease. The infectome is a component which spans the whole life and may begin at the earliest stages right up to the time when the first symptoms manifest, and may thus contribute to the understanding of the pathogenesis of autoimmunity at the prodromal/asymptomatic stages. We provide practical examples and research tools as to how we can investigate disease-specific infectomes, using laboratory approaches employed from projects studying the “immunome” and “microbiome”. It is envisioned that an understanding of the infectome and the environmental factors that affect it will allow for earlier patient-specific intervention by clinicians, through the possible treatment of infectious agents as well as other compounding factors, and hence slowing or preventing disease development.     

Hyperferritinemia is Associated with Serologic Antiphospholipid Syndrome in SLE Patients

Ferritin may play a direct role on the immune system. We sought to determine if elevated levels of ferritin in lupus patients correlate with disease activity and organ involvement in a large cohort. Ferritin levels (gender and age adjusted) were assessed in 274 lupus serum samples utilizing the LIASON Ferritin automated immunoassay method. Significant disease activity was determined if European Consensus Lupus Activity Index (ECLAM)?>?2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)?>?4. Utilizing an EXCEL database, we compared elevated ferritin levels to manifestations grouped by organ involvement, serology, and previous therapy. The patients were predominantly female (89%), median age was 37 years old, and disease duration was 10.6?±?7.7 years. Hyperferritinemia was found in 18.6% of SLE patients. Compared to subjects with normal ferritin levels, a significantly greater proportion of patients with hyperferritinemia had thrombocytopenia (15.4% vs. 33.3%, p?=?0.003) and lupus anticoagulant (11.3% vs. 29.0%, p?=?0.01). Additionally, compared to normoferritinemic subjects, hyperferritinemic subjects had significantly higher total aCL (99.7?±?369 vs. 30.9?±?17.3 GPI, p?=?0.02) and aCL IgM antibody levels (75.3?±?357.4 vs. 9.3?±?10.3 GPI, p?=?0.02), and marginally lower aCL IgG antibody levels (9.2?±?4.9 vs. 9.7?±?3.9 GPI, p?=?0.096). While the ECLAM score significantly correlated with hyperferritinemia (p?=?0.04), the SLEDAI score was marginally associated with hyperferritinemia (p?=?0.1). Serositis was marginally associated with hyperferritinemia, but not with other manifestations. An association with serologic APS was encountered. Hyperferritinemia was associated with thrombocytopenia, lupus anticoagulant, and anti-cardiolipin antibodies suggest that it may be an early marker for secondary antiphospholipid syndrome in SLE patients.     

Colorectal cancer screening, intentions, and predictors in Jewish and Arab Israelis: a population-based study.

Random samples of 358 Jews and 162 Arabs in Israel aged 50 to 75 were compared by telephone survey for colorectal cancer (CRC) screening performance and intentions. Participants completed questionnaires on CRC screening, health beliefs, health locus of control, and CRC worries; rate of CRC screening and intention to be screened proved lower among Arabs. They received fewer recommendations from physicians, perceived lower severity of CRC and lower benefits of early detection of CRC, and had lower cancer worries, lower internal health locus of control, and higher external health locus of control. Jewish/Arab ethnicity predicted ever undergoing screening and screening intention before cognitive perceptions and worries were entered. After that, perceiving higher susceptibility and more benefits to screening, and having lower external health locus of control predicted CRC screening and screening intention, which was associated with higher cancer worries. Programs should be tailored to address ethnic groups' different health beliefs.     

Regulation of p53: intricate loops and delicate balances

The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the p53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways, which integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the beta catenin protein and the other centering on the Akt/protein kinase B. In both cases, the central module is the interplay between p53 and the murine double minute 2 (Mdm2) protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated beta catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and downregulation of beta catenin. Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion.     

Centro-somatic staged tuberculous vertebral osteitis: a case report

Centro-somatic tuberculous vertebral osteitis is defined as tuberculous infection of the vertebral body with preserved integrity of the adjacent intervertabral disk. Other types of vertebral tuberculosis include Pott's spondylodiscitis and exceptional lesions of the posterior arch. We report a case of centro-somatic tuberculous vertebral osteitis in a 14-year-old boy who developed staged lesions of the L2 to S1 bodies, associated with a posterior epidural collection but without any deterioration of the intervertebral disk on plain x-rays and computed tomography. This atypical aspect of the lesions required a surgical biopsy which yielded a yellow-whitish fibro-oleagenous, friable product more suggestive of neoplasm than infection, but histology rectified the diagnosis, showing typical caseo-follicular tuberculosis. A 6-month anti-tuberculosis regimen was rapidly followed by symptom improvement. We emphasize the importance of modern imaging techniques for the diagnosis of vertebral lesions and for guided biopsy or drainage.     

Increased emotional distress in daughters of breast cancer patients is associated with decreased natural cytotoxic activity,elevated levels of stress hormones and decreased secretion of Th1 cytokines

DBCP who are aware of their increased risk of developing breast cancer may suffer from high emotional distress. Chronic stress may interfere with NCA and low NCA is associated with increased cancer risk. We studied 80 DBCP and 47 age- and education-matched healthy females (controls). Heparinized venous blood (30 ml) was drawn from all subjects between 8 and 9 A.M., and each participant answered a set of psychologic questionnaires. In addition, the first-morning urine sample was collected. DBCP scored significantly higher in emotional distress compared to controls. Levels of stress hormones in DBCP were higher and in vitro secretion of IL-2, IL-12 and IFN-gamma lower compared to controls. NCA against NK-resistant (MCF-7, COLO-205, U937) and NK-sensitive (K562) cell lines was significantly lower in DBCP and much less augmented by in vitro preincubation with IL-2 or IL-12 compared to controls. NCA and in vitro Th1 cytokine secretion were inversely correlated with the degree of emotional distress and the level of stress hormones in blood or urine. High emotional distress and elevated levels of stress hormones are associated with impaired immune surveillance functions in DBCP. This may contribute to the increased risk of DBCP to develop breast cancer. An interventional trial to enhance coping and reduce stress levels may help to decrease the risk for breast cancer onset in DBCP.