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The Role of IgG in Pathophysiology of Amyotrophic Lateral Sclerosis
No full textAmyotrophic lateral sclerosis (ALS) is an adult-onset disease, characterized principally
by progressive degeneration of upper and lower motoneurons. Since numerous studies
described perturbed processes in other cell types as well, the disease is considered
multifactorial and multi-systemic. The role of the immune system in ALS pathology is
still obscure, especially in the early stages, but with the disease progression, strong
neuroinflammation is evident. Over the years, different groups reported antibodies
reactive to various motoneuronal structures, and recent study suggested that prolonged
and sustained intraperitoneal injection of ALS patients’ sera induced the experimental
motor neuron disease model in mice. Glycosylation patterns of ALS IgG and their
potential use as biomarkers are also currently in focus. Some of the early work done by
our group demonstrated that in cultured rat hippocampal neurons ALS IgG suppressed
KCl-induced [Ca2+]i rise through P/Q- type calcium channels, and later on, that they
increased the frequency of spontaneous excitatory postsynaptic currents. Thereafter, as
our focus shifted to astrocytes, we demonstrated that ALS IgG increased the mobility
of endosomes and lysosomes and induced a transient increase of intracellular calcium
in cultured rat cortical astrocytes. Our current research aims at deeper understanding of
functional activity of ALS IgG on the one hand and the patophysiological changes they
induce in cultured neurons and astrocytes on the other. We now have evidence that
astrocytes also release glutamate upon treatment with ALS IgG. In experiments with
neuronal cultures it became apparent that ALS IgG directly affect spontaneous
synchronized calcium activity, an effect that is missing when such calcium activity is
not present (in premature neurons) or is abolished by blockers. Our research indicates
probably a non- Fc receptor-mediated IgG effect, even though the experiments with
fragmented IgG do not exclude the importance of Fc region for their pathological
functionality
COPD patients exhibit lower IgG sialylation level in comparison to acute bronchitis patients
No full textChronic obstructive pulmonary disease (COPD) is characterized by decreased air flow
in the airways leading to shortness of breath, coughing and wheezing. Inflammation
and oxidative stress play an important role in the pathophysiology of COPD. One of
the primary goals of therapy is to reduce the number and frequency of exacerbations.
Inhaled corticosteroids and phosphodiesterase inhibitors are used in addition to
bronchodilators in patients with high rates of exacerbations. However, the use of
inhaled corticosteroids can cause pneumonia. Mucolytics play an important role in the
prevention of exacerbations. The goal of this work was to analyze immune parameters
at the onset of disease/exacerbation and upon one month of supplementation with NAcetyl cysteine (NAC) or propomucil (NAC with propolis) in age matched acute
bronchitis patients and COPD patients. Cytokines: IL-17, IL-6, and IL-8, were analyzed
from patients’ plasma with commercial ELISA kits. IgG sialylation was assessed in
ELISA with Protein G for IgG capture and SNA I – a lectin specific for sialic acid
attached to terminal galactose with α-2,6 glycosidic bond. We were not able to detect
significant differences in plasma cytokine levels irrespective of the patient group or
treatment. No difference was found in IgG sialylation upon treatment. However, COPD
patients had significantly lower level of IgG sialylation compared to acute bronchitis
patients. The obtained results indicate that the influence of NAC on the immune system,
with or without propolis can not be evaluated by assessing plasma cytokine levels, as
the effects might be localized. While there were no differences in sialylation related to
treatment, the obtained lower level of IgG sialylation is an indicator of increased level
of chronic inflammation present in COPD patients, which is in accordance with
literature data. As no differences were noted in this group within one month this likely
represents a permanent state
Epidemiological, clinical and laboratory characteristics of the measles resurgence in the Republic of Serbia in 2014-2015
Get PDFThe Republic of Serbia is a country with ongoing endemic transmission of measles. The aim of this study is to summarize the main characteristics of the measles resurgence that occurred in Serbia in 2014-2015. The national surveillance data on measles was analysed in relation to the clinical, epidemiological and laboratory data. Between November 2014 and December 2015 a measles resurgence with 420 cases was observed in Serbia. Measles virus was initially introduced by and spread among citizens of Bosnia and Herzegovina with temporary residence in Serbia, before spreading to the resident population. Of the 223 patients with available medical records, 173 (77.6%) were unvaccinated. The overall measles incidence during the outbreak was 5.8/100.000. The highest age-specific incidence rate was recorded in children aged lt = 4 years (25.9/100.000), but most cases (67.9%) were gt = 20 years old. Hospitalization rate was high (32.9%) and included two cases of encephalitis associated with measles. In total, 42 health-care workers and 22 related cases including hospitalized patients (n = 13) contracted measles. The overall percentage of laboratory confirmed cases was 81.7% (n = 343/420). All measles virus sequences except one (D9) belonged to genotype D8, suggesting interruption of transmission after the previous outbreak in 2010-2011 caused by genotype D4 viruses. The growing number of adult patients as compared to previous epidemics, suggests an urgent need for supplementary immunization activities targeting susceptible health care workers, unvaccinated or incompletely vaccinated adults as well as people without vaccination records. The comprehensive investigation of the 2014/2015 measles resurgence will contribute to decisions about appropriate countermeasures to stop the future measles resurgences in Serbia
The impact of prophylactic treatment of recombinant banana lectin on the innate immune response in TNBS induced colitis in C57BL/6 mice
No full textBanana lectin (BanLec) is a mannose-specific lectin that belongs to the
jackalin-related family of lectins. Having in mind an already reported
immunomodulatory activity of BanLec, we wanted to explore its prophylactic
effect in a murine model of 2,4,6- trinitrobenzene sulfonic acid (TNBS) -induced
colitis. Particular focus was on the impact of prophylactic BanLec application on
parameters of oxidative stress. In the research we used a BanLec isoform
produced by recombinant technology (rBanLec) which possess structural and
functional characteristics similar to naturally occurring counterparts
Titter and avidity of serum antibodies reactive with Lactobacillus spp. Is changed in local and systemic inflammatory diseases of bone tissues
No full textThe gut microbiota is necessary to establish an effective immune response, but also
related to the onset of local and systemic inflammatory diseases of bonne tissue. Genus
Lactobacillus is one of the main bacterial inhabitants of digestive tract, and we
analysed, with in-house ELISA, titter and avidity of serum IgM, IgG, and IgA
antibodies reactive with whole Lactobacillus plantarum and Lactobacillus reuteri, of
25 periodontal disease (PD) patients without any systematic disease, 26 rheumatoid
arthritis (RA) patients, and of 21 healthy people. In healthy people we found no
correlation between titters of different immunoglobulin isotypes reactive with
Lactobacillus spp. Moderate correlation between IgG and IgA titters was detected in
PD and RA. Only in RA, the correlation between IgG and IgM, and IgA and IgM titters
was found. No difference between the groups in titters and avidity of anti-Lactobacillus
IgG and IgA was found. However, both titter and avidity of IgM antibodies reactive
with any of two Lactobacillus species was lower in RA then in PD and in healthy
people. We also observed that serum antibodies “discriminated” two Lactobacillus
species. Thus, in healthy people and in PD patients titter and avidity of IgG to L. reuteri
were of significantly lower values than those to L. plantarum. Besides, high correlation
between titters of IgG antibodies against L. plantarum and L. reuteri was found in all
groups, high correlation between titters of IgA antibodies to two Lactobacillus sp. was
detected in PD and RA, and of IgM antibodies only in RA. The results showed that the
serum anti-Lactobacillus antibodies reactivity in PD and RA patients differed of the
reactivity observed in healthy people. This might reflect a disturbed immunoglobulin
reactivity caused by disease-related hyper stimulation and/or a disorder in the gut
microbiome level. The significance of the results remains to be elucidate
Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor
No full textPharmacological blockade of alpha(1)-adrenoceptor is shown to influence development of experimental autoimmune encephalomyelitis (EAE), an IL-17-producing CD4+TCR+ (Th17) cell-mediated disease mimicking multiple sclerosis. Considering significance of CD4+ cell priming for the clinical outcome of EAE, the study examined alpha(1)-adrenoceptor-mediated influence of catecholamines, particularly those derived from draining lymph node (dLN) cells (as catecholamine supply from nerve fibers decreases with the initiation of autoimmune diseases) for CD4+ cell priming. The results confirmed diminishing effect of immunization on nerve fiber-derived noradrenaline supply and showed that antigen presenting and CD4+ cells synthesize catecholamines, while antigen presenting cells and only CD4+CD25+Foxp3+ regulatory T cells (Tregs) express alpha(1)-adrenoceptor. The analysis of influence of alpha(1)-adrenoceptor antagonist prazosin on the myelin basic protein (MBP)-stimulated CD4+ lymphocytes in dLN cell culture showed their diminished proliferation in the presence of prazosin. This was consistent with prazosin enhancing effect on Treg frequency and their Foxp3 expression in these cultures. The latter was associated with upregulation of TGF-beta expression. Additionally, prazosin decreased antigen presenting cell activation and affected their cytokine profile by diminishing the frequency of cells that produce Th17 polarizing cytokines (IL-1 beta and IL-23) and increasing that of IL-10-producing cells. Consistently, the frequency of all IL-17A+ cells and those co-expressing GM-CSF within CD4+ lymphocytes was decreased in prazosin-supplemented MBP-stimulated dLN cell cultures. Collectively, the results indicated that dLN cell-derived catecholamines may influence EAE development by modulating interactions between distinct subtypes of CD4+ T cells and antigen presenting cells through alpha(1)-adrenoceptor and consequently CD4+ T cell priming
Noradrenaline through beta-adrenoceptor contributes to sexual dimorphism in primary CD4+T-cell response in DA rat EAE model?
No full textMales exhibit stronger sympathetic nervous system (SNS) activity, but weaker primary CD4 + T-cell (auto) immune responses. To test the role of catecholamines, major end-point SNS mediators, in this dimorphism, influence of propranolol (beta-adrenoceptor blocker) on mitogen/neuroantigen-stimulated CD4 + T cells from female and male EAE rat draining lymph node (dLN) cell cultures was examined. Male rat dLNs exhibited higher noradrenaline concentration and frequency of beta(2)-adrenoceptor-expressing CD4 + T lymphocytes and antigen presenting cells. Propranolol, irrespective of exogenous noradrenaline presence, more prominently augmented IL-2 production and proliferation of CD4 + lymphocytes in male than female rat dLN cell cultures. In neuroantigen-stimulated dLN cells of both sexes propranolol increased IL-1 beta and IL-23/p19 expression and IL-17 + CD4 + cell frequency, but enhanced IL-17 production only in male rat CD4 + lymphocytes, thereby abrogating sexual dimorphism in IL-17 concentration observed in propranolol-free cultures. Thus, beta-adrenoceptor-mediated signalling may contribute to sex bias in rat IL-17-producing cell secretory capacity
Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia
No full textSympathetic dysfunction was proposed to participate in development of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). This may be linked with findings indicating that noradrenaline, the key sympathetic end-point mediator, through β adrenoceptor exerts immunomodulatory action. Considering importance of the target tissue for the clinical outcome of EAE, the study investigated the effects of propranolol, a non-selective β adrenoceptor blocker, on the disease severity in Dark Agouti rats. Administration of propranolol over the effector phase of EAE substantially moderated neurological symptoms of the disease. This correlated with the increased proportion of spinal cord microglia expressing CX3CR1, the crucial neuroinflammation-limiting molecule, and upregulated expression of Nrf2, the key CX3CR1 downstream target gene. Additionally, in spinal cord of propranolol-administered rats the expression of heme-oxigenase 1, Nrf2 target gene, was upregulated. Consequently, microglia from propranolol-administered rats, exhibited increased proportion of IL-10–expressing cells, but decreased those of IL-1β– and IL-23–expressing ones. Propranolol also downregulated the IL-6 and MCP-1/CCL2 expression in spinal cord. Furthermore, propranolol affecting CXCR1/Nrf2 signaling pathway enhanced microglial phagocytic/endocytic capacity and surface expression of anti-inflammatory CD163/CD83 markers. Results from in vitro pharmacological study examining influence of noradrenaline/propranolol on functional properties of microglia showed that microglia synthesize noradrenaline, which, in turn, through β-adrenoceptor, downregulated their Nrf2 expression, in a CX3CR1-independent manner. In accordance with microglial shift towards a more anti-inflammatory profile, in spinal cord of propranolol administered rats was found: i) decreased infiltration with blood-borne myeloid and CD4+ T cells, and ii) reduced CD4+ T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF. The study suggests a neuroinflammation-promoting role for central noradrenaline in EAE, via β-adrenoceptor–mediated modulation of microglial Nrf2 expression. Thus, it points out to a putative target for future translational pharmacological research to optimize multiple sclerosis therapy. Funding: MPNTR RS (grant number 175050
Bacterial Diversity among the Sediments of Glacial Lakes in the Western Balkans: Exploring the Impact of Human Population
No full text16S rRNA gene-based metagenomic approach was used to assess the biodiversity of bacterial communities in the sediments of selected glacial lakes in the Western Balkans and to assess the impact of human population on these microbial communities. Sediment samples were collected from three glacial lakes, viz., Plav Lake (in a zone of the highest impact of human population), Black Lake (a zone of medium impact of human population), and Donje Bare Lake (a remote lake with minimal impact of human population). Canonical correlation analysis analysis indicated correlation between the distance of the lake from urbanized population and bacterial diversity in Donje Bare Lake sediment. Bacterial diversity of Black Lake sediment was correlated with high content of phosphorous and pH value. Chemical compounds exhibiting the most prominent correlation with bacterial diversity of Plav Lake were NH4-N, K2O, CaCo3, and total nitrogen . Additionally, CCA analysis indicated that population density was correlated with biodiversity of bacterial communities in Plav Lake sediment, which is the most exposed to human population. Multivariate regression revealed the highest correlation between the presence of Proteobacteria classes and population density and levels of NH4-N. The influence of human population was observed to be important for shaping the sediment communities in addition to biological and chemical factors
Binding activity to intestinal cells and transient colonization in mice of two Lactobacillus paracasei subsp. paracasei strains with high aggregation potential
No full textSurface properties like hydrophobicity, aggregation ability, adhesion to mucosal surfaces and epithelial cells and transit time are key features for the characterization of probiotic strains. In this study, we used two Lactobacillus paracasei subsp. paracasei strains (BGNJ1-64 and BGSJ2-8) strains which were previously described with very strong aggregation capacity. The aggregation promoting factor (AggLb) expressed in these strains showed high level of binding to collagen and fibronectin, components of extracellular matrix. The working hypothesis was that strains able to aggregate have an advantage to resist in intestinal tract. So, we assessed whether these strains and their derivatives (without aggLb gene) are able to bind or not to intestinal components and we compared the transit time of each strains in mice. In that purpose parental strains (BGNJ1-64 and BGSJ2-8) and their aggregation negative derivatives (BGNJ1-641 and BGSJ2-83) were marked with double antibiotic resistance in order to be tracked in in vivo experiments in mice. Comparative analysis of binding ability of WT and aggregation negative strains to different human intestinal cell lines and mucin revealed no significant difference among them, excluding involvement of AggLb in interaction with surface of intestinal cells and mucin. In vivo experiments showed that surviving and transit time of marked strains in mice did not drastically depend on the presence of the AggLb aggregation factor