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Biomedical subjects

L M Grimaldi

Publications and source records attributed to L M Grimaldi.

At least 19 recordsLinked to original sources
PubMed2005

Ctla4 and multiple sclerosis in the Italian population.

CTLA4 protein is a receptor molecule that plays a critical role as a negative regulator of the immune response. Therefore, genetic variations in CTLA4 may confer susceptibility to autoimmune diseases such as multiple sclerosis (MS). In order to investigate the association of two CTLA4 polymorphisms (+49 A/G and -318 C/T) with multiple sclerosis, sporadic MS patients and healthy controls from Italy were genotyped through direct DNA sequencing. Considering single-loci variations, no differences in the allelic and genotypic frequencies between patients and controls were found. However, considering a putative interaction at the two loci, the T/G combination was more frequently observed in patients than in controls. This result suggests that this allelic combination of the CTLA4 polymorphisms may be involved in the susceptibility to MS in the Italian population.

Antigens, CD↗
PubMed2005

Analysis of Chlamydia pneumoniae-specific oligoclonal bands in multiple sclerosis and other neurologic diseases.

OBJECTIVE: Paired serum and cerebrospinal fluid (CSF) specimens were investigated for Chlamydia pneumoniae-specific oligoclonal bands (OCBs) to determine band specificity in multiple sclerosis (MS). MATERIAL AND METHODS: Serum and CSF samples were collected from patients with relapsing-remitting MS (n = 56), other inflammatory (n = 18) or non-inflammatory (n = 15) neurologic diseases, and from 10 healthy controls. OCBs were determined with affinity immunoblotting of C. pneumoniae-specific IgG onto antigen-coated nitrocellulose paper after protein separation with agarose isoelectric focusing. RESULTS: Chlamydia pneumoniae-specific OCBs were present in 5 of 56 patients with MS, and in 3 of 18 patients with other inflammatory neurologic diseases. CONCLUSIONS: The intrathecal production of C. pneumoniae-specific oligoclonal IgG occurs in a minority of patients with MS. This intrathecal anti-C. pneumoniae reactivity is likely part of a polyspecific humoral immune response in MS.

AIDS Dementia Complex↗
PubMed2003

Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease.

Proinflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their high production have been shown to be associated with AD. Thus, AD patients display a proinflammatory genotype and the control of inflammation might play a protective role in AD development. By sequence-specific probes, we have evaluated the role of anti-inflammatory cytokine interleukin(IL)-10 in AD, by analysing in 132 AD patients and 213 healthy controls the prevalence of three different haplotypes, involving three single-nucleotide polymorphisms (SNPs) at -1082 (G-->A), -819 (C-->T) and -592 (C-->A) nucleotides of IL-10 promoter, associated with different IL-10 production. The percentage of -1082A carrier subjects was significantly increased among AD patients, and this increase was mainly due to the increase of ATA haplotype. Analysing these results according to the well-known genetic risk factor APOE-e4 allele, no significant differences were observed in SNP IL-10 allele distribution between AD patients carrying the genotype or not. So we may conclude that the presence of -1082A allele and in particular of -1082A/-819T/-592A haplotype, associated with a low production of anti-inflammatory cytokine IL-10, may be considered as an additive and independent genetic risk factor for AD.

Alzheimer Disease↗
PubMed2001

High incidence and increasing prevalence of MS in Enna (Sicily), southern Italy.

Twenty years after a first survey, a follow-up study was performed on the prevalence of MS in Enna (Sicily), southern Italy. The prevalence of definite MS rose from 53 to 120.2 per 100,000 population. The incidence of definite MS for the period 1986 to 1995 was 5.7 per 100,000 per year. The innermost part of Sicily shows an elevated prevalence of MS, second only to Sardinia in the Mediterranean area.

Adolescent↗
PubMed2001

Pharmacogenomics of neurodegenerative diseases.

Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease.

Alzheimer Disease↗
PubMed2001

Neuroinflammation and the genetics of Alzheimer's disease: the search for a pro-inflammatory phenotype.

The role of interleukin 1 (IL-1) and interleukin 6 (IL-6) in the pathogenesis of Alzheimer's disease (AD) is reviewed within the framework of "inflamm-aging", i.e., the characteristic chronic pro-inflammatory status which develops in old age, and neuroinflammation, i.e., the peculiar inflammatory process which is present in the brain of AD patients. In particular, the data suggesting that several IL-1 and IL-6 gene polymorphisms can contribute to the risk of developing AD are reviewed. The possibility as well as the difficulty in identifying a pro-inflammatory phenotype, and its importance for the prevention, diagnosis and therapy of AD and other age-related pathologies are discussed.

Aged↗
PubMed2000

Cytokines and immunity in multiple sclerosis: the dual signal hypothesis.

Multiple sclerosis (MS) is considered an immune-mediated disease of the central nervous system (CNS) sustained by a chronic inflammatory process leading to patchy demyelination and axonal loss. However, the inflammatory triggering event as well as the target of the pathogenic process in MS are still partially unknown. We report evidence that a 'local' inflammatory process occurring in the CNS (considered as a reaction of blood vessels in vascularized living tissue to a local injury leading to the accumulation of fluid and blood cells) along with a concomitant, but possibly unrelated, peripheral inflammatory event may trigger a CNS-specific autoimmune reaction cascade sustaining the MS pathogenesis. In the CNS, inflammatory mediators (mainly cytokines) act either as regulatory (i.e. activation of glial cells, shaping the autoimmune response) or effector molecules (i.e. myelinotoxicity, oligodendrotoxicity). In the periphery, inflammatory cytokines induce, in a bystander fashion, activation of monocytes and T cells. Among this latter cell population there are myelin-specific T cells belonging to the normal 'autoimmune' repertoire that home to the CNS where they may trigger the continuous recruitment of effector cells (macrophages) from the periphery. The concept that two concomitant, but possibly unrelated, inflammatory events, occurring in the CNS and in the periphery, represent the crucial elements sustaining MS, might reveal a more comprehensive view (dual signal hypothesis) of the entire etiopathogenic process underlying this disease.

Animals↗
PubMed2000

Association study of a new polymorphism in the PECAM-1 gene in multiple sclerosis.

Genetic polymorphisms of immunorelevant genes may modulate occurrence or clinical features of multifactorial diseases. PECAM-1 is an adhesion molecule crucial for transmigration of cells from blood to tissues, but its genetic contribution to multifactorial diseases has never been investigated. We have identified and characterized a tetranucleotide repeat polymorphism within the third intron of PECAM-1. In a cohort of healthy controls (HC), we found 10 alleles. An assessment of the association of this polymorphism with multiple sclerosis (MS) showed similar allele and genotype frequencies in HC and MS patients as well as in MS patients differing for the gravity of their disease course. We conclude that although potentially able to affect organ-specific autoimmune diseases, this new PECAM-1 polymorphism, does not seem to contribute to the genetic background of MS.

Adult↗
PubMed2000

Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain?

Plasma concentrations of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), C reactive protein (CRP) and alpha-1-antichymotrypsin (ACT) in 145 patients with probable Alzheimer's disease (AD) and 51 non-demented controls were measured. To investigate the cellular activation of peripheral immune system, plasma levels of neopterin were also investigated. Plasma levels of IL-1 were detectable in 17 patients with AD (13%) and only in one control (2%) and average levels of IL-1 were higher in AD patients than in controls (p < 0.001). IL-6 plasma levels were detectable in a higher proportion of AD and controls (53% and 27%, respectively), and were increased in patients with AD (p < 0.001). Plasma levels of ACT were increased in patients with AD (p < 0.001) and CRP levels were in the normal range. Plasma levels of neopterin were slightly lower in AD patients than in controls, but differences were not statistically significant. No significant correlation was observed between IL-1 and IL-6 levels or neopterin and cytokine levels in plasma from AD patients. Plasma levels of ACT negatively correlated with cognitive performances, as assessed by the mini mental state examination (MMSE; R = -0.26, p < 0.02) and positively correlated with the global deterioration state (GDS) of AD patients (R = 0.30, p < 0.007). Present findings suggested that detectable levels of circulating cytokines and increased ACT might not be derived by activation of peripheral immune system of AD patients. Detection of these molecules might be used for monitoring the progression of brain inflammation associated with AD.

Aged↗
PubMed2000

The pervasiveness of interleukin-1 in alzheimer pathogenesis: a role for specific polymorphisms in disease risk.

Interleukin-1 (IL-1) has been implicated as a key molecule in Alzheimer pathogenesis based on findings of an IL-1 overexpression in Alzheimer brain that is directly related to plaque progression and tangle formation, and on findings that IL-1 induces excessive synthesis, translation, and processing of neuronal beta-amyloid precursor protein (betaAPP) as well as synthesis of most known plaque-associated proteins. In addition, IL-1 activates astrocytes, with the important consequence of overexpression of the neuritogenic cytokine S100beta and overgrowth of dystrophic neurites in neuritic plaques. As further evidence of the importance of IL-1 in Alzheimer pathogenesis, two new genetic studies of inheritance of specific polymorphisms in IL-1 genes in Alzheimer and control patients show that homozygosity for a specific IL-1A gene polymorphism at least triples risk for development of Alzheimer's disease. This increase is associated with earlier age of onset. Homozygosity for this polymorphism plus another in the IL-1B gene further increases risk.

Alzheimer Disease↗
PubMed2000

Lack of association between the interferon regulatory factor-1 (IRF1) locus at 5q31.1 and multiple sclerosis in Germany, northern Italy, Sardinia and Sweden.

Interferon regulatory factor-1 (IRF-1) is a transcriptional inducer of the interferon-beta (IFN-beta) gene and other interferon-stimulated genes. A GT repeat polymorphism in the 7th intron of the IRF-1 gene was used as a marker to test for association with multiple sclerosis (MS) in a case-control study including individuals from Germany, Northern Italy and Sweden. In none of these populations, did we find any significant allelic association with disease. This lack of association was confirmed by testing transmission disequilibrium of individual IRF1 alleles in a representative sample of Sardinian simplex MS families. No deviation of the expected 50% transmission rates was seen. Therefore, our work does not provide evidence in favor of IRF1 being a candidate for conferring genetic susceptibility to, or protection against, MS in Europe.

Adolescent↗
PubMed2000

Association of early-onset Alzheimer's disease with an interleukin-1alpha gene polymorphism.

Overexpression of the pluripotent cytokine interleukin-1 (IL-1) by microglial cells correlates with formation of neuritic beta-amyloid plaques in Alzheimer's disease (AD). We evaluated polymorphisms in the genes coding for the IL-1alpha, IL-1beta, and IL-1 receptor antagonist cytokines, and tested their association with the occurrence and age at onset of sporadic AD. We found a strong association between the IL-1A T/T genotype and AD onset before 65 years of age (odds ratio, 4.86), with carriers of this genotype showing an onset of disease 9 years earlier than IL-1A C/C carriers. A weaker association with the age at onset was also shown for the IL-1B and IL-1RN genes. These data suggest either a direct effect of the IL-1 gene family, mainly IL-1A, on the clinical onset of AD, or a linkage dysequilibrium with an unknown locus relevant to AD on chromosome 2.

Adult↗
PubMed2000

Induction of IL-1 receptor antagonist by interferon beta: implication for the treatment of multiple sclerosis.

IFNbeta has been the first drug approved for the treatment of multiple sclerosis patients, but we still lack a full understanding of the mechanisms underlying its clinical effects and the great variability of its therapeutic efficacy among different patients. Serum levels of the anti-inflammatory cytokine IL-1 receptor antagonist increase after IFNbeta administration in MS patients. We now report that IFNbeta induced IL-1ra mRNA and mature protein in three myelomonocytic cell lines. The induction of IL-1ra was already visible after 2 h of stimulation and persisted at least for 24 h. The amounts of induced IL-1ra were equal or higher than those obtained using other IL-1ra stimuli (LPS, IL-1beta, IFNgamma, IL-4, dexamethasone). This prolonged and quantitatively elevated induction of IL-1ra may contribute to the anti-inflammatory effect of IFNbeta and partially account for the reduction of exacerbation rate shown in most IFNbeta-treated MS patients.

Adjuvants, Immunologic↗
PubMed2000

Gene polymorphism affecting alpha1-antichymotrypsin and interleukin-1 plasma levels increases Alzheimer's disease risk.

Plasma levels of alpha1-antichymotrypsin (ACT) and interleukin-1beta (IL-1beta) were increased in patients with probable Alzheimer's disease (AD). A common polymorphism within ACT and IL-1beta genes affected plasma levels of ACT or IL-1beta, and AD patients with the ACT T,T or IL-1beta T,T genotype showed the highest levels of plasma ACT or IL-1beta, respectively. The concomitant presence of the ACT T,T and IL-1beta T,T genotypes increased the risk of AD (odds ratio: 5.606, confidence interval: 1.654-18.996) and decreased the age at onset of the disease.

Aged↗