Grażyna Gromadzka

Estrogen and Cytokines Production - The Possible Cause of Gender Differences in Neurological Diseases

Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders. These include head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases (Parkinsons disease (PD), Alzheimers disease (AD) or amyotrophic lateral sclerosis (ALS). Accumulating evidence suggests that observed differences between men and women could result from estrogens wide range of effects within the mammalian central nervous system (CNS), with its neuroprotective effect being one of the most important. It seems possible that neuroprotective activity of estrogen could be partially a result of its anti-inflammatory action. It has been well established that inflammation plays an important role in the etiopathogenesis and manifestation of brain pathological changes. In this regard, an important role has been suggested for pro-inflammatory cytokines produced by activated glial cells, neurons and immune cells that invade brain tissue. Within the CNS, cytokines stimulate inflammatory processes that may impair blood-brain barrier permeability as well as promote apoptosis of neurons, oligodendrocytes and induce myelin damage. Given that estrogen may modulate cytokine expression, coupled with the fact that gender differences of cytokine production are apparent in animal models of PD and MS, suggests an important connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS patients and mice subjected to experimental autoimmune encephalomyelitis (EAE) display gender specific alterations of IFN-gamma and IL-12, variations of TNF and IL-6 were associated with PD. Also in case of more acute neurodegenerative conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was different in males and females. Given that our understanding of the role of estrogen on cytokine production and accompanying CNS pathological conditions is limited, the present reviews aims to present some of our recent findings in this area and further evaluate the evidence that may be relevant to the design of new hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.

Gender differences in neurological disease: role of estrogens and cytokines.

Increasing evidence suggests that inflammatory response may be a critical component of different brain pathologies. However, the role played by this reaction is not fully understood. The present findings suggest that neuroinflammtory mediators such as cytokines may be involved in a number of key steps in the pathological cascade of events leading to neuronal injury. This hypothesis is strongly supported by experimental and clinical observations indicating that inhibition of the inflammatory reaction correlates with less neuronal damage. Estrogens are thought to play a role in the sex difference observed in many neurological diseases with inflammatory components including stroke, Alzheimers and Parkinsons diseases, multiple sclerosis, or amyotrophic lateral sclerosis. Clinical and experimental studies have established estrogen as a neuroprotective hormone in these diseases. However, the exact mechanisms involved in the neuroprotective effects of estrogens are still unclear. It is possible that the beneficial effects of these hormones may be dependent on their inhibitory activity on the inflammatory reaction associated with the above-mentioned brain pathologies. Here, we review the current clinical and experimental evidence with respect to the inflammation-modulating effects of estrogens as one potential explanatory factor for sexual dimorzphism in the prevalence of numerous neurological diseases.

Elevated Levels of Anti-Heat Shock Protein Antibodies in Patients with Cerebral Ischemia

One of the important mechanisms involved in the development of vascular lesions leading to ischemic stroke could be an immune response to heat shock proteins (hsp). For carotid atherosclerosis and myocardial infarction, an association with an increase in anti-hsp 65 antibodies has been demonstrated. The aim of our study was (1) to investigate whether ischemic stroke is associated with a humoral immune response to hsp; (2) to study the connection between anti-hsp antibodies and other stroke risk factors; (3) to estimate if the elevated levels of anti-hsp antibodies could be an independent risk factor for stroke. We examined 180 patients (in the first 48 h after stroke onset) and 64 age-matched healthy controls. The levels of IgG and IgM antibodies to hsp 65 and 70 were measured by ELISA. Ischemic stroke was connected with a significant elevation of anti-hsp 65 and anti-hsp 70 antibody levels (IgG and IgM) compared with controls (p < 0.0001). The multifactorial logistic regression analysis showed that increased levels of anti-hsp 65 and anti-hsp 70 IgG antibodies are independent risk factors for stroke. Our results suggest that humoral immunity to hsp is common in stroke patients and that elevated levels of anti-hsp antibodies could be triggering factors for stroke.

Monozygotic female twins discordant for phenotype of Wilson's disease†

Wilsons disease (WD) is an autosomal recessive disorder characterized by the functional disruption of the copper‐transporting protein adenosine triphosphatase 7B (ATP‐ase 7B). The disease is caused by mutations in ATP7B gene. It seems that the type of mutation in ATP7B only to some degree determines phenotypic manifestation of WD. We examined two pairs of monozygotic twins discordant for WD phenotype. The first set of twins were ATP7B compound heterozygotes c.3207C>A (p.H1069Q)/c.1211_1212insA (p.N404Kfs). The index case developed severe liver failure followed by depressive symptoms, dysarthria, and tremor at the age of 36. Her sister remained presymptomatic at diagnosis at the age of 39. The second twins were ATP7B c.3207C.A (p.H1069Q) homozygotes. The index case presented with dysarthria and tremor at the age of 26. Her sister remained clinically presymptomatic at diagnosis at the age of 28. We concluded that the phenotypic characteristics of WD are possibly attributable to epigenetic/environmental factors.

Association of IL1A, IL1B, ILRN, IL6, IL10 and TNF-α polymorphisms with risk and clinical course of multiple sclerosis in a Polish population.

Single nucleotide polymorphisms in human pro- and anti-inflammatory genes, including IL1RN VNTR (rs315952), IL1A 4845G>T (rs17561), L1B-511C>T (rs16944), IL6-174G>C (rs1800795), IL10-1082 A>G (rs 1800896) and TNFα-308G>A (rs1800629) and their impact on multiple sclerosis risk and disease progression in a Polish population were investigated. Increased risk of MS was found for IL6-174 CC homozygotes (OR, 2.88; p<0.00001). In turn, IL1A 4845 TT genotype determined earlier appearance of MS onset whereas IL1B-511 TT genotype was associated with later occurrence of MS but faster disability progression.

Late onset Wilson's disease: Therapeutic implications

The clinical symptoms of Wilsons disease (WD) usually develop between 3 and 40 years of age and include signs of liver and/or neurologic and psychiatric disease. We report on an 84‐year‐old woman with WD. Despite the absence of treatment, the only symptom she presented with, until the age of 74 years, was Kayser‐Fleisher rings. At the age of 74, she developed slightly abnormal liver function. This case raises the following issues: (a) Should WD be considered in all patients of all ages who manifest signs related to the disease? (b) Are ATP7B mutations fully penetrant? (c) Should all patients diagnosed presymptomatically receive anticopper therapy?

Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Significance Wilson disease (WD) is a disorder of copper overload whose variable presentation poses diagnostic and treatment challenges. WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper by trafficking from the TGN to the plasma membrane. This multidisciplinary study established that a patient mutation, ATP7B-S653Y, has Cu(I) transport activity in the TGN, but completely disrupts Cu(I)-responsive trafficking. ATP7B-S653Y perturbs long-range interdomain interactions mediated by transmembrane segments TM1/TM2, suggesting a new functional role for this region. ATP7B-S653Y is the best-characterized example of a new functional class of WD mutants. We suggest that functional classification of WD mutations may facilitate targeted therapy for patients. Wilson disease (WD) is a monogenic autosomal-recessive disorder of copper accumulation that leads to liver failure and/or neurological deficits. WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane. To date, most WD mutations have been shown to disrupt ATP7B activity and/or stability. Using a multidisciplinary approach, including clinical analysis of patients, cell-based assays, and computational studies, we characterized a patient mutation, ATP7BS653Y, which is stable, does not disrupt Cu(I) transport, yet renders the protein unable to exit the TGN. Bulky or charged substitutions at position 653 mimic the phenotype of the patient mutation. Molecular modeling and dynamic simulation suggest that the S653Y mutation induces local distortions within the transmembrane (TM) domain 1 and alter TM1 interaction with TM2. S653Y abolishes the trafficking-stimulating effects of a secondary mutation in the N-terminal apical targeting domain. This result indicates a role for TM1/TM2 in regulating conformations of cytosolic domains involved in ATP7B trafficking. Taken together, our experiments revealed an unexpected role for TM1/TM2 in copper-regulated trafficking of ATP7B and defined a unique class of WD mutants that are transport-competent but trafficking-defective. Understanding the precise consequences of WD-causing mutations will facilitate the development of advanced mutation-specific therapies.

BDNF − 270 C>T polymorphisms might be associated with stroke type and BDNF − 196 G>A corresponds to early neurological deficit in hemorrhagic stroke

Genetic factors might be involved in stroke prognosis, however the role of brain-derived neurotrophic factor (BDNF) in stroke recovery is unknown. We have studied BDNF -196 G>A and -270 C>T polymorphisms in ischemic and hemorrhagic stroke and their impact on stroke prognosis. There was higher occurrence of BDNF -270 CC genotype in patients with hemorrhagic than ischemic stroke (96% versus 86%, p=0.0495). In hemorrhagic stroke BDNF -196 GG carriers scored better in NIHSS at admission (14.23 versus 21.00, p=0.0192) and after 7days (8.60 versus 15.00, p=0.0408) of onsets. None of the determined polymorphisms had any impact on 30-day early outcome in ischemic and hemorrhagic stroke.

Neurological presentation of Wilson's disease in a patient after liver transplantation.

We report of a 32‐year‐old man who showed dystonic symptoms within few days after liver transplantation (LT). The clinical, biochemical, and, finally, genetic evaluation confirmed Wilsons disease diagnosis in this patient. We suspect that extrapyramidal signs in this case could be a result of acute brain injury because of the massive copper release from liver to the circulation just before and during LT.

Association of MMP1, MMP3, MMP9, and MMP12 polymorphisms with risk and clinical course of multiple sclerosis in a Polish population

Single nucleotide polymorphisms in human MMP genes, including MMP1 (-1637 1G>2G), MMP3 (-1612 5A>6A), MMP9 (-1562 C>T), and MMP12 (-82 A>G), and their impact on multiple sclerosis risk and disease progression in a Polish population were investigated. Increased risk of MS was found among carriers of at least one T allele of MMP9 -1562 C>T (OR, 1.7; p=0.0030) and one G allele of MMP12 -82 A>G (OR, 3.9; p<0.00001). Additionally, an association between MMP9 genotype and MMP-9 levels in peripheral blood was detected. Our results suggest that MMP9 -1562 C>T and MMP12 -82 A>G polymorphisms affect susceptibility to multiple sclerosis.