Demographic And Clinical Aspects Of Epilepsy Biology Essay

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Epilepsy is a brain disorder that has a higher incidence in developing countries (Mac et al., 2007) which includes Malaysia and some other countries in Asia. More than half of the 50 million epilepsy sufferer worldwide are estimated to be from Asia even though a great development in health services management has been established (Mac et al., 2007). The exact prevalence of epilepsy in Malaysia has not being stated in any published papers, so we had to rely on the incidence in neighbouring countries such as Singapore with 5 over 1000 people had epilepsy, Thailand (7.2/1000) and Vietnam with 14 over 1000 (Mac et al., 2007). This study was conducted merely to achieve the objectives stated which is mainly to figure out the possible association that can link between epilepsy, lymphocyte subsets, activation markers and herpes virus infections. To our knowledge, there was no other study in Malaysia linking between all this three main factors and the results obtained here may imply some idea to be a step closer to find the solution to this worldwide disorder.

Demographic and Clinical aspects of the study

A total of 95 patients from all around Kelantan who comes to HUSM for routine check up and fulfil the inclusion and exclusion criteria were recruited for the study. All patients had medical record of more than 1 year in HUSM which is quite useful for further reference. In this study, the distribution difference between male and female patients was not significant which reflects a non gender-biased disorder and this finding is similar to most of epilepsy research done elsewhere (Mac et al., 2007, Sander and Shorvon, 1996, Kim et al., 2010, Forsgren et al., 2005, Fong et al., 2003). This shows us that either male or female has an equal risk to be affected with epilepsy, however, males usually has a higher numbers but still, not significant and their epilepsy are mostly due to head injuries during accidents (Sander and Shorvon, 1996). Majority of the patients involved in this study were Malays (93.7%) followed by Chinese (4.2%) and Indian with only 2.1%. This is not surprising as according to Kelantan statistics itself, the most numbers goes to Malay ethnic with 95% of total citizen (Vimalan et al., 2000). A study on newly diagnosed epilepsy in University of Malaya Medical Centre (UMMC) found no evidence of any ethnic predisposition to epilepsy among those three ethnics which is in coincidence with this study done here (Manonmani and Tan, 1999). However, an inadequate sample size may also be a factor contributing to the incidence of ethnicity distortion towards Malays. These insufficient patient subjects are due to budget constraint in collecting and processing samples.

In terms of clinical aspects, all the epilepsy patients were diagnosed to have epilepsy by qualified HUSM medical neurologist. Type of epilepsy and the type of seizure for each patient were based on electroencephalography (EEG) and magnetic resonance imaging (MRI) analysis.

(Age at Seizure Onset)

This study found out that the patients' average age when first encountered epilepsy was 15.6 years and not that far from a previous study in UMMC (Manonmani and Tan, 1999) which had their mean age at onset was 18.7 years. This difference may be due to age range involved as we only include those who are between 18 to 50 years old whereas the previous study had some of their patients' onset at the age of more than 70. In 2003, a study in Hong Kong on 736 adult epilepsy patients, had their patient's mean age of onset was 19.9 years which is only a year difference from those being observed by Manonmani and Tan, (1999), however the age range for this study was 25 to 30 years (Mac et al., 2007).- kenapa.. n research lain??

Epilepsy is not just about recurring seizures but it is often associated to social problems that involves education, employment, marriage and emotion (Tlusta et al., 2009). Experiencing epilepsy since childhood usually creates a great impact in educational progress and later may face difficulties in finding a promising job (Tlusta et al., 2009).

Even though not significant, the prevalence of epilepsy in India and Pakistan was found to be higher in rural areas rather than in urban areas (Mac et al., 2007). - wrong sentence placement


Djibouti and Shakarishvili, (2003) conducted a study and found out that over 115 epilepsy patients, only 39.1 % completed their tertiary education level while the rest, (60.9%) had their highest formal education up to secondary level only. This numbers are quite high when compared to the present study in where, only 28.4% completed their tertiary level while 54.7% finished secondary level, and 14.7% had primary education only. Another 2.1% had no formal education due to the epilepsy disorder itself. ++ lagi


Some previous studies stated that epilepsy patients have lower marriage rates (Djibuti and Shakarishvili, 2003, Hermann et al., 2008) and higher divorce rates (Kim et al., 2010). Kim et al. (2010) reported that 333 patients out of 584 are married (57.0%) while 43.0% remains single and another 11.4% was divorced due to the disease. They too had figured out that men with epilepsy is more likely to be unmarried (52.5%) when compared to female patients (34.4%), and the probability of being single for men was 3.5-fold greater than women (Kim et al., 2010). -research ni??


Epilepsy patients are more likely to be underemployed or unemployed (Djibuti and Shakarishvili, 2003). Epilepsy patients has high reported rates of unemployment, lower income (less than $25 thousand per year) and lower education (Hermann et al., 2008).


The findings from this study display less than 10% of the epilepsy patients had any of their close relatives which are their parents or siblings suffered from epilepsy. Fong et al., (2003) discovered only 31 epilepsy patients (4.2%) had close relatives with history of seizure disorders with majority of them (77.4%) had idiopathic epilepsy. This result suggests that genetic inheritance is not a major cause in contributing to epilepsy (Manonmani and Tan, 1999) and there's possibly some other causative factor that plays a great role in epilepsy. However, a study in Kerala, south India proved that family history of epilepsy was three times more common in patients with epilepsy than in controls and two times higher in another study in north India and the same goes in Laos and China where family history was also found to be a risk factor (Mac et al., 2007).


This study observed only four patients (4.2%) had encountered febrile fits during childhood and this result was in accordance with ......... Sander and Shorvon, (1996) stated in their paper that only 3% of children who experience febrile convulsion with no previous neurological abnormalities, develops epilepsy.

However, most researchers agrees to the fact that the risk to develop epilepsy after some febrile fit incidence is quite small, only 2-10%, depending on the type of febrile fit they encountered (Shorvon, 2010, Tsai and Hung, 1995).


This study resulted... semua idiopathic... classification utk temporal lobe?

A study in Hong Kong observed that out of 736 epilepsy patients they recruited, 38.7% had idiopathic epilepsy while the rest are of cryptogenic and symptomatic epilepsy type (Fong et al., 2003). Idiopathic epilepsy were classified according to the standards by ILAE (Commission on Epidemiology and Prognosis, 1993) referring to patients that had partial or generalised epilepsy syndromes with specified clinical characteristics and EEG results (Fong et al., 2003). Idiopathic generalised epilepsy was found out to be the most frequent type that affected newly diagnosed generalized epilepsy in Malaysia (Tan and Lim, 1997).


The most common seizure occurrence in this study was the secondary generalised complex partial seizure (82.1%) followed by complex partial seizure (12.6%), secondary generalised simple partial seizure (3.2%) while simple partial seizure only affects 2.1% patients.

In 1993, a total of 86% adult epilepsy patients encountered generalised seizures in Malaysia (Mac et al., 2007). Previous study in Malaysia had most of their patients were secondary generalised seizure type (32.7%), followed by simple partial seizure with secondary generalisation (9.1%), complex partial seizure with secondary generalization (6.7%), simple partial seizure (6.1%), and complex partial seizure (3%)(Manonmani and Tan, 1999).

However, a study found that the most frequent seizure occurred were the partial seizures with secondary generalisation and followed by complex partial seizure (Fong et al., 2003).


The most frequent used anticonvulsants among the epilepsy patients in this study were carbamazepine (27.7%), levetiracetam (24.8%), sodium valproate (17.7%), lamotrigine (15.6%), phenytoin (8.5%), topiramate (2.8%), phenobarbitone (1.4%), and clonazepam and acetazolamide (0.7%).

Tan and Lim, (1997), stated that the most common anticonvulsants used in Malaysia were phenytoin (57.5%), carbamazepine (17.5%), valproic acid (12.5%) and phenobarbitone (12.5%) while in Singapore, carbamazepine (52%), valproic acid (24.3%) and phenytoin (22.3%).

Most antiepileptic drugs are effective to control seizures as soon as possible in almost 60-70% of patients (Duncan et al., 2006). These antiepileptic drugs are functioned suppress the seizure symptoms as to increase inhibition, decrease excitation or to prevent aberrant burst-firing of neurons (Duncan et al., 2006).

Lymphocyte subsets and activation markers in epilepsy

Lymphocytes were known to have both regulating and effector functions determined by different subsets in blood. Commonly, these subsets were found to be altered in most disease involving the immune system (Backteman and Ernerudh, 2007) which sometimes were affected by varying environmental factors (Dhaliwal et al., 1995). Bauer et al., (2008), assured that there are alterations of systemic immune parameters in epileptic patients in where their IL-1 and IL-6 counts increased in serum and cerebrospinal fluid after experiencing generalized tonic-clonic seizures (Bauer et al., 2008).

Apart from that, other commonly observed markers in epilepsy patients were activated markers. These activation antigens are composed by cellular molecules that can be expressed on T and B lymphocytes and NK cells and also on other cells which were stimulated during inflammation by pathogens or mitogens (Rea et al., 1999). Early antigens were marked by CD69, and are upregulated immediately four hours after activation. According to Rea et al., (1999), this antigen initiates protein tyrosine kinase and calcium flux activity and also the transcription of IL-2 and TNF. Next, CD25 (IL-2Rα) upregulation at the period of 12 to 24 hours on cell membranes, facilitates the production of an IL-2 high affinity receptor that will initiate cell proliferation and differentiation (Rea et al., 1999). Rea et al., (1999) too had suggested that between 48 to 60 hours after antigenic challenge, HLA-DR is upregulated advocating antigen presentation, marking progress towards specific and adaptive phases of the immune response.



Among all this above mentioned lymphocyte subsets studied, none of them were found to have any significant differences when compared to healthy controls. CD3, CD4, CD8 and CD19 subsets were found to be lower in epilepsy patients however not statistically significant. The decrease of CD4 T cells was normally found in patients treated with sodium valproate (Bauer et al., 2008). Sodium valproate was found to be the third most prescribed to patients in this study which may be the cause why CD4 T cells were found to be lower compared to healthy controls but, still not significant. Bauer et al., (2008) discovered that their patients experiencing frontal or temporal lobe epilepsy had a decreased total T cells and CD4 T cells counts after left hemisphere cortical resection, however, right hemisphere surgery revealed opposite effects. +lagi info...


NK cells are found to have the capability of releasing inflammatory cytokines like GM-CSF and TNF-α which has an cytotoxic affects against tumor cells, leukemic and virally infected cells without prior sensitization (Dhaliwal et al., 1995) (sinkovics and Horvath,2005). A decreased numbers of circulating NK is normally associated with the development and progression of cancer as well as in acute and chronic infections, however, a higher levels of NK cells may also be caused by a higher exposure of viruses in that particular population (Dhaliwal et al., 1995). NK cell activity were found to decrease in patients with epilepsy (Bauer et al., 2008) and some other studies too had patients with epilepsy that showed a decrease in NK cell activity (margaretten and warren1986; wang et al,1989). However, CD16+56+ were found to be significantly higher in epileptic patients (result) when compared to healthy controls in this present study. Even so, other studies' observations reflected interictal states which are quite difficult to compare them to the present results.

It was also found that levetiracetam medication has an effect of lowering NK-like t cells (Bauer et al., 2008) and almost 25% of the patients in this study had levetiracetam.

CD4CD25, CD8CD25

CD25+ subset is a homogenous population of T reg cells in the peripheral blood are not a discrete population, because they coexist with a large and overlapping population of CD25+ dim cells. It is unknown to what extent conventional activated T cells contribute to the CD4+CD25+ populations, but it possibly depends on the state of activation of the immune system of the donor in that particular moment (Liotta et al., 2005).

Eventhough CD425 has been studied thoroughly but only CD825 were found to be significantly lower in epileptic patients (result) when compared to healthy controls (result).

A study on multiple sclerosis (MS) patients resulted to a lower percentage in inactive MS than healthy subjects; however it did not reach statistical significance (Okuda et al., 2005).

None nevertheless, the observed results of a difference in CD8 activation marker in epileptic patients is obviously related to continuous immune disturbance but not in disease activity.

CD4CD25 regulatory T cells has an important role in peripheral tolerance (Azuma et al., 2003). The depletion of CD4+CD25+ T cells before tumor implantation is effective in evoking specific tumor immunity and generating cytotoxic cells (Azuma et al., 2003). <- xtau la.. and rephrase too.

The thymus is the primary source of this CD4+CD25+ T reg subset, which then participates in the active suppression of potentially autoreactive T cells in the periphery. CD4+CD25+ have been described in a variety of experimental systems to provide protection from T cell-mediated autoimmune disorders (Liotta et al., 2005).

A new population of human regulatory thymocytes being CD8+CD25+ cells have also been recently described by our group. The CD8+CD25+ thymocytes share similar phenotypic characteristics and functions with CD4+CD25+ thymocytes. In fact, CD8+CD25+ thymocytes could be detected in the same areas of human thymus where CD4+CD25+ cells had been observed, and more importantly, they constitutively expressed the X-linked forkhead/winged helix transcription factor, Foxp3 and glucocorticoid-induced TNF receptor family-related receptor (GITR) mRNA. CD8+CD25+ thymocytes expressed both surface snd cytoplasmic markers of CD4+CD25+ thymocytes, whereas did not exhibit the presence of either perforin or granzyme A. CD8+CD25+ thymocytes did not produce any cytokine, but expressed both cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and transforming growth factor-β type 1 (TGF-β1) on their surface as CD4+CD25+ thymocytes did (Liotta et al., 2005).


HLA antigens and haplotypes have been described in connection with different epilepsie since the early 1970s. The HLA system, which is genetically determined, plays a central role in the generation of immune responses. A defective or deficient HLA factor may make viruses surviving, and we are presented to a persistent virus infection. The HLA complex is also of importance for the development of Tcells, which in turn are of importance for the development of B-cells and their immunoglobulins. Different cytokines are also involved in this process (Eeg-Olofsson, 2003).

Although it is not clear what role an activated HLA-DR+CD8+CD57+ ƒŸ utk ape?? Subset might have, and why it might be increased in older age groups, it is known that CD8+CD57+ cells have antiviral and tumoricidal activity (Garrido et al., 1993; Wang et al., 1993; Garcia-Sanz et al., 1996; Merino et al., 1998) and that viruses within cells can manipulate Class 1 or 11 expression through cytokines (Erlich, 1997). It is also possible that the activated subsets themselves produce the cytokines that continue to amplify and perpetuate the immune activation. Because cytokines play a role in initiating and driving immune activation, we assessed any relationship between early inflammatory cytokine mediators and upregulation of the activation antigen subsets. IFN-γ is known to increase HLA-DR expression on mononuclear cells, or at high levels to induce Class 11 molecule expression on nonimmune cells (Basham et al., 1987; Cabrera et al., 1995) (Rea et al., 1999).

It is possible, but not proven, that the function of increased HLA-DR antigen expression may be to promote recognition and elimination of damaged or virus-infected cells. The mechanism that regulates this process could be mediated by the cytokines including TNF-α, which are produced early in the inflammatory cycle by tissue damage from whatever source.

The increase in the CD3+HLA-DR+ activation subset also needs to be considered

alongside the decrease in the CD3+CD25+ activation subset described in this study, which

could compromise exogenous antigen processing, and the increase in NK and CD8+CD57+

subsets, previously described in this cohort of subjects (Rea et al., 1999).

Both HLADR activation markers were found to have no significant differences (result) when compared to activation markers in healthy controls (result).

Herpes virus infection in epilepsy


In HSV viral antibody, the amount of subjects being infected is relatively high in both groups and not significantly associated to epilepsy, but is still comparable with previous study done in Malaysia where 61.4% of the study subjects over the whole peninsular is immune to HSV (Dora et al., 1981).


We found a total of 98.9% of subjects studied were immune to EBV. This is similar to which a study conducted by Norzuriza et al. (2008)(Norzuriza et al., 2008) who found 77.5% of public citizen between the age 0-20 years, and 100% of people aged above 60 years had previous infection of EBV in Malaysia.

A similar study conducted in Bangladesh showed that 85% of the study group had positive EBV IgG after the age of 10 (Norzuriza et al., 2008, Haque et al., 2001) while a research in Papua New Guinea reported that approximately 93% people in rural areas were positive for EBV antibodies (Giovanni et al., 2001, Norzuriza et al., 2008). This proves to us that EBV is not an unusual infection as 90% of world population has EBV antibody and infection varies throughout countries due to their environmental, geographical, socioeconomic and hygienic conditions (Thompson and Kurzrock, 2004).


This present study too, had 87% of their subjects, both control and epilepsy group were immune to VZV as the result of previous infection with chicken pox and shingles. This result is equivalent to a report that stated a near 100% seropositivity to VZV in USA 24-26. VZV is not a rare infection as individuals usually get infected to chicken pox during childhood although VZV infection is quite severe in immunocompromised patients (Steiner et al., 2007).


According to this study, antibody against CMV IgG infection was significantly associated with epilepsy whereas VZV IgG, EBV IgG and HSV (1+2) IgG were not significant. Previously, a polymerase chain reaction (PCR) study was conducted on the brain tissue from the hippocampus of temporal lobe epilepsy (TLE) patients and they found 45% of the study subjects were positive with CMV DNA (Eeg-Olofsson et al., 2004). About two decades before, a brain tissue biopsy study on Rasmussen Syndrome patients was carried out using the in-situ hybridization method and resulted to 70% of their study subjects were positive with CMV DNA (Power et al., 1990). However, in the present study, we only determine the immunity to herpes viral infections based on the specific IgG levels from peripheral blood serum. CMV antibody had been clearly detected in all patients from the present study, however, in terms of epilepsy type, we found that only 36.8% of them suffered from TLE while the rest remains unknown. This could be the reason why this present study did not show exactly similar results due to different method usage and also different type of epilepsy patients.

Suzuki et al., (2008), on the other hand, studied epilepsy in congenital CMV and found that seven of 19 subjects with congenital CMV developed epilepsy. These findings were in conjunction with the present study in terms of relation between CMV and epilepsy but, still we couldn't say whether these epilepsy patients were infected by CMV during infancy (congenital) as no present data were recorded.

CMV is actually an infectious disease that may be acquired very early during childhood and may also be infected during breastfeeding and during the process of giving birth through the birth canal (Schleiss, 2009). Stating that the epilepsy patients in this study was infected with CMV during their early life, is quite unacceptable as an obviously low count of epilepsy patient (4.2%) experienced febrile fits during their childhood and also, most epilepsy cases in this study had their first seizure onset during childhood and adolescents at mean age of 15 years. However, most researchers agrees to the fact that the risk to develop epilepsy after some febrile fit incidence is quite small, only 2-10%, depending on the type of febrile fit they encountered (Tsai and Hung, 1995, Shorvon, 2010) and besides, only 10-15% of CMV infected infants actually express the clinical symptoms while the rest remains asymptomatic and latent (Schleiss, 2009, Suzuki et al., 2008).

A previous report (Landolfo et al., 2003) found that children from low socioeconomic backgrounds have a higher prevalence in getting infected with CMV when compared to those who lived in the urban areas which is comparable to our study where almost all patients came from rural areas.

Relation between lymphocyte subsets, activation markers and herpes virus in epilepsy disorder (mungkin leh gabung sume je)

The brain is connected to the immune system by the neuro-immune-endocrine network. Brain induced alterations of the immune system are mediated by the sympathetic nervous system, which directly innervates the lymphatic organs, or by the endocrine mechanisms (Wrona, 2006).

NK cells and the CNS

CD8CD25 and CNS


NK cells, CD8CD25 and CMV in epilepsy

Viral infections play a role in the etiology by more than one possible mechanism: (1) fever per se; (2) a degree of fever that exceeds the individual threshold convulsive temperature; and (3) an elevated cytokine or abnormal immune response to infection [4] (Millichap and Millichap, 2006).

There is strong circumstantial evidence that CMV may be a dominant factor to drive CD8 T cell differentiation and hereby induce premature immune senescence (13). CMV-specific CD8 T cells have also been shown to occur as large expanded clones that may dominate the repertoire (14). In a recent publication (15), we demonstrated that aging as well as CMV infection lead to a decrease in the size of the naive CD8 T cell pool.

Lifelong latent CMV infection thus seems to diminish the size of the naive and early memory T cell pool and to drive a Th1 polarization within the immune system. A recent publication demonstrates that the humoral immune response to influenza vaccination is reduced in CMV carriers (16). This finding indicates that lifelong CMV infection may restrict immunological diversity and thus compromise immunological memory in old age.

CD8 T cells that display a central memory-like phenotype and constitutive CD25 expression, yet without regulatory function (17).

Stimulation with immunodominant peptides from EBV (LMP2) and CMV (pp65) led to the propagation of T cells with respective Ag specificities in both subpopulations.

This is in agreement with recently published data showing that CD8+CD25+ cells rarely occur in subjects with latent CMV infection (15).

These apparently beneficial CD8+CD25+ T cells are rare or even absent in elderly persons

with latent CMV infection.

CD8+CD25+ T cells are also rare in young individuals who still have high numbers of naive T cells (15, 17). However, a change in the composition of the CD8 T cell pool toward cells of a higher differentiation stage in the elderly (14, 32, 33), as observed in patients with latent CMV infection, negatively correlates with the occurrence of CD8+CD25+ cells (15).

CD8+CD25+ T cells display a central memory-like phenotype.

These cells display a constitutive expression of the IL-2R α-chain (CD25) and CD25 mRNA. They have not been recently activated, because they do not express CD69 and HLA-DR. CD25 has also been reported to be expressed at higher levels on Th2 than on Th1 cells upon stimulation (37).

CD8+CD25+ T cells grow well after stimulation with IL-2 only.

CD8+CD25+ cells can prevent loss of the CD28 molecule (40), assist memory cell generation (41), induce MHC class II up-regulation on Ag-presenting B cells, and promote Ab isotype switching to IgG1 and IgE (42).

Phenotypic characterization revealed that up to 20% of the CD8+CD25+ T cell population coexpressed the CD4 molecule.

We also demonstrate that the TCR repertoire of CD8+CD25+ memory cells is highly diverse, whereas the CD8+CD25+ subset has a more restricted clonality.

This has also been shown with respect to Ag specificity, because CD8+CD25+ T cells contain greater numbers of different specificities, which proliferate rapidly upon Ag encounter. Our results suggest that continuous differentiation of CD8 T cells throughout life leads to the loss of certain Ag specificities, but to the unproportional accumulation of others, for instance for persistent Ags, and appears to be associated with the inability to raise a sufficient cellular

immune response to pathogens such as influenza (11, 17).

We propose that CD8+CD25+ cells represent an early stage in the differentiation of CD8 T cells and demonstrate a lineage relationship from CD25+ to CD25- memory CD8 T cells.

because CD25-expressing memory CD8 T cells appear to be a prerequisite for intact immune responsiveness in the absence of naive T cells in old age.

(Herndler-Brandstetter et al., 2005)

The size of the CD8+ memory T-cell population, which grows well and produces interleukin-2 (IL-2) and IL-4, also increases with aging, but this increase is missing in CMV carriers. Life-long latent CMV infection seems thus to diminish the size of the naive and the early memory T-cell pool and to drive a Th1 polarization within the immune system. This can lead to a reduced diversity of CD8 responses and to chronic inflammatory processes which may be the basis of severe health problems in elderly persons. In immunosuppressed persons, such as patients with human immunodeficiency virus type 1 infection or children following bone marrow transplantation, CMV infection may cause life-threatening diseases of a variety of different organs, such as the lung, the retina, the liver, and the central nervous system (6, 7, 15, 20). In immunocompetent persons, CMV infection remains mostly unnoticed, as it causes no or few relatively nonspecific symptoms. This lack of clinical manifestation is due to the fact that CMV-specific CD8 T cells, many of which have specificity for the immediate-early protein IE-1 and the structural protein pp65, are capable of controlling the virus by preventing its replication and by killing virus-infected cells (1, 31, 36, 37). This mostly long-lasting attempt of the immune system to defend a host from spreading of CMV leads to characteristic changes in the CD8+ T-cell repertoire,

However, a recent publication demonstrated that the humoral immune response to influenza vaccination is reduced in CMV carriers (35). This finding may indicate that life-long CMV infection may restrict immunological diversity and compromise immune responsiveness in old age. In spite of the strong circumstantial evidence that CMV may be a dominant factor to drive CD8 T-cell differentiation and hereby induce premature immune senescence (29).

In the absence of latent CMV infection, the size of the naive CD8 T-cell pool was unchanged in the middle aged group but significantly reduced in elderly persons. Latent CMV infection led to a decrease in the number of naive T cells in each age group compared with uninfected age-matched controls, but the size of the naive T-cell pool was most severely reduced in elderly persons with latent CMV infection.

Cytokine production by CD8+ T cells is affected by CMV infection.

Aging per se led to an increase in the production of all three cytokines upon nonspecific

stimulation, as the numbers of IL-2-, IL-4-, and IFN-γ- producing cells were increased in elderly persons in the absence of latent CMV infection (Fig. 2A).

The age-related increase in the production of IL-2 and IL-4 was, however, not observed in persons with a positive CMV antibody serology, leading to a pronounced difference in the production profile of these two cytokines between elderly persons with and those without latent CMV infection.

Elderly persons have a CD25-expressing IL-2-, IL-4-producing memory T-cell subpopulation, the size of which decreases in the presence of latent CMV infection.

A CD25+CD8+ T-cell subpopulation of substantial size is found within the CD45RA-CD28+ memory population in elderly persons without CMV infection. This population is decreased in size in elderly persons with latent CMV infection as well as in younger age groups.

The occurrence of this specific CD8 T-cell population is associated with a good humoral immune response in old age.

Although it does not appear to have a regulatory function, it constitutively expresses CD25 and can be easily identified.

The size of this population was significantly reduced in elderly persons with CMV infection, suggesting that the low IL-2 and IL-4 production capacity of the total CD8 T-cell population

of CMV-infected elderly persons may be due to the partial loss of a physiologically occurring age-related T-cell subset with specific stimulatory properties. These changes seem to start in mid-life, as a minor (not significant) decrease in the number of CD25+CD8+ T cells was also observed in CMV-infected persons in the middle-aged group compared with noninfected age-matched controls.

Our results demonstrate that long-term latent CMV infection leads to pronounced changes in the CD8 T-cell repertoire. Although we cannot presently provide data on the exact time point of primary infection in these persons is not known ƒŸ amik ayat jek.

The extremely low number of CD8 naive T cells in CMV-infected elderly persons (<15% of CD8 cells may lead to difficulties in the immunological response to neoantigens in old age.

Secondly, latent CMV infection seems to reduce the number of IL-2- and IL-4-producing CD8 memory T cells in old age. CMV-specific CD8 T cells produce IFN- butno IL-4 and very little IL-2.

In conclusion, our data illustrate that long-term latent CMV infection leads to characteristic changes in the CD8 T-cell repertoire which may drive a Th1 polarization within the immune


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