Babies Have Higher Risk of Hepatitis B Due to T Lymphocytes
Indian J Med Res. 2013 November; 138(five): 700–710.
Immunological mechanisms of hepatitis B virus persistence in newborns
Nirupma Trehanpati
* Section of Research, Institute of Liver & Biliary Sciences, New Delhi, Bharat
Syed Hissar
* Department of Research, Institute of Liver & Biliary Sciences, New Delhi, India
Shikha Shrivastav
* Department of Enquiry, Plant of Liver & Biliary Sciences, New Delhi, India
Shiv 1000. Sarin
* Section of Research, Institute of Liver & Biliary Sciences, New Delhi, India
** Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
Abstract
Chronic hepatitis B virus (HBV) infection affects millions of people worldwide and about a half million people dice every year. India represents the second largest pool of chronic HBV infection worldwide with an estimated 40 one thousand thousand infected people. The prevalence of chronic HBV infection in pregnant women is shown to be 0.82 per cent with the gamble of mother-to-kid vertical transmission. Hepatitis B due east antigen (HBeAg) positivity indicates replicative grade of HBV which may play a part in immunotolerance in utero by crossing the placenta. In case of HBeAg positivity and high viral load of mother, HBV immunoglobulin is preferably given along with HBV vaccination. Antiviral therapy is recommended for use in the third trimester of pregnancy to reduce the perinatal transmission of HBV, however, use of antiviral therapy should be individualized during pregnancy. Chronic HBV infection in neonates is linked with strong presence of Tregs (T regulatory cells) and defective CD8 T cells pool to produce interferon (IFN)-γ. T cell receptor (TCRζ) concatenation defects were also associated with decreased CD8 T cell dysfunction. Decreased TCRζ expression could exist due to persistent intrauterine exposure of the viral antigens early in embryonic evolution leading to immune tolerance to HBV antigens in the newborns positive for hepatitis B surface antigen (HBsAg+ve). Therefore, due to HBV infection, T cell tolerance to HBV-antigen may probably leave the newborn as a chronic carrier. However, HBV vaccination may accept benefits in restoring acquired immunity and better product of HBV specific antibodies.
Keywords: Chronic infection, HbeAg, HbsAg, hepatitis B virus (HBV), perinatal, pregnancy
Hepatitis B virus infection in pregnant mothers and transmission to newborns
Chronic hepatitis B virus (HBV) infection affects over 240 million people worldwide and virtually a half million people die every year due to the acute or chronic consequences leading to liver failure and liver cancer1. HBV is present in blood, saliva, semen, vaginal secretions, and menstrual blood of infected individualsii.
In Southeast Asia and China, the prevalence of HBV infection among women of child-bearing age is equally high as 10-20 per cent3. India represents the second largest puddle of chronic HBV infection worldwide with an estimated 40 million people. In India, the prevalence of chronic HBV infection in meaning females is 0.82 per cent4 and during pregnancy, hepatitis B virus infection presents the take a chance of mother-to-child (vertical) transmission.
To analyze the source of acquisition of HBV infection in chronic HBV infected patients, mothers of 384 chronic hepatitis B index patients were screened for HBV infection. The mothers of 40.ane per cent alphabetize patients were positive for HBsAg. The mothers of 34.1 per cent index patients were positive only for antibodies (total anti-HBc and/or anti-HBe) indicating that the mothers were exposed to HBV infection some time in past5. These information provide substantial bear witness of present or past HBV infection in mothers of chronic HBV patients, suggesting possible perinatal transmission. It could be possible that one third of mothers, who were initially hepatitis B surface antigen (HBsAg) positive, could have cleared the infection during post-partum period and remained positive only for HBV antibodiesv. Therefore, vertical transmission of hepatitis B virus could be one of the principal causes of chronic HBV infection in our country.
The neonates born to mothers infected with chronic hepatitis B, have xc per cent gamble of acquiring chronic HBV infection and its persistence6. In contrast, when HBV is acquired during adulthood, merely 5-ten per cent of adults develop persistent chronic HBV infectionseven. Most of the developed countries screen all pregnant women for HBV infection, yet, in the developing countries it depends upon the run a risk factors. In India, there is no consistent policy of screening the meaning women beyond the country. A meta-analysis of prevalence of hepatitis B in Republic of india showed two.4 per cent prevalence in full general population8. Nevertheless, the prevalence charge per unit of HBsAg positivity in significant women varied from ane-9 per cent in different parts of the country and e antigen (HBeAg) positivity rates among them varied from four.viii-68.7 per cent8.
A big single centre report from north India of 20,104 pregnant women showed a chronic HBsAg positivity rate of 1.ane per cent9. Bulk of pregnant women with viral hepatitis B are considered as chronic hepatitis B infected but a few may develop astute hepatitis in the third trimester of pregnancy resulting in one per cent fulminant hepatitisx ,11. During pregnancy, acute viral hepatitis involves a detail risk both for the mother and the baby.
Of the two secretory proteins; HBsAg and HBeAg, HBsAg does not ordinarily cross the placenta, however, pocket-size sized HBeAg passes through the placental bulwark fifty-fifty with low maternal viral load titre12 ,13 (Fig. 1). In newborn, transplacental HBeAg can be detected at one month of age but it would disappear before 4 months of age. However, in a few, infected newborns with HBV viral titres, persistent detection of HBeAg for more than 4 months strongly indicates HBV chronicity14 ,15. It is also observed that anti-HBc (antibodies to core antigen) positivity can exist detected more than anti-HBe in the babies born to hepatitis B infected mothers12 ,13. Therefore, anti-HBe till i year of historic period and anti-HBc till 2 years of age correspond the transplacental maternal antibodies to the virus, and may not be an indicator of present agile or past HBV infection in babies born to hepatitis B infected mothers.
Secretory proteins crossing the placenta and vertical transmission through during and afterwards delivery.
Hepatitis B envelope antigen spillage through placenta induces HBV specific T cell tolerance in utero xvi and intrauterine infection could be the primary cause of the failure of immunoprophylaxis17 ,eighteen ,xix (Fig. 1). However, in that location are several evidences to evidence that the incidence of intrauterine transmission is rare and only happens in case of placental leakage20 ,21.
Infants born to HBeAg positive mothers are probable to be infected and progress to chronicity, notwithstanding, infants born to HBsAg positive mothers develop astute hepatitis and less likely to progress to chronicity13. In north India, HBeAg positivity was 7.8 per cent, and risk of perinatal transmission was 18.6 per cent from HBsAg positive mothers vs. 3 per cent among infants of HBsAg-negative mothers22 ,23.
Effect of HBs and HBe antigen on pregnancy
HBV infection does certainly touch the outcome of pregnancy and influence spontaneous abortion, stillbirth, or prematurity. Increased frequencies of reproductive casualties were reported, in pregnant women with acute or chronic hepatitis B infection24. With HBV infection, the incidence of preterm nascency observed was quite high around 21.ix vs 12.1 per cent in healthy controls25.
The gestational diabetes and antepartum haemorrhage were as well associated with chronic hepatitis B infection26. In a example-control study, HBeAg positivity was proved to be more important with high HBV DNA levels in manual of HBV to infants27. HBeAg positivity indicates replicative form of HBV which may play a role in the immunotolerance in utero past crossing the placenta28. In HBV genotype C, HBeAg seroconversion is longer, which may be the reason for higher perinatal transmissions in this genotype29. Therefore, in prenatal screening of pregnant women, it is of import to check the HBeAg status forth with HBsAg.
Serovaccination of the newborn
There are chances of vertical transmission and resulting chronic hepatitis B infection in a newborn from a chronic hepatitis B infected mother with HBsAg positivity30. Therefore, vaccination against HBV has been implemented recently to preclude HBV infection predominantly acquired perinatally or in childhood31. In many countries, immunization programmes for HBV are implemented, despite this HBV prevalence is not decreasing32. This may be due to incomplete vaccination or inefficacy of the immunization program. Screening for HBsAg is essential in all significant women. All infants built-in to mothers who are HBsAg positive must receive a serovaccination confronting this virus, by intramuscular injection of HBV vaccine and of hepatitis B immune globulin (H-Large, 100 or 200 IU), in the first 12 hours of birth9. Despite improved wellness policies, at that place is no national hepatitis B immunization programme in India, thus chronic HBV infection nonetheless remains a considerable medical brunt, affecting young adults.
HBV vaccine
HBV vaccines are directed against mutual antigenic epitopes of genotype A and D of HBV surface region, which provide sufficient cross-protection beyond genotypes to prevent infection33. Hepatitis B vaccination alone can prevent transmission in 80-95 per cent of cases, withal, in example of HBeAg positivity and high viral load of mother, HBV immunoglobulin is preferrablly given forth with HBV vaccination at different sites. Although HBV vaccination along with H-BIG has been reported effective in many studies and transmission rates can be reduced betwixt 0 and fourteen per cent34, the recent data from India showed no significant upshot of the combination of vaccination and H-BIG vs. HBV vaccination alone, especially when the viral load is very high during pregnancy35.
In fact, in many other studies, standard passive-active immunoprophylaxis with hepatitis B immunoglobulin and the hepatitis B vaccine had a failure rate equally high as 10 to 15 per cent36 and these failures are associated with high maternal serum HBV DNA levels37. In some cases, vaccine failures are also associated with intrauterine infection in women during pregnancy38. Therefore, it is existence considered that HBV vaccination alone or forth with HBV immunoglobulin is not sufficient and may be prevented by nucleotide analogue therapy. Equally antiviral therapies are being used to prevent HIV transmission from mother to child, like strategy could be beneficial in the case of HBV.
Apply of antivirals during pregnancy: its safety and business organisation
Levels of HBV Deoxyribonucleic acid and alamine transaminase (ALT) are highly variable during entire course of pregnancy. In a few cases, HBV DNA levels seemed to rise in the 3rd trimester or in the post-partum menstruation, otherwise for entire duration of pregnancy the levels of HBV Dna remain stable. There are limited data available on anti-viral treatment during pregnancy which bear witness symptomatically or asymptomatically HBV infection clearance during subsequent pregnancies and postpartum37 ,38.
Pregnant women with a low HBV viral load do not require immediate handling, because due to the passive immunization and active HBV vaccination of the newborn, chances of acquiring infection due to perinatal manual are negligible. Treatment of the mother can, therefore, be postponed until after the nascence. Yet, with loftier HBV viral load (>ten5 copies/ml in serum), strategy for treating with antivirals during the last trimester of pregnancy is beingness considered39. Antiviral therapy was also used in pregnant woman with acute exacerbation of hepatitis B, equally this was quite effective in reducing possible HBV-associated hepatitis flares or reactivation and made a divergence to maternal morbidity and bloodshed earlier hepatic decompensation40 ,41. However, vertical transmission has been reported fifty-fifty with the treatment of hepatitis B during the pregnancy and when there was an undetectable viral load at delivery39.
In antivirals, lamivudine was the showtime drug which was used to diminish viral load and considered effective in the third trimester of pregnancy and resulted in reduced gamble of chronic hepatitis B in the kid41 ,42 ,43. Oral dose of 150 mg of lamivudine every day during the last month of pregnancy reduced serum HBV Dna concentration and normalised ALT levels till the fourth dimension of delivery. In the lamivudine-treated group, only 12.five per cent infants were tested positive for HBsAg in comparison to 28 per cent untreated historical control subjects. Therefore, lamivudine therapy was considered effective in reducing HBV transmission from highly viraemic mothers to their infants who received passive/active immunization. Despite, the fact that lamivudine therapy leads to suppression of the HBV DNA to undetectable levels in the mother, in that location is a example study of a newborn with raised ALT levels and positive for HBV Deoxyribonucleic acid at birth, followed by developing chronic hepatitis B virus infection44.
Recently, telbivudine was evaluated for its efficacy and safety in the tertiary trimester of pregnant women in one of the clinical trials and as well compared with lamivudine41 ,44. Both antivirals, showed reduction in HBV Dna levels in mothers from log 8 to log ii. Newborns were given hepatitis B vaccination every bit well as immunoglobulin within 24 h of nascency and completed vaccine schedule. After one year of birth, eighteen per cent of children in lamivudine group showed HBsAg positivity, still, in telbivudine group only ii per cent children showed HBsAg positivity. Therfore, telbevudine was considered to exist improve antiviral than lamivudine41. Use of antivirals from the first trimester showed more nativity defects than their use in third trimester. Usage of contempo antivirals in the first trimester, including emtricitabine, tenofovir, lamivudine, telbivudine, and adefovir showed more than one.v fold increase in overall birth defects41.
Nigh of the antiviral data support lamivudine and tenofovir usage in the pregnancy than adefovir and entecavir, every bit rubber of entecavir is questionable. The global recommendations are to use tenofovir, lamivudine, and telbivudine during pregnancy and substantial registry testify positively supports the utilize of tenofovir, which is a strong inhibitor of HBV44. Still, in the example of lamivudine or telbivudine antiviral therapy, genotypic resistance should exist assessed during treatment45.
Antiviral therapy is recommended to go along in mail-partum catamenia just the safety of anti-viral therapy during lactation catamenia is a business. Though HBsAg has been detected in the breast milk, but globally breast feeding has not been contraindicated in HBsAg positive mothers46. There are not many studies discussing the effects of antiviral therapy during lactation period47 ,48, however, a study on lamivudine treated significant women showed that infant received but 2 per cent of recommended antiviral dose through breast milk and the tenofovir treated HIV group showed only 0.03 per cent release of recommended dose in breast milk49.
Antiviral therapy might not forbid perinatal transmission of HBV infection in every newborn, therefore, apply of antivirals during pregnancy need to be individualized and as the evaluation and management of aberrant liver tests in the pregnant women is challenging, importance of agreement case past case natural history of chronic HBV infection in the peri-partum period is extremely vital.
Afterward birth, HBsAg positivity in children varies. In Bharat, children below 15 yr accept 1.iii-12.vii per cent HBsAg positivity, whereas in other countries it ranges from 0-7.eight per cent3 ,4 ,5. Ultimately children later perenatal transmission with detectable HBV DNA levels are being treated with antivirals and interferonfifty, however, the success rate and adverse effects need to be determined.
Role of human leukocyte antigens (HLA)
The implantation of a fertilized ovum followed by placental and foetal development can be compared to a transplanted graft having both maternal and paternal HLA molecules. The foetal derived placental trophoblasts ensure survival by avoiding rejection from the maternal immune system and evading infection. The trophoblast cells lack expression of classical HLA grade I and Two molecules, express HLA-G, which is instrumental in preventing placental prison cell death past maternal NK cells in maternal deciduas51.
Pregnancy supports HBV infection
The liver also plays a crucial role in the metabolism of different hormones, including estrogens and progesterone. The normal course of pregnancy is bound to accept a number of physiological changes and these changes may bear upon the normal class of chronic hepatitis B infection in infected women52 ,53 ,54. During pregnancy, successful foetal development is necessary by eliciting poor immune response against foetal antigens. Therefore, weak immunity of the female parent might allow HBV viral replication and increases the chances of perinatal transmission of HBV infection in children.
Sex hormones such every bit androgens, estrogens and progestrone tin can directly collaborate with the cells of the allowed organisation, thus impacting the development of immune responses. The female person sex hormones estrogen and progesterone have been implicated equally playing a role in modulating the local immune system and altering cytokines during pregnancy.
Progesterone, a hormone associated with the maintenance of pregnancy, is immunosuppressive and decreases NK cell cytotoxicity, inhibits nitric oxide (NO) and tumour necrosis gene (TNF)-α production. Progesterone induced binding factor inhibits the action of dendritic cells (DCs) that generate proinflammatory responses and favour the induction of tolerogenic DCs. It also controls the activity of natural killer (NK) cells and the differentiation of T cells into T helper cell type two (Th2) like clones (Fig. 2). Therefore, progesterone mediates the immunological furnishings, and induces the production of Th2 ascendant cytokines like IL-3, IL-4, and IL-1055 (Fig. 2). The Th2 phenotype induced by progesterone is a prerequisite for the maintenance of pregnancy, which is associated with the susceptibility and the existing affliction exacerbation56 ,57. The anti-inflammatory properties of progesterone prevent the evolution of Th1 responses that could event in foetal ballgame58.
Release of hormones induce immune suppression and fetal tolerance during pregnancy.
In contrast to progesterone, estrogen is considered a proinflammatory mediator. Estrogen has been shown to stimulate the product of the proinflammatory cytokine TNF59 ,60, which is known to directly interact with the interferon (IFN)-γ promoter61, and further has been shown to enhance antigen-specific CD4+ T cell responses62. The ability of estrogen to drive proinflammatory, Th1-associated immune responses induces higher concentrations of the proinflammatory cytokines, IL-6 and IFN-γ. Th1 responses are associated with protective immunity and favour disease resolution. Therefore, progesterone favours Th2 response which protects foetal development and estrogen leads to Th1 response, which favours HBV disease resolution.
Pregnancy being a relatively immunosuppressed state, some of the chronic hepatitis B infected mothers may develop hepatitis flare or fulminant hepatic failure (FHF) due to allowed restoration during the peri-partum flow63 ,64 ,65. Generally, after delivery a significant increase in liver illness activity is being observed. , Overt liver dysfunction was maximum, observed in 43 per cent of mothers who were HBeAg positive within the first post-partum month66. These robust immune responses have cleared HBeAg in 12.5 per cent of mothers during the first month of post-partum period67.
HBV infection and T cell immunity
HBV is not cytopathogenic, nonetheless HBV infection carries a pregnant take a chance of developing severe liver diseases, including chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma (HCC). HBV specific T cells mediated host immune response plays an of import part in viral clearance besides as viral persistence which leads to chronicity as well equally HCC67. Different HBV genotypes have been constitute in different ethnicity and global locations. Mechanism of allowed tolerance may be influenced past different HBV markers and it is observed that exposure of the immature immune system in uterus to transplacental HBeAg induces immunotolerance leading to low HBeAg sero-conversion rates in children68 ,69.
The constant immunologic changes that occur during pregnancy announced to mostly occur locally, yet, these changes modify the maternal immune system grossly during gestation. Increase in systemic inflammation also results in different complications related to pregnancy and delivery70. Infiltrations of virus- non specific inflammatory cells in the liver also participate actively in HBV-associated liver pathogenesis. The downregulation of Th1 cytokines such as TNF-α and IFN-γ was found in early pregnancy71. Therefore, a delicate balance of cytokine effects is necessary because overproduction of IFN-γ during the first trimester of human pregnancy leads to foetal rejection. As pregnancy progresses, the most uniform tilt occurs towards the Th2-type cytokine profile such as IL-iv, IL-5, IL-ix, and IL-25 and a T repressor type 1 (Tr1) or T-helper type 3 (Th3) such every bit TGF-β and IL-x and away from Th1-type cytokines72 ,73. When Th2-like activity is increased during pregnancy, the elevated immune suppressive CD4+ CD25+ Treg cells suppress both Th1-like and Th2-like immunity confronting paternal/foetal alloantigens and checks IFN-γ reactions during pregnancy74 ,75 (Fig. three).
Role of regulatory T-cells in regulating Th1/Th2 response leading to fetal rejection of fetal tolerance.
These alterations in the immune system during pregnancy induces a surge in cell mediated amnesty cytokines such equally TNF-α and IFN-γ, which could play a significant function in clearing the underlying HBV infection in HBsAg positive mothers during pregnancy and thereby help to tailor therapy subsequently commitment to enhance the clearance of HBV72.
During pregnancy, the regulatory T cells suppress Th1 response and induce Th2 blazon amnesty, contributing to an inadequate immune response against the virus with rise in viral load and decline in ALT levels76. A retrospective report has observed that in nearly 50 per cent of HBsAg positive pregnant mothers, afterward delivery there is increment in ALT when the immune condition recovers which likewise influences with more maternal morbidity77 ,78.
The precise roles of the hormones and cytokines alterations happening during "immunological orchestra" of pregnancy have non been clearly studied in HBsAg positive mothers. A written report focused on the immune cells in HBsAg positive and negative mothers and their newborns. This study revealed that at that place was no difference in the frequencies or percentage of CD4, CD8 T cells in HBsAg+ve mothers and their newborns compared to HBsAg-ve and good for you mothers79. So question is how the HBsAg+ve newborns develop chronic liver illness at a later stage of life. Shrivastava et al 76 take analysed the allowed cells functionality. When functional assays were performed for CD8 T cells, functionality was compromised at birth in HBsAg+ve newborns. Along with not functional CD8 T cells, presence of higher levels of immunosuppressive regulatory T cells was also observed, which probably was instrumental in establishing chronic infection in neonates (Fig. iv).
Allowed response in HBV infected pregnant mothers and its outcomes.
It is known that the regulatory T cells suppress the proliferation, cytokine-product (IFN-γ, IL-two), cytolytic activity of naïve and antigen specific CD4 and CD8 T cells, functions of antigen presenting cells (APCs) and B cells through secretion of anti-inflammatory cytokines such every bit IL-ten or TGF-βlxxx. These specialized regulatory T cells could perchance facilitate allowed tolerant environment of newborns preventing the evolution of mature protective immune response and also support Medawar hypothesis; "Antigen encountered during fetal life induces a country of acquired immunological tolerance and mammals exposed to foreign homologous tissue cells during fetal life never react immunologically, or react to a limited degree only"81. Initially immune tolerance was also considered due to deletion or inactivation of T cells82 and, therefore, neonatal menstruation has been viewed as a 'window of opportunity' for inducing tolerance to specific antigen83. At the time of nascency with HBV infection, T cell tolerance to HBV-Ag may probably leave the newborn as a chronic carrier. Therefore, one aspect of chronic HBV infection in neonates is linked with stiff presence of Tregs (regulatory T cells) and some other aspect is why CD8 T cells chapters to produce IFN-γ and CD107a cytotoxicity decreased. In the literature, TCR signaling defects were significantly linked with functionality of T cells, in many diseases, downregulated expression of TCRζ chain on CD8 T cells have been observed, TCRζ chain defects eventually pb to decreased TCRζ expression positively correlated with decreased CD8 T cell dysfunction84 ,85. Decreased TCRζ expression could be due to persistent intrauterine exposure of the viral antigens early in embryonic evolution leading to allowed tolerance to HBV antigens in the HBsAg+ve newborns.
Shrivastava et al 78 likewise observed that HBsAg+ve newborns had lower expression of chemokine receptors CCR1, CCR3 and CCR5 on CD4+ and CD8+T cells at nascency. In many chronic diseases, presence of chemokines and toll like receptor was as well not observed on leuckocytes, which may eventually contribute to infection persistence86 ,87.
Till date, there are only phenotypic studies which suggested possible defects in prison cell setting and mechanisms, in which diminished expression of TCRζ chain associated with CD8 T cell dysfunction in HBsAg+ve newborns was observed compared to HBsAg-ve and healthy uninfected newborns78. These observations add a new perspective to our growing understanding of the central mechanisms by which HBV could promote T cell dysfunction related to the loss of TCRζ chain expression. Additionally, nosotros also speculate the office of T regs in the setting of immune tolerance.
The predisposition of newborns to infections has been attributed to defects in both the humoral and cellular arms of the adaptive allowed responses. Infants with a diminished pool of B and T lymphocytes show lower serum complement levels and dumb antigen presenting ability of DCs and eventually reduced immunoglobulin production of B cells even afterward regular vaccination88 ,89 ,90. Evolution of mature B cells from naïve population is very of import and HBV viral infection in adults are characterized by increased number of activated and wearied B cells, increased levels of short lived plasma B cells or immature transitional B cells or decreased retentiveness B cell response91 ,92 ,93.
There was a full general tendency of college levels of transitional B cells and lower memory B cells in HBsAg+ve newborns equally compared to HBsAg-ve newborns immediately at nascence. After 12 months post HBV vaccination, immature transitional B cells were declined and there was a rise in memory B cell with increased frequencies of CD69+ and CCR5+ activated memory B prison cell subpopulation93. The improved B cell responses advise that HBV vaccination is somehow benign for improving the overall allowed competency in HBsAg +ve newborns, just to understand the precise machinery of disease progression further, larger cohort and long-term studies are needed.
In summary, higher levels of immunosuppressive T regulatory cells and CD8+ T prison cell dysfunction in HBsAg +ve newborns are suggestive of already established chronic and immune tolerant country of HBV infection at birth during vertical transmission. Withal, HBV vaccination may have benefits in restoring acquired immunity and better production of HBV specific antibodies.
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