lymphoreticular infections i
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LYMPHORETICULAR INFECTIONS I. Bacterial Viral Parasitic Fungal. Bacterial Viral Parasitic Fungal. Viral. Epstein - Barr Virus : EBV has developed into the ultimate B-lymphocyte parasite EBV is a member of the subfamily Gammaherpesvirinae - PowerPoint PPT PresentationTRANSCRIPT
BacterialViralParasiticFungal
BacterialViralParasiticFungal
ViralEpstein-Barr Virus :EBV has developed into the ultimate B-
lymphocyte parasiteEBV is a member of the subfamily
Gammaherpesvirinae The primary receptor for EBV is also the
receptor for the C3d component of the complement system (also called CR2 or CD21). It is expressed on B cells of humans
EBVcauses heterophile antibody-positive infectious
mononucleosis and has been causally associated with AfBL (endemic Burkitt lymphoma), Hodgkin disease, and nasopharyngeal carcinoma. EBV has also been associated with B-cell
lymphomas in patients with acquired or congenital immunodeficiencies.
EBV stimulates the growth and immortalizes B cells in tissue culture.
EBVEBV encodes more than 70 proteins, different
groups of which are expressed for the different types of infections.
The main viral proteins produced:early antigen (EA), viral capsid antigen (VCA),Epstein-Barr nuclear antigens (EBNAs)latent proteins (LPs); latent membrane proteins (LMPs) 1 and 2; and two small Epstein-Barr-encoded RNA (EBER)
molecules, EBER-1 and EBER-2.
EBVThe diseases of EBV result from either an overactive immune response (infectious mononucleosis) or
the lack of effective immune control (lymphoma and hairy cell leukoplakia)
ViralDisease Mechanisms of Epstein-Barr Virus:Virus in saliva initiates infection of oral epithelia
and spreads to B cells in lymphatic tissue.There is productive infection of epithelial and B
cells.Virus promotes growth of B cells (immortalizes).T cells kill and limit B-cell outgrowth. T cells are
required for controlling infection. Antibody role is limited.
ViralDisease Mechanisms of Epstein-Barr Virus:EBV establishes latency in memory B cells and
is reactivated when the B cell is activated.T-cell response (lymphocytosis) contributes to
symptoms of infectious mononucleosis.There is causative association with lymphoma
in immunosuppressed people and African children living in malarial regions (African Burkitt lymphoma) and with nasopharyngeal carcinoma in China.
Infectious mononucleosisresults from a "civil war" between the EBV-
infected B cells and the protective T cells. The T cells are surrounded by infected B cells
and are activated by viral antigenic peptides presented on both the MHC I and II molecules. The classic lymphocytosis (increase in mononuclear cells), swelling of lymphoid organs (lymph nodes, spleen, and liver), and malaise associated with infectious mononucleosis results mainly from the activation and proliferation of T cells.
Infectious mononucleosisThe T cells appear as atypical lymphocytes
(also called Downey cells) They increase in number in the peripheral
blood during the second week of infection, accounting for 10% to 80% of the total white blood cell count at this time (hence the "mononucleosis").
Children have a less active immune response to EBV infection and therefore have very mild disease.
Atypical T cell (Downey cell) characteristic of infectious mononucleosisThe cells have a more basophilic and vacuolated cytoplasm than normal lymphocytes, and the nucleus may be oval, kidney shaped, or lobulated. The cell margin may seem to be indented by neighboring red blood cells.
EBVThe virus persists in at least one memory B
cell per milliliter of blood for the person's lifetime.
EBV may be reactivated when the memory B cell is activated (especially in the tonsils or oropharynx) and may be shed in saliva.
EBVis transmitted in saliva . More than 90% of EBV-infected people
intermittently shed the virus for life, even when totally asymptomatic.
Children can acquire the virus at an early age by sharing contaminated drinking glasses. Children generally have subclinical disease
EBVSaliva sharing between adolescents and
young adults often occurs during kissing; thus EBV mononucleosis has earned the nickname "the kissing disease."
Disease in these people may go unnoticed or may manifest in varying degrees of severity.
At least 70% of the population of the United States is infected by age 30.
In developing countries more than %90
EBVThe geographic distribution of some EBV-associated
neoplasms indicates a possible association with cofactors.
The immunosuppressive potential of malaria has been suggested as a cofactor in the progression of chronic or latent EBV infection to AfBL.
The restriction of nasopharyngeal carcinoma to people living in certain regions of China indicates a possible genetic predisposition to the cancer or the presence of cofactors in the food or environment.
More subtle mechanisms may facilitate the role of EBV in 30% to 50% of cases of Hodgkin disease
EBVTransplant recipients, patients with the acquired immune deficiency
syndrome (AIDS), and genetically immunodeficient people are at high risk for lymphoproliferative disorders initiated by EBV.
These disorders may appear as polyclonal and monoclonal B-cell lymphomas. Such people are also at high risk for a productive EBV infection in the form of hairy oral leukoplakia.
Hairy oral leukoplakiaUncontrolled lytic infection by EBV
Diagnosis of Epstein-Barr Virus
Diagnosis of EBV infectionBy serology:Heterophile antibody:Recognition of Paul-Bunnell antigen on
sheep, horse, or bovine erythrocytesEBV-induced B-cell proliferation promotes
production of heterophile antibodyEarly symptom occurs in more than 50% of
patients MONOTEST
If monotest is negativeAsk for ELISA VCA-IgM
Diagnosis of EBV infection in Transplant recipients, patients with the acquired immune deficiency
syndrome (AIDS), and genetically immunodeficient people to follow if lymphoproliferative disorders areinitiated by EBV:
EBV DNA quantitation by real-time PCR
RetrovirusesOncoviruses:immortalize or transform target
cells, A,B,C,D type according to their core and capsid
Lentiviruses:slow viruses associated with neurologic and immunosuppresive disease
Spumaviruses:no diseaseEndogenous viruses:transmitted vertically,
1% of human chromosome, in many animal species and humans, one detected in placental tissue which facilitates placental function
Subfamily Examples
Oncovirinae
B
C
D
Lentivirinae
Spumavirinae
Endogenous viruses
Mouse mammary tumor virus
HTLV-I,HTLV-II, Rous sarcoma virus
HIV-1,HIV-2
Human foamy virus
Human placental virus
AIDS cause by HIVRetroviridae familyLentivirinae genusEnveloped, positive strand RNA virus2 identical 9-10kb RNA
AIDSHuman immunodeficiency virus
type 1 and 2 (HIV-1, HIV-2)
HIVHIV-1: isolated in1983 Responsible from AIDS pandemicHIV-2: isolated in 1986HIV-2 less pathogenic slow progression to AIDS
HIV group and subtypes
Rapid mutation and recombinationHIV-1Group M (major): A-JGroup OHIV-2A-E subtypes
Gp120CD4 surface receptor proteinInitially expressed on cells of the macrophage
lineage (macrophage, dendritic cells, microglial cells) (M-tropic)+ second receptor CCR5
Later on helper T cells (T-tropic) +fusin (CXCR4)
Human immunodeficiency virus(HIV)
Disease Mechanisms of HIVHuman immunodeficiency virus primarily infects CD4 T cells and cells of the macrophage lineage (e.g., monocytes, macrophages, alveolar macrophages of the lung, dendritic cells of the skin, and microglial cells of the brain).
Disease Mechanisms of HIVVirus causes lytic infection of CD4 T
cells and persistent low-level productive infection of macrophage lineage cells.
Virus causes syncytia formation, with cells expressing large amounts of CD4 antigen (T cells); subsequent lysis of the cells occurs.
Disease Mechanisms of HIVVirus alters T-cell and macrophage cell function.
Virus reduces CD4 T cell numbers and helper-cell maintenance of CD8 T cell and macrophage function.
CD8 T cell numbers and macrophage function decrease.
Acute retroviral syndromeFirst signs occur in days to several weeksTransient %50-70 Activation of immune systemMultisystem dysfunctionFlu or infectious mononucleosis sydrome
like findingsThen a latent period
AIDSContinuous viral replicationImmune system dysfunction
CD4 T lymphocyes> 500 /µl (> %29) 1200-499 (% 14-28) 2< 200 /µl (< %14) 3
Incubation
Adults with no treatment: 10-11 years
‘rapid progressors’ : 2-3 years
‘non-progressor’ : 7-10 years Stable CD4 cell count
AIDS may be manifested in several different waysLymphadenopathy and FeverOpportunistic InfectionsMalignanciesDementia Related to AIDS
HIV Viral RNA (in free Virion )Viral DNA: integrated in host cell DNA
(Provirus)
SeroconversionUsually 3 weeks1.5,3,6,12 months
Viral Kinetics
Laboratory diagnosisSerology: Adults and children older than 15
months:Initial screening: ELISA, latex agglutinationConfirmation: Western-blotMolecular techniques:-qualitative DNA detection: babies younger
than 15 months-quantitative RNA: follow up of HIV infected
people who are on therapy
Western blot (WB)
Other testsImmunologic status: CD4:CD8 ratio LowAntiretroviral resistance tests
OncovirinaeRNA tumor virusesAssociated with leukemias, sarcomas and
lymphomas in many animalsNot cytolyticDistinquished by the mechanism of cell
transformation and length of latency period between infection and the development of disease
OncovirinaeSarcoma and acute leukemia viruses:Protooncogenes(at least 35)Highly oncogenic, direct effectNo human virusLeukemia viruses:No oncogeneLong latency periodHTLV-I,HTLV-II,HTLV-5
Human T lymphotropic virus type 1( HTLV-I)Adult acute T-cell lymphocytic leukemia
(ATLL)HTLV-associated myelopathy (tropical spastic
paraparesis)Blood transfusion, sexual intercourse, breast
feedingLong latency period: approximately 30 years
Human T lymphotropic virus type 1( HTLV-I)Endemic in southern JapanATLL (1 in 20 people over a 30-50 yearsDiagnosis: ELISA+WBViral RNA by RT-PCR
HTLV-2: Hairy cell leukemiaHTLV-5: malignant cutaneous lymphoma