lymphoreticular infections i

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