NEOPLASIA

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NEOPLASIA:

NEOPLASIA Dr. Prabesh K Choudhary 3rd year Resident MD Pathology NAMS

TOPICS:

TOPICS Molecular Basis of Multistep Carcinogenesis Carcinogenic Agents and Their Cellular Interactions Radiation Carcinogenesis Microbial Carcinogenesis Host Defense against Tumors-Tumor Immunity Immune survillence and immune Escape

Molecular Basis of Multistep Carcinogenesis :

Molecular Basis of Multistep Carcinogenesis Each cancer must result from the accumulation of multiple mutations . Individual tumors accumulate an average of 90 mutant genes. Mutated genes are: oncogenes and tumor suppressor genes. Not yet established which of these mutations establish the transformed state, contribute to tumor progression, or are "passengers“: neutral mutations cells can generally be transformed by combinations of oncogenes. Each oncogene is specialized to induce part of the phenotype necessary for full transformation. For instance, the RAS oncogene and the MYC oncogene

Carcinogenic agents:

Carcinogenic agents Chemical carcinogens Radiation energy Oncogenic viruses & some other microbes 5

Carcinogenic Agents and Their Cellular Interactions:

Carcinogenic Agents and Their Cellular Interactions >200 years ago the London surgeon Sir Percival Pott correctly attributed scrotal skin cancer in chimney sweeps to chronic exposure to soot . Steps Involved in Chemical Carcinogenesis Initiation Initiation causes permanent DNA damage Promoters can induce tumors in initiated cells, but they are nontumorigenic by themselves

PowerPoint Presentation:

Experiments demonstrating the initiation and promotion phases of carcinogenesis in mice. Group 2: application of promoter repeated at twice-weekly intervals for several months. Group 3: application of promoter delayed for several months and then applied twice weekly. Group 6: promoter applied at monthly intervals

Events in Chemical Carcinogenesis:

Events in Chemical Carcinogenesis

Direct-Acting Agents:

Direct-Acting Agents Require no metabolic conversion to become carcinogenic . Most of them are weak carcinogens but are important because some are cancer chemotherapeutic drugs (e.g., alkylating agents) that have successfully cured, controlled, or delayed recurrence of certain types of cancer (e.g., leukemia, lymphoma, and ovarian carcinoma), only to evoke later a second form of cancer, usually AML. The risk is low, but its existence dictates judicious use of such agents .

Indirect-Acting Agents:

Indirect-Acting Agents Require metabolic conversion to an ultimate carcinogen Most potent indirect chemical carcinogens-the polycyclic hydrocarbons -are present in fossil fuels. Others, for example, benzo[ a ]pyrene, are formed in the high-temperature combustion of tobacco in cigarette smoking. Polycyclic hydrocarbons may also be produced from animal fats during the process of broiling meats and are present in smoked meats and fish. The principal active products are epoxides, which form covalent adducts with molecules in the cell, principally DNA, but also with RNA and proteins. The aromatic amines and azo dyes are another class that were widely used in the past in the aniline dye and rubber industries.

Major Chemical Carcinogens:

Major Chemical Carcinogens

Metabolism of Carcinogens:

Metabolism of Carcinogens Most require metabolic activation for conversion into ultimate carcinogens Other pathways may lead to the inactivation of procarcinogen . Carcinogenic potency of a chemical: determined not only by its electrophilic derivative but also by balance between metabolic activation and inactivation reactions. Metabolized by cytochrome P-450-dependent mono- oxygenases . The genes that encode these enzymes are quite polymorphic

Metabolism of Carcinogens:

Metabolism of Carcinogens Susceptibility to carcinogenesis :regulated by polymorphisms in genes E.g. Highly inducible form of CYP1A in 10% of white>increase risk of lung cancer in smoker Deletion of glutathione-S-transferase (normally metabolize polycyclic aromatic hydrocarbons)>>higher risk of lung & bladder cancer Age, sex, and nutritional status also determine the internal dose of toxicants.

Molecular Targets of Chemical Carcinogens:

Molecular Targets of Chemical Carcinogens 4 groups of genes: Amest test: ability of chemical carcinogen to cause mutation in salmonella typhimurium Initiating chemicals are mutagenic. DNA is primary target . Commonly mutated oncogenes and tumor suppressors, such as RAS and p53. Eg: aflatoxin B 1 .

Molecular Targets of Chemical Carcinogens:

Molecular Targets of Chemical Carcinogens Strong correlation between dietary level of aflatoxin and incidence of HCC in Africa and Far East. Aflatoxin B 1 produces mutations in the p53 gene ; 90% or more of these mutations are a characteristic G : C→T : A transversion in codon 249 (called 249(ser) p53mutation) . vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides, and polychlorinated biphenyls are potential carcinogens Nitrites cause nitrosylation of amines.Nitrosoamines: carcinogenic.

Initiation and Promotion of Chemical Carcinogenesis:

Initiation and Promotion of Chemical Carcinogenesis Unrepaired alterations in DNA are 1st steps in process of initiation. For change to be heritable,damaged DNA template must be replicated. In liver, many chemicals form reactive electrophiles, yet most do not produce ca. In normally quiescent tissues, mitogenic stimulus provided by carcinogen itself cell proliferation may be induced by concurrent exposure to biologic agents:viruses,parasites, dietary factors, or hormonal influences. Agents that do not cause mutation but instead stimulate division of mutated cells are known as promoters .phorbol esters, hormones, phenols, and drugs. Process of tumor promotion includes multiple steps: proliferation of preneoplastic cells, malignant conversion, and eventually tumor progression

Radiation Carcinogenesis:

Radiation Carcinogenesis Radiant energy, UV rays or as ionizing electromagnetic and particulate radiation, is a well-established carcinogen. UV light: skin cancers, and ionizing radiation: medical or occupational exposure, nuclear plant accidents, and atomic bomb detonations. Well-known latency of damage caused by radiant energy and its cumulative effect require extremely long periods of observation and make it difficult to ascertain its full significance. An increased incidence of breast cancer has become apparent decades later among women exposed during childhood to atomic bomb tests. The incidence peaked during 1988-1992 and then declined.

Ultraviolet Rays:

Ultraviolet Rays ↑ incidence of SCC,BCC and possibly melanoma of the skin. Risk: type of UV rays, intensity of exposure, and quantity of the light-absorbing "protective mantle" of melanin in the skin. Non-melanoma skin ca :total cumulative exposure to UV radiation, whereas melanomas:intense intermittent exposure. UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm). Carcinogenicity of UVB light: formation of pyrimidine dimers in DNA.

Ultraviolet Rays:

Ultraviolet Rays DNA damage repaired by the nucleotide excision repair pathway. 5 steps,involve 30 or more proteins. The pathway is overwhelmed, and error-prone nontemplated DNA-repair mechanisms become operative :provide survival of cell at cost of genomic mutations that in sometimes cause cancer. xeroderma pigmentosum Mechanism of carcinogenesis: -protooncogen activation: RAS -tumor suppressor gene mutation: p53

Ionizing Radiation:

Ionizing Radiation Electromagnetic (x-rays, γ rays) and particulate (α particles, β particles, protons, neutrons) radiations are all carcinogenic. Individuals pioneering use of x-rays developed skin cancers. Miners of radioactive elements:10 fold ↑ ed incidence of lung ca. Initially marked increase in incidence of AML and CML-average latent period: 7 years. Subsequently incidence of many solid tumors. A hierarchy of vulnerability of tissues to radiation-induced cancers . Most frequent are AML and CML. Ca Thyroid follows closely. Intermediate category :ca breast, lungs, and salivary glands. Skin, bone, and GIT are relatively resistant. Practically any cell can be transformed into a cancer cell by sufficient exposure to radiant energy.

Microbial Carcinogenesis:

Microbial Carcinogenesis

Oncogenic RNA Viruses:HTLV-1:

Oncogenic RNA Viruses:HTLV-1 Causes a form of T-cell leukemia/lymphoma HTLV-1 has tropism for CD4+ T cells (T-regulatory cells) , major target for transformation. Sexual intercourse, blood products, or breastfeeding. Leukemia :only 3% to 5% ,after 40 to 60 years. HTLV-1 doesnt contain oncogene, and no consistent integration In leukemic cells:viral integration shows a clonal pattern. The site of viral integration in host chromosomes is random , the site of integration is identical within all cells of a given cancer. HTLV-1 genome contains gag, pol, env , and long-terminal-repeat regions, but it contains another region, referred to as tax.

Tax:Inducer of Neoplasm:

Tax:Inducer of Neoplasm Stimulates transcription of viral mRNA,acts on 5' long terminal repeat. Can also activate transcription of several host cell genes involved in T cells: immediate early gene FOS, genes encodes IL-2, and GM-CSF. Inactivates cell cycle inhibitor p16/INK4a. Activates NF-κb,activates pro-survival/anti-apoptotic genes. Genomic instability. Interferes with DNA-repair functions and inhibits ATM-mediated cell cycle checkpoints activated by DNA damage. Infection by HTLV-1 causes expansion of a nonmalignant polyclonal cell population through stimulatory effects of Tax on cell proliferation. The proliferating T cells are at increased risk of mutations and genomic instability induced by Tax. This instability allows the accumulation of mutations and chromosomal abnormalities, and eventually a monoclonal neoplastic T-cell population emerges.

Oncogenic DNA viruses:

Oncogenic DNA viruses several oncogenic DNA viruses in animals have been identified. Of the various human DNA viruses, HPV, Epstein-Barr virus (EBV), hepatitis B virus (HBV), and Kaposi sarcoma herpes virus , also called human herpes virus 8 Merkel cell polyoma virus

Human Papilloma virus:

Human Papilloma virus At least 70 genetically distinct types of HPV . Some types (e.g., 1, 2, 4, and 7) cause benign warts High-risk HPVs (types 16 and 18) implicated in several cancers. At least 20% of oropharyngeal cancers are ass. with HPV. Genital warts have low malignant potential In benign warts: HPV genome :a nonintegrated episomal form, while in cancers:HPV genome integrated into host genome.

Human Papilloma virus:

Human Papilloma virus Site of viral integration is random, but integration is clonal. Cells after intrgration shows genomic instability. Integration interrupts the viral DNA within the E1/E2 open reading frame, leading to loss of the E2 viral repressor and overexpression of the oncoproteins E6 and E7. E6 & E7 of HPV 6 & 11>binds p53 & Rb with low affinity>>no inactivation

Is HPV alone sufficient for malignancy?:

Is HPV alone sufficient for malignancy? Primacy of HPV infection in cervical ca confirmed by the effectiveness of anti-HPV vaccines in preventing cervical ca. Infection is not sufficient for carcinogenesis . When human keratinocytes are transfected with DNA from HPV types 16, 18, or 31 in vitro, they are immortalized but do not form tumors in experimental animals. Co- transfection with a mutated RAS gene results in full malignant transformation . Cigarette smoking, coexisting microbial infections, dietary deficiencies, and hormonal changes important. A high proportion of women infected with HPV clear the infection by immunological mechanisms , but some do not for unknown reasons .

Epstein-Barr Virus: EBV :

Epstein-Barr Virus: EBV Implicated in the pathogenesis of several human tumors: Burkitt lymphoma; B-cell lymphomas ;Hodgkin lymphoma; nasopharyngeal and some gastric carcinomas and T cell lymphomas and NK cell lymphomas. Infects B lymphocytes and epithelial cells of oropharynx. EBV uses the complement receptor CD21 to attach to and infect B cells . The molecular basis of B-cell proliferations induced by EBV is complex, but involves the "hijacking" of several normal signaling pathways. One EBV gene , latent membrane protein-1 ( LMP-1), acts as an oncogene.

LMP-1:

LMP-1 Behaves like a constitutively active CD40 receptor , a key recipient of helper T-cell signals that stimulate B-cell growth . Activates the NF-κB and JAK/STAT signaling pathways and promotes B-cell survival and proliferation, all of which occur autonomously in EBV-infected B cells. LMP-1 prevents apoptosis by activating BCL2. Virus "borrows" a normal B-cell activation pathway to expand the pool of latently infected cells. Another EBV gene, EBNA-2, encodes a nuclear protein that mimics a constitutively active Notch receptor . EBNA-2 transactivates several host genes, including cyclin D and the src family of proto-oncogenes. EBV genome contains a viral cytokine, vIL-10 , that was hijacked from the host genome. This viral cytokine can prevent macrophages and monocytes from activating T cells and is required for EBV-dependent transformation of B cells.

Association of EBV and BL:

Association of EBV and BL Association between endemic Burkitt lymphoma and EBV quite strong More than 90% of African tumors carry EBV genome. 100%patients have elevated Ab titers against viral capsid antigens . Serum Ab titers are correlated with risk of developing the tumor. Additional factors must also be involved. (1) EBV infection is not limited to the geographic locales where Burkitt lymphoma is found, but it is a ubiquitous virus that asymptomatically infects almost all humans worldwide. (2) The EBV genome is found in only 15% to 20% of sufferers of Burkitt lymphoma outside Africa. (3) There are significant differences in the patterns of viral gene expression in EBV-transformed (but not tumorigenic) B-cell lines and Burkitt lymphoma cells. Burkitt lymphoma cells do not express LMP-1, EBNA2, and other EBV proteins that drive B-cell growth.

How does EBV contribute to genesis of endemic BL? :

How does EBV contribute to genesis of endemic BL? Concomitant infections (malaria) impair immune competence:sustained B-cell proliferation. T-cell immunity directed against EBV antigens eliminates most of the EBV-infected B cells, but a small number of cells downregulate expression of these immunogenic antigens. Lymphoma cells may emerge only with the acquisition of specific mutations, most notably translocations that activate the c- MYC oncogene. In nonendemic areas 80% of tumors do not harbor the EBV genome, but all tumors possess the t(8;14) or other translocations that dysregulate c -MYC .

How does EBV contribute to genesis of endemic BL? :

How does EBV contribute to genesis of endemic BL? EBV is not directly oncogenic, but by acting as a polyclonal B-cell mitogen, it sets the stage for the acquisition of the t(8;14) translocation and other mutations, which ultimately release the cells from normal growth regulation e.g.p14ARF/MDM2/p53 pathway & inactivation of p16INK4a by deletion or hypermethylation In normal individuals, EBV infection is readily controlled by effective immune responses

PowerPoint Presentation:

Possible evolution of EBV-induced Burkitt lymphoma .

Nasopharyngeal carcinoma :

Nasopharyngeal carcinoma is also associated with EBV infection. is endemic in southern China, in some parts of Africa, and in the Inuit population of the Arctic. In contrast to Burkitt lymphoma, 100% of nasopharyngeal carcinomas contain EBV DNA. The viral integration in the host cells is clonal . Ab titers to viral capsid antigens are greatly elevated, and in endemic areas patients develop IgA antibodies before the appearance of the tumor. LMP-1 is expressed in epithelial cells as well LMP-1 activates the NF- κB pathway.induces the expression of pro- angiogenic factors such as VEGF, FGF-2, MMP9, and COX2, which may contribute to oncogenesis .

Hepatitis B and C Viruses:

Hepatitis B and C Viruses Close association between HBV infection and liver cancer. 70% to 85% of HCC are due to infection with HBV or HCV. HBV is endemic in countries of the Far East and Africa; HBV and HCV genomes do not encode any viral oncoproteins, and although the HBV DNA is integrated within the human genome, there is no consistent pattern of integration in liver cells. Dominant effect seems to be immunologically mediated chronic inflammation with hepatocyte death leading to regeneration and genomic damage. One key molecular step: activation of the NF-κB pathway in hepatocytes in response to mediators derived from the activated immune cells. Activation of the NF-κB pathway within hepatocytes blocks apoptosis.

PowerPoint Presentation:

Both HBV and HCV also contain proteins within their genomes that may more directly promote the development of cancer. The HBV genome contains a gene known as HBx that can directly or indirectly activate a variety of transcription factors and several signal transduction pathways . In addition, viral integration can cause secondary rearrangements of chromosomes, including multiple deletions that may harbor unknown tumor suppressor genes. In addition to chronic liver cell injury and compensatory regeneration, components of the HCV genome, such as the HCV core protein, may have a direct effect on tumorigenesis , possibly by activating a variety of growth-promoting signal transduction pathways.

H. pylori:

H. pylori Implicated in genesis of gastric adenocarcinomas and lymphomas. Involves ↑ ed epithelial cell proliferation in background of chronic inflammation. Initial development of chronic gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer. This sequence takes decades to complete Strains associated with gastric adenocarcinoma contain a " pathogenicity island “ : cytotoxin-associated A ( CagA ) gene. CagA penetrates into gastric epithelial cells, where it initiates a signaling cascade that mimics unregulated growth factor stimulation. The gastric lymphomas are of B-cell origin, are often called lymphomas of mucosa-associated lymphoid tissue, or MALTomas

PowerPoint Presentation:

Their molecular pathogenesis involve strain-specific H. pylori factors, as well as host genetic factors, such as polymorphisms in the promoters of inflammatory cytokines such as IL-1β and TNF . Infection leads to appearance of H. pylori -reactive T cells, which stimulate a polyclonal B-cell proliferation. In chronic infections, currently unknown mutations may be acquired These cells grow out into a monoclonal "MALToma" that remains dependent on T-cell stimulation of B-cell pathways that activate the transcription factor NF-κB. At this stage, eradication of H. pylori by antibiotic therapy "cures" the lymphoma by removing the antigenic stimulus for T cells. At later stages, however, additional mutations may be acquired, such as an (11;18) translocation, that cause NF-κB to be activated constitutively. At this point, the MALToma no longer requires the antigenic stimulus of the bacterium for growth and survival.

Host Defense against Tumors-Tumor Immunity:

Host Defense against Tumors-Tumor Immunity Conceived by Paul Ehrlich, who proposed that immune recognition of autologous tumor cells may be capable of eliminating tumors. Lewis Thomas and Macfarlane Burnet formalized this concept by coining the term immune surveillance, The occurrence of lymphocytic infiltrates around tumors and in LNs draining sites of cancer; incidence of ca in immunodeficient individuals; and direct demonstration of tumor-specific T cells and Abs in patients. Immune surveillance is imperfect; tumor in immunocompetent The concept of tumor immune surveillance encompass not only the protective role but also the effect of the immune system in selecting for tumor variants. The term cancer immunoediting is used to describe effects of the immune system in preventing tumor formation and also in "sculpting" the immunogenic properties of tumors

Tumor Antigens:

Tumor Antigens They were broadly classified into two categories based on their patterns of expression: tumor-specific antigens , which are present only on tumor cells and not on any normal cells, and tumor-associated antigens , which are present on tumor cells and also on some normal cells The modern classification of tumor antigens is based on their molecular structure and source . The early attempts to characterize tumor antigens relied on producing monoclonal antibodies specific for tumor cells and defining the antigens that these antibodies recognized. important advance was development of techniques for identifying tumor Ags that were recognized by CTLs, because CTLs are major immune defense mechanism against tumors.

Oncofetal Antigens:

Oncofetal Antigens are proteins that are expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues . Genes encoding these proteins are silenced during development and are derepressed upon malignant transformation. They provide markers that aid in tumor diagnosis. Their expression in adults is not limited to tumors. Amounts of these proteins are increased in tissues and in the circulation in various inflammatory conditions, and they are found in small quantities even in normal tissues There is no evidence that oncofetal antigens are important inducers or targets of antitumor immunity. The two most thoroughly characterized oncofetal antigens are carcinoembryonic antigen (CEA) and α-fetoprotein (AFP)

Altered Cell Surface Glycolipids and Glycoproteins:

Altered Cell Surface Glycolipids and Glycoproteins Tumors express higher than normal levels and/or abnormal forms of surface glycoproteins and glycolipids , which may be diagnostic markers and targets for therapy. These include gangliosides , blood group antigens, and mucins . Most of the epitopes recognized by these antibodies are not specifically expressed on tumors, they are present at higher levels on cancer cells than on normal cells. This class of antigens is a target for cancer therapy with specific antibodies.Among the glycolipids expressed at high levels in melanomas are the gangliosides GM 2 , GD 2 , and GD 3 .

Cell Type-Specific Differentiation Antigens:

Cell Type-Specific Differentiation Antigens Tumors express molecules that are normally present on the cells of origin. These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types . Are typically normal self-antigens, and therefore they do not induce immune response in tumor-bearing hosts. Their importance is as potential targets for immunotherapy and for identifying the tissue of origin of tumors . For example, lymphomas may be diagnosed as B cell-derived tumors by the detection of surface markers characteristic of this lineage, such as CD20. Antibodies against CD20 are also used for tumor immunotherapy.

Products of Mutated Genes:

Products of Mutated Genes Mutated proteins represent Ags that have never been seen by immune system and thus can be recognized as non-self. Because of genetic instability of tumor cells, many different genes may be mutated in these cells Products of these mutated genes can also be potential tumor antigens. Products of altered proto- oncogenes , tumor suppressor genes, or other mutated genes not associated with transformation are synthesized in the cytoplasm of tumor cells, and like any cytoplasmic protein , they may enter the class I MHC antigen-processing pathway and be recognized by CD8+ T cells. These proteins may enter the class II antigen-processing pathway in APC that have phagocytosed dead tumor cells, and thus be recognized by CD4+ T cells also. Because these altered proteins are not present in normal cells, they do not induce self-tolerance. Some cancer patients have circulating CD4+ and CD8+ T cells that can respond to the products of mutated oncogenes such as RAS, p53, and BCR-ABL proteins.

Overexpressed or Aberrantly Expressed Cellular Proteins:

Overexpressed or Aberrantly Expressed Cellular Proteins Tumor antigens may be normal cellular proteins that are abnormally expressed in tumor cells and elicit immune responses. In a subset of human melanomas some tumor antigens are structurally normal proteins that are produced at low levels in normal cells and overexpressed in tumor cells. Tyrosinase, an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas. T cells from melanoma patients recognize peptides derived from tyrosinase Tyrosinase is normally produced in such small amounts and in so few cells that it is not recognized by the immune system and fails to induce tolerance. Another group, the "cancer-testis" antigens, are encoded by genes that are silent in all adult tissues except the testis-hence their name. Although the protein is present in the testis it is not expressed on the cell surface in an antigenic form, because sperm do not express MHC class I antigens. Prototypic of this group is the melanoma antigen gene (MAGE) family. are expressed by a variety of tumor types. For example, MAGE-1 is expressed on 37% of melanomas and a variable number of lung, liver, stomach, and esophageal carcinomas. Similar antigens called GAGE, BAGE, and RAGE have been detected in other tumors.

Tumor Antigens Produced by Oncogenic Viruses:

Tumor Antigens Produced by Oncogenic Viruses Several viruses are associated with cancers. These viruses produce proteins that are recognized as foreign by the immune system . The most potent of these antigens are proteins produced by latent DNA viruses; HPV and EBV. There is abundant evidence that CTLs recognize antigens of these viruses and that a competent immune system plays a role in surveillance against virus-induced tumors because of its ability to recognize and kill virus-infected cells. In fact, the concept of immune surveillance against tumors is best established for DNA virus-induced tumors. Vaccines against HPV antigens are effective in preventing cervical cancers in young females.

Anti-tumor Effector Mechanisms:

Anti-tumor Effector Mechanisms Cytotoxic T lymphocytes : protective role against virus-associated neoplasms. Natural killer cells : After activation with IL-2 and IL-15, NK cells can lyse a wide range of human tumors, including many nonimmunogenic for T cells.Tumors that fail to express MHC class I antigens may trigger NK cells. NKG2D proteins expressed on NK cells and some T cells are important activating receptors. Macrophages : T cells, NK cells, and macrophages may collaborate in antitumor reactivity, because interferon-γ, a cytokine secreted by T cells and NK cells, is a potent activator of macrophages . Activated macrophages may kill tumors by mechanisms similar to those used to kill microbes Antibodies : administration of monoclonal antibodies against tumor cells can be therapeutically effective. A monoclonal antibody against CD20, a B-cell surface antigen, is widely used for treatment of lymphomas.

Immune Survillence and Escape:

Immune Survillence and Escape Is there any evidence that they operate in vivo to prevent emergence of neoplasms ? The increased frequency of cancers in immunodeficient hosts. Immunosuppressed transplant recipients and persons with AIDS also have an increased incidence of malignancies. Most (but not all) of these neoplasms are lymphomas, often diffuse large B-cell lymphomas. Particularly illustrative is the rare X-linked recessive immunodeficiency disorder termed XLP (X-linked lymphoproliferative syndrome) , caused by mutations in the gene encoding an adapter protein (SAP), which participates in lymphocyte signaling pathways. When affected boys develop an EBV infection, such infection does not take the usual self-limited form of infectious mononucleosis but instead evolves into a chronic or sometimes fatal form of infectious mononucleosis or, even worse, B-cell lymphoma.

Mechanism Of Immune Escape:

Mechanism Of Immune Escape Selective outgrowth of antigen-negative variants Loss or reduced expression of MHC molecules. Lack of costimulation Immunosuppression Antigen masking Apoptosis of cytotoxic T cells:

THANK-Y0U:

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