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Immunodeficiency Diseases• Components of the immune response system are absent or

nonfunctional– Deficiencies involve B and T cells, phagocytes, and complement system

• Primary immunodeficiency – Genetically based congenital lack of B-cell and/or T cell activity

• B cell defect – agammaglobulinemia – patient lacks antibodies

• T cell defect – thymus is missing or abnormal– Severe combined immunodeficiency (SCIDS)

• Both parts of lymphocyte system are missing or defective No adaptive immune response

• Secondary immune deficiency – Acquired– Due to damage after birth

• Viral infections, drugs, radiation

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Sequestered Antigen Theory

Some tissues are not scanned by the immune system during embryonic growth.CNS, lens, thyroid & testes

Infection, trauma or deterioration

Sequestered behind anatomical barriers

Self reacting lymphocyte clones

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Self antigens are sequestered and later incorrectly identified as foreign antigens by B lymphocytes

Failure of the fetus to eradicate all self-reacting lymphocyte clones (forbidden clones)

Another hypothesis: Immune DeficiencyB lymphocytes have defective receptorsCan not distinguish between self & non-self

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Viral Infection Theory

Self antigens are altered by a viral infectionProduces an immune response against perceived foreign antigens

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AutoAbs produced against cells of the islets of Langerhans T cells become specific for all the insulin-producing cells in the islets destroy the cells and greatly reduce insulin synthesis

Hypothesized to be caused by viral infectionCell receptor is altered by a viral infectionImmune cells attack that tissues bearing viral damaged receptor

Viral infections of the pancreas Several viruses have been implicated but not conclusively demonstrated:Mumps virus, rubella virus, hepatitis C

insulin-dependent

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Other Autoimmune Diseases

LupusAutoAb against organs & tissuesButterfly rash across nose & cheeks (page 516)

Kidneys, bones marrow, skin, nervous system, joints, muscles, heart, GI tract, nucleoprotein & mitochondria

Generalized loss of self tolerance

Exact cause not known:Epstein-Barr Virus may play a role

Rheumatoid arthritisAutoAb bind to the synovial membranes of jointsChronic inflammation, scar tissue & joint destruction (page 516)

IgM anti-IgG antibody (rheumatoid factor)

Exact cause not known: Epstein Barr virus may play a role

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More Autoimmune DiseasesGraves DiseaseAutoAb to receptors of cells in the thyroid that produce thyroxinOverproduction of thyroxinHyperthyroidism

HTLV-1 (Human T-Lymphotropic Virus)

Hashimoto thyroiditisAutoAb & T cells reduce thyroid productionHypothyroidism

HTLV-1

Myasthenia gravisAutoAb bind to receptors of acetylcholine Damages muscles paralysis

Viral etiology proposed but none has been identified

Multiple sclerosisAutoAb & T cells damage myelinMuscular weakness & tremorsDifficulties in speech, vision & paralysis

Hypothesis: Human herpes virus, possibly EBV

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Herpes Viruses• dsDNA linear genome• Enveloped DNA viruses• After entering the cells the capsid then travels along a microtubule to the

nucleus• Binds to a nuclear pore • Viral DNA enters the nucleus through the pore and circularizes• Latency

– May integrate into the host chromosome in a ganglia• Bud from the inner nuclear membrane • Envelope then fuses with the outer nuclear envelope and naked capsids enter

the cytoplasm • Enter the into Golgi vesicles full of viral proteins• Capsid receives envelope in Golgi• Golgi vesicles delivers virions to the plasma membrane • New virus particle can infect another cell• Cause many diseases

www.cdc.gov

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Herpes simplex virus (HSV-1 + HSV-2)oral herpes (cold sores) genital herpes congenital herpes (neonatal herpes) can cause blindness and neurological problems keratoconjunctivitis (ocular herpes) herpes encephalitis herpes meningitis

Varicella-Zoster Virus (VZV): chickenpox shingles (herpes zoster)

Cytomegaloviruses (CMV) or Human herpesvirus 5 (HHV-5) Human Herpes Virus 6 (HHV-6):

sixth disease / roseola infantum Human Herpes Virus 7 (HHV-7) isolated from T cells of AIDS patients but does not seem to cause a disease

Epstein-Barr Virus (EBV) Hodgkin's Disease Burkitt's lymphoma Infectious mononucleosis (mono) or kissing disease

Human Herpes Virus 8 (HHV-8) or Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Kaposi's sarcoma

Herpes simplex HSV-1Varicella-Zoster (VSV)Epstein-Barr (EBV)90% of the human population

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The herpes simplex virus life cycle. (a) Herpes simplex virus (HSV) is shown undergoing the lytic cycle (entry, uncoating, viral transcription and DNA replication in the nucleus, particle assembly, exit from the cell) in epithelial cells of the skin to cause a primary infection. (b) Some virus enters the sensory neuron terminals and travels retrogradely to the nucleus where it establishes latency. (c) Periodic reactivation results in anterograde transport of viral particles, shedding from the neuron, and re-infection of epithelial cells, which leads to asymptomatic shedding or recurrent lesions.

www-ermm.cbcu.cam.ac.uk/fig001rlc.gif

HSV-1 & HSV-2

Latency

StressFeverTraumaSunlightMenstruationInfectionImmune suppression

Mucous membrane

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• Worldwide distribution• Most people are infected by EBV

– Estimated that 95% of U.S. adults between 35 and 40 years of age have been infected• Common childhood infection

– Asymptomatic – Brief illnesses of childhood

• B-lymphocyte infection• Linear virus genome circularizes • Virus subsequently persists within the cell as an episome • EBV infections during adolescence or young adulthood may causes infectious mononucleosis

– Fever, sore throat, and swollen lymph glands– Transmission via saliva of an infected person– A lifelong dormant infection in B-lymphocyte

• Causes Burkitt's lymphoma and nasopharyngeal carcinoma– Rare cancers that are not typically found in the United States

• No antiviral drugs or vaccines are available• Chronic fatigue syndrome

– Impossible to state that this is caused by EBV– Not plausible by the CDC

Epstein-Barr Virus

Cytotoxic T cells attempt to eliminate infect B cells

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Cancer

≡ any of various neoplasms characterized by the proliferation of anaplastic cells that tend to invade surrounding tissue and metastasize to new body sites

New abnormal growth of tissue

A lack of differentiation

Spread to other regions of the body via blood andlymph vessels or spinal fluid

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Neoplasms• Benign

– Noncancerous• Grow slowly

• Retain surface recognition proteins

• Remain in a home tissue

• Malignant – Cancerous

• Grow and divide abnormally

• Disrupt surrounding tissues physically & metabolically

• Mutated antigens escape detection

• Retain self antigens

Immune SurveillanceMajority of precancerous / cancer cells are destroyed:

NK Cells (natural killer cells)Macrophages

TC Cells

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Causes of Death - Worldwide

13.5

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Originate in connective tissue such as bone, muscle, cartilage &blood vessels.

CarcinomasOriginate in the outer layer of cells of the skin and internal membranes. Examples include: breast, lung, intestinal, skin & prostate cancer.

Sarcomas

Lymphomas & LeukemiasHematologic cancersBlood or blood-forming organs such as the spleen, lymph nodes & bone marrow.

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Ten Most Common Cancers

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Cancer vs. Age

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• An individual’s chance of developing cancer within his or her lifetime is almost twice as great today as it was 50 years ago

• People are living longer

• Cancer is more prevalent in older people

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Proto-oncogenes & Oncogenes

Normal Growth Control

Proto-oncogenesCode for proteins that stimulate mitosis

OncogenesOver-expression of proteins that promote mitosis

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Oncogenes are Mutant Forms of Proto-Oncogenes

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Tumor Suppressor Genes

Tumor suppressor genesCode for proteins that inhibit mitosis

No longer inhibit mitosis

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p53 Tumor Suppressor Gene

Normal cell

Cancerous cell

50% of all cancershave an aberrant p53 gene

p53 that can trigger cell apoptosis

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DNA Repair Genes

Mutations in DNA repair genes can lead to a failure in DNA repair, which in turn allows subsequent mutations in tumor suppressorgenes and proto-oncogenes to accumulate

DNA repair genes code for proteins whose normal function is to correct DNA errors

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Classes of Carcinogens

1. Physical

2. Chemical

3. Biological

4. Heredity

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Physical Causes

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Nuclear medicine 4%

Consumer products 3%

Other 1%Medical X rays 11%

Chemical reactionsin the body11%

Cosmic waves 8%

Radon54%

Other chemical sources 8%

Radiation Sources

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Chemical Causes

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Biological CausesSome viruses carry oncogenes whose products cause transformation of host cells into cancer cells.Viral genome may be inserted into regulatory sites.

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Heredity and Cancer Cancer is not considered an inherited illness because most cases of cancer, perhaps 80 to 90 %, occur in people with no family history of the disease. However, a person's chances of developing cancer can be influenced by the inheritance of certain kinds of genetic alterations. These alterations tend to increase an individual's susceptibility to developing cancer in the future. For example, about 5% of breast cancers are thought to be due to inheritance of particular forms of a "breast cancer susceptibility gene”.

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HTLV-1Human T Cell leukemia/lymphoma virus type I • Oncogenic retrovirus

– Two (+) sense strands of RNA– gag, pol & env genes– Tax

• Transcriptional activator

– Rex• Regulates viral mRNA splicing

• Adult T cell leukemia (ATL)• Long list of autoimmune diseases• Infects from 15 - 25 million individuals world-wide• Endemic to south-western Japan, central portion of Africa, the

Caribbean basin, central and South America, Melanesia, regions of Iran, southern India, aboriginal groups in Australia

• Common among IV drug users

Nature Medicine 2004  10J Clin Pathol 2000 53:581-586

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• Three major modes of transmission – Breast milk– Sexual transmission– Blood transfusion

• Blood is screened for HTLV-1

• Similar to the Simian TLV-1– Chimpanzees and mandrill baboons– Transferred from animals to humans

• Asymptomatic for as long as 50 years• CD4 T lymphocytes are the main target• Virus binds to the receptor for glucose

– GLUT-1

• Immunoassays are used to detect Ab made in response to the virus• No method to assess prognosis of asymptomatic infected individuals• No methods to assess risk • No treatment

– Some success with interferons and AZT

• No vaccine