1
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
2
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
3
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
4
Viral Infection Theory
Self antigens are altered by a viral infectionProduces an immune response against perceived foreign antigens
5
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
6
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
7
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
8
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
9
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
10
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
11
• 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
12
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
13
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
14
Causes of Death - Worldwide
13.5
15
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.
16
Ten Most Common Cancers
17
Cancer vs. Age
18
• 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
19
Proto-oncogenes & Oncogenes
Normal Growth Control
Proto-oncogenesCode for proteins that stimulate mitosis
OncogenesOver-expression of proteins that promote mitosis
20
Oncogenes are Mutant Forms of Proto-Oncogenes
21
Tumor Suppressor Genes
Tumor suppressor genesCode for proteins that inhibit mitosis
No longer inhibit mitosis
22
p53 Tumor Suppressor Gene
Normal cell
Cancerous cell
50% of all cancershave an aberrant p53 gene
p53 that can trigger cell apoptosis
23
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
24
Classes of Carcinogens
1. Physical
2. Chemical
3. Biological
4. Heredity
25
Physical Causes
26
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
27
Chemical Causes
28
Biological CausesSome viruses carry oncogenes whose products cause transformation of host cells into cancer cells.Viral genome may be inserted into regulatory sites.
29
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”.
30
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
31
• 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