Transcript Foundations in Microbiology

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
Sequestered behind anatomical barriers
Self reacting lymphocyte clones
Infection, trauma or deterioration
Some tissues are not scanned
by the immune system during
embryonic growth.
CNS, lens, thyroid & testes
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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 Deficiency
B lymphocytes have defective receptors
Can not distinguish between self & non-self
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Viral Infection Theory
Self antigens are altered by a viral infection
Produces an immune response against perceived foreign antigens
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insulin-dependent
Hypothesized to be
caused by viral infection
Cell receptor is altered by
a viral infection
Immune cells attack that
tissues bearing viral
damaged receptor
AutoAbs produced against b cells
of the islets of Langerhans
T cells become specific for all the
insulin-producing b cells in the
islets destroy the cells and greatly
reduce insulin synthesis
Viral infections of the pancreas
Several viruses have been implicated
but not conclusively demonstrated:
Mumps virus, rubella virus, hepatitis C
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Other Autoimmune Diseases
Lupus
AutoAb against organs & tissues
Butterfly 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 arthritis
AutoAb bind to the synovial
membranes of joints
Chronic 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 Diseases
Graves Disease
Hashimoto thyroiditis
AutoAb to receptors of cells
in the thyroid that produce
thyroxin
Overproduction of thyroxin
Hyperthyroidism
AutoAb & T cells reduce thyroid production
Hypothyroidism
HTLV-1 (Human TLymphotropic Virus)
Myasthenia gravis
AutoAb bind to receptors of
acetylcholine
Damages muscles  paralysis
Viral etiology proposed but none
has been identified
HTLV-1
Multiple sclerosis
AutoAb & T cells damage myelin
Muscular weakness & tremors
Difficulties in speech, vision &
paralysis
Hypothesis: Human herpes virus,
possibly EBV
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Herpes Viruses
www.cdc.gov
• 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
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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 simplex HSV-1
herpes meningitis
Varicella-Zoster (VSV)
Varicella-Zoster Virus (VZV):
chickenpox
shingles (herpes zoster)
Epstein-Barr (EBV)
90% of the human population
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):
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Kaposi's sarcoma
Latency
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,
Stress
exit from the cell) in epithelial
Fever
cells of the skin to cause a
Trauma
primary infection. (b) Some virus
Sunlight
enters the sensory neuron
Menstruation
terminals and travels retrogradely
Infection
Immune suppression 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.
Mucous membrane
HSV-1 & HSV-2
www-ermm.cbcu.cam.ac.uk/fig001rlc.gif
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Epstein-Barr Virus
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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
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Common childhood infection
– Asymptomatic
– Brief illnesses of childhood
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Cytotoxic T cells attempt to
eliminate infect B cells
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
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Causes Burkitt's lymphoma and nasopharyngeal carcinoma
– Rare cancers that are not typically found in the United States
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No antiviral drugs or vaccines are available
Chronic fatigue syndrome
– Impossible to state that this is caused by EBV
– Not plausible by the CDC
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Cancer
New abnormal growth of tissue
≡ any of various neoplasms characterized
by the proliferation of anaplastic cells
that tend to invade surrounding tissue and
metastasize to new body sites
A lack of differentiation
Spread to other regions of the body via blood and
lymph vessels or spinal fluid
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Neoplasms
Immune Surveillance
Majority of precancerous / cancer cells
are destroyed:
• Benign
NK Cells (natural killer cells)
– Noncancerous
Macrophages
• Grow slowly
TC Cells
• 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
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Causes of Death - Worldwide
13.5
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Carcinomas
Originate in the outer layer of cells of the skin and
internal membranes. Examples include: breast, lung, intestinal,
skin & prostate cancer.
Sarcomas
Originate in connective tissue such as bone, muscle, cartilage &
blood vessels.
Lymphomas & Leukemias
Hematologic cancers
Blood 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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Normal Growth Control
Proto-oncogenes & Oncogenes
Proto-oncogenes
Code for proteins that
stimulate mitosis
Oncogenes
Over-expression of proteins
that promote mitosis
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Oncogenes are Mutant Forms of ProtoOncogenes
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Tumor Suppressor Genes
Tumor suppressor genes
Code for proteins that inhibit mitosis
No longer inhibit mitosis
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p53 that can trigger cell apoptosis
p53 Tumor Suppressor Gene
50% of all cancers
have an aberrant p53 gene
Normal cell
Cancerous cell
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DNA Repair Genes
DNA repair genes code
for proteins whose
normal function is to
correct DNA errors
Mutations in DNA repair genes can lead to a
failure in DNA repair, which in turn allows
subsequent mutations in tumor suppressor
genes and proto-oncogenes to accumulate
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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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Radiation Sources
Nuclear
medicine 4%
Consumer products 3%
Other 1%
Medical X
rays 11%
Chemical
reactions
in the body
11%
Radon
54%
Other chemical
sources 8%
Cosmic waves 8%
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Chemical Causes
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Biological Causes
Some 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-1
Nature Medicine 2004 10
J Clin Pathol 2000 53:581-586
Human 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
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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
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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
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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
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