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Flashcards in Perturbations Deck (33):
1

How do superantigens differ from conventional peptides that require uptake and processing prior to presentation to T lymphocytes?

In contrast to conventional peptides that require uptake and processing prior to
presentation to T lymphocytes, superantigens interact with the ‘side’ of the MHC Class II - TCR complex.

molecules prod. by microorganisms that bind Class II and TCR. bind outside peptide binding groove, cross link MHC II to TCR. as many as 20% of T cells can be cross linked in this manner
so T cells are thus highly activated

These molecules bind TCR’s on many CD4 T cells and MHC class II molecules on APC’s, overstimulating the immune system, producing a cytokine storm.

The individual’s MHC and TCR binding characteristics dictate the magnitude of T cell
activation and hence the level of cytokine production. The advantage to the infecting
microorganism is that highly activated immune effector cells undergo widespread apoptosis and lose their ability to effectively react against the invading microorganism.

2

The intensity of the superantigen response is strongly dependent on the polymorphism of the host's MHC class II. Which HLA might have a stronger effect?

the same bacterial strain might cause death in some patients (e.g. those
with TCR-Vbeta3 and specific HLA-DR molecules) and hardly any clinical disease in
others with differing HLA

3

What is thought to contribute to toxic shock syndrome toxin 1 (TSST1)?

Disease results from body’s response to staphylococcal superantigens

Why tampons can
result in the syndrome is not completely clear but may be due to abrasion of host tissue
and introduction of staphylococci

The disease is manifest not just in women but also in children and men likely due to abrasion of the skin.)

What is clear is that exposure to the microorganism and its
superantigens results in the syndrome, which include the signs and symptoms in Figure
2, and especially, a rash on palms and soles

4

Describe the polyclonal extensive activation of T cells caused by TSST1. Describe the cytokines and their effects.

Polyclonal extensive activation of T cells
Over-production of INF-γ

Activates Macrophages
Over-production of IL-1, IL-6 and TNF-α

Toxic shock syndrome toxin 1- when that happens those T cells interact w MHC through superantigen. T-Cells activated to prod. large quantities of IFNgamma. that wills stimulate macrophages to prod. IL1, 6, and TNFalpha (can cause fever). (TNFalpha will interact w capillaries and induce capillary permeability …therefore bp drops fever caused by these 3 cytokines TNF can interact w vasculature and (local interaction in this cause) causing platelets to aggregate causing localized coagulation effect. When this is severe- systemic effect and get DIC, multi-organ failure, coma and death. serious situation induced by super antigens.

5

What is DIC? Describe.

Disseminated intravascular
Coagulation

DIC leads to the formation of small blood clots inside the blood vessels throughout the body. As the small clots consume coagulation proteins and platelets, normal coagulation is disrupted and abnormal bleeding occurs from the skin, the GI, the respiratory tract and surgical wounds. The small clots also disrupt normal blood flow to organs (such as the kidneys), which may malfunction as a result.

6

What do the following indicate clinically?

low blood pressure, fever, diarrhea, extensive skin rash, and shedding of the skin

Toxic Shock Syndrome


Fever
Hypotension
Rash
Desquamation 1 to 2 weeks after onset of illness, particularly involving palms and soles

7

What are s. aureus strains related to?

release toxic shock syndrome toxin (TSST-1)

8

What is CCR5? Describe its significance.

CCR5 is a receptor for chemokines that attract and direct the migration of T cells to the site of infection.

CCR5 is also a co-receptor (along with CD4) for binding and entry into human T lymphocytes by HIV-1.

Individuals that lack a functional CCR5 (known as CCR5-delta32) are not susceptible to HIV-1 but are susceptible to infection with WNV.

9

There are individuals who have been infected with HIV but whose disease has not progressed or has progressed slowly compared to the average experience. What
makes these people less susceptible to HIV?

HIV-1 needs two receptors to gain entry into human cells; the CD4 receptor and the chemokine receptor, CCR5.

Once HIV has bound to CD4 and CCR5 the
virus can fuse with the human cell, permitting entry of the viral genetic material into the cell.

10

What protein on the surface of HIV binds to T cells?

gp41 binds to CD4 positive T cells... can only bind though if CCR5 is present.

slide 9

11

Why do CCR5 deficient individuals succumb more easily to West Nile virus?

CCR5 is a receptor for chemokines that attract and direct the migration of T cells to the site of infection.

if T cells cannot migrate to site of infection, (no CCR5 present) then one succumbs to West nile which traffics to brain and causes encephalitis

T cells cannot get to site of infection without CCR5 bc there is not chemotactic responsivitiy

Protection from WNV encephalitis is dependent upon the accumulation
of CCR5+leukocytes including; CD4+, CD8+, CD14+ and CD56+.

12

What is the significance of homozygosity or heterozygosity for the CCR5-delta32 gene?

The individuals who seem to have complete natural resistance to the HIV virus are homozygous for the CCR5-delta32 gene. (CCR5-delta32 is a polymorphism in the gene
encoding CCR5 in which a segment of 32 base pairs has been deleted, resulting in a nonfunctional
protein.)

The individuals who are termed “slow progressors” are heterozygous for the CCR5-delta32 gene. Hence, the polymorphism in CCR5 does not permit HIV to bind and infect
cells when homozygous and reduces infection when heterozygous. Quite advantageous for those exposed to HIV.

13

Protection against WNV is dependent upon the accumulation of which leukocytes?

Protection from WNV encephalitis is dependent upon the accumulation
of CCR5+leukocytes including; CD4+, CD8+, CD14+ and CD56+.

14

What type of cells cause autoimmune disorders?

Autoimmune Disorders are caused by self-reactive T and B lymphocytes.

Normal immunity depends upon the ability to discriminate between self and non-self.
(for B and T cells to become auto-reactive- had to be break in tolerance to some sort)

15

Describe central and peripheral T tolerance. Describe B cell tolerance.

Central tolerance is dependent on the thymus.
Tolerance occurs by virtue of negative selection and clonal deletion of strongly self reactive thymocytes
Autoimmune regulator complex (AIRE) located in the medullary thymic epithelium expresses self peptides in the thymus.

T cells tolerarized in thymus. any T cell highly reactive against MHC I and II will be deleted. any T cell highly reactive against peptides (pres. of consequence of AIRE gene complex) will be deleted as well… thats central tolerance

Peripheral tolerance an active, antigen specific process enforced by CD4+25+ FoxP3+
T regulatory cells (T regs) that prevent auto-attacks by self-reactive T cells that have escaped deletion during thymic development.

B cell Tolerance. Deletion of self- reactive B cells during their development in the bone marrow is not as stringent as that for T cells.

16

What is the significance of the AIRE gene? Where is it located?

What will mutations in AIRE or absence of AIRE result in?

A second major intra-thymic tolerance mechanism is a gene complex, designated the autoimmune regulator complex (AIRE) located in the medullary thymic epithelium.

These genes control the display of a wide variety of tissue peptide antigens (especially neural structures and endocrine) on thymic epithelium. High affinity TCR interaction with these antigens deletes the T cell. Low affinity interactions promote T reg development, which are distinguished by the presence of the nuclear transcription factor-
FoxP3.

Mutations in AIRE give rise to an autoimmune disease known as autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECD). Individuals with a complete absence of AIRE do not express self peptides in the thymus and auto-reactive
cells escape to the periphery resulting in multiple autoimmune diseases.

17

What might lead to self-reactive B cell development? What may result if these go unchecked?

During antigen driven somatic hyper-mutation in the periphery, self-reactive B cells may
develop.

They usually die from “neglect” however, or are directly suppressed by CD4, 25, FoxP3 T regs.

When self- reactive B cells are unchecked, they may synthesize antibodies that block functions of cells, may accelerate cell functions by mimicking
agonists or promote cytotoxic responses.

18

What are the two systemic autoimmune diseases? Describe mechanisms.
What type of hypersensitivty?

Systemic lupus erythematosus (SLE)
Rheumatoid arthritis

Systemic lupus erythematosus- (III)
Ab to DNA, immune complex deposition basement membranes

Rheumatoid arthritis- (IV)
CD4 response that stimulates an inflammatory response within the joints

19

Describe the mechanism for the following autoimmune disease:
What type of hypersensitivty?

T1DM

CD8 and Ab response to pancreatic beta cells, beta cell destruction

Type IV

20

Describe the mechanism for the following autoimmune disease:
What type of hypersensitivty?

Graves’ disease

Ab to TSH receptor, excessive thyroid hormone, hyperthyroidism

Effector mechanism: auto-reactive antibodies against thyroid stimulating hormone (TSH) receptor
Stimulates the excessive production of thyroid hormone. Excessive thyroid hormone causes hyperthyroidism.

Type II

21

Describe the mechanism for the following autoimmune disease:
What type of hypersensitivty?

Goodpasture’s syndrome

Ab to type IV collagen (lung and kidney), pulmonary hemorrhage and glomerulonephritis

Antibodies to type IV collagen in alveolar and glomerular basement membranes. Characterized by pulmonary hemorrhage and glomerulonephritis

Type II

22

Describe the mechanism for the following autoimmune disease:
What type of hypersensitivty?

Myasthenia gravis

Ab to acetylcholine receptor, blocks neurotransmission, muscle weakness

Type II

Antibodies to the nicotinic acetylcholine receptor, present on skeletal muscle cells at neuromuscular junstions, Block neuromuscular transmission.

early sign of this disease where the eyelid cannot be retracted.

23

Describe the mechanism for the following autoimmune disease:
What type of hypersensitivty?

Multiple sclerosis

CD4 reactive with myelin basic protein, demyelination

Type IV

24

Describe SLE.
What is most common autoantibody?
What are some clinical indications?
What is hallmark of disease?

How do you diagnose in the lab?

-Autoantibodies to many autoantigens (ds-DNA, RNA or histones)
-Most common autoantibody is to ds-DNA

Immune complex deposition on basement membranes with complement activation and inflammation

Musculoskeletal (joint and muscle pain)
Dermatological (malar rash/butterfly)
Renal (glomerulonephritis=hallmark of disease)


Laboratory diagnosis:
Anti-nuclear antibody (ANA)
Anti ds-DNA
C3 level decreased

25

Describe T1DM.

What type of effector mechanism?

CD8 T cells and autoantibodies against beta cells

Female to male ratio of 1:1

Pancreatic beta cells are damaged by
-Infectious agents
-Mumps virus, rubella virus
coxsackie B virus
-Toxic chemicals

26

Females are more often afflicted by autoimmune diseases. What is the exception?

Insulin dependent diabetes mellitus

Female to male ratio of 1:1

27

What can Mumps virus, rubella virus, or
coxsackie B virus lead to?

T1DM

28

Describe Rheumatoid arthritis. How is it characterized?

Describe Rheumatoid factor.

Characterized by inflammation of synovial membrane of joints and articular surfaces of cartilage and bone

-CD4 T cells, activated B cells, macrophages and plasma cells
- 85% of patients have rheumatoid factor

Rheumatoid factor
-IgM, IgG and IgA specific for IgG
-Immune complex formation
-Exacerbates inflammation within joints

29

Describe the mechanism of RA.

inflammation occurs. T cells to site. respond to antigen presented by DC or macrophages, activate cell populations and draw other cell populations to site. IMPORTANT: TNFalpha and IL6 are prod. by macrophages and those directly interact w fibroblasts in joint- those fibroblasts release MMP (matrix metalo proteases) which destroy tissue. they also release RANK-ligand- binds to RANK on bone cells activating osteoclasts, osteoclasts resorb and affect the structure of the bone and cartilage causing the disease

30

Describe MS. What type of hypersensitivity? Effector mechanism? How is it characterized?

T cells are effector mechanism

Chronic unpredictable disease of CNS with multiple possible clinical courses

Characterized by patches of demyelination and inflammation of myelin sheath
Myelin basic protein is primary autoantigen for CD4 cells

31

Which disease prevalence is higher in Northern Hemisphere?

MS

32

What four factors increase risk for autoimmune disease?

Genetic (HLA type)

Female

Environmental
Smoking with RA

Infections

33

In what diseases might you observe glomerulonephritis?

Systemic lupus erythematosus

Good pastures