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Microbiology I Flashcards

Explain the possible mechanisms of induction of Autoimmunity For each autoimmune disease, recognize the symptoms, describe the autoimmune mechanism, list what type of hypersensitivity reaction is involved, and discuss potential treatments Discuss the experimental approaches to treatment of Autoimmune disease

1
Q

Myasthia Gravis

A

Ach receptor affected , so ACh released from presynaptic neuron has nowhere to bind

Antibodies binding to cells/tissues
non-cytotoxic: wont kill the tissue initially
; only Change the FUNCTION of the tissue
-Altering its normal function

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2
Q

Who are most affected by Autoimmune diseases?

A

Females

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3
Q

What plays a major role in inducing autoimmunity?

A

Hormones

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4
Q

What is tightly controlled?

A

T cell activation

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5
Q

What is autoimmunity?

A

The response of the immune system against self components

- can be organ specific and systemic

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6
Q

What are the defining characteristics of autoimmunity?

A

autoantibody or auto reactive T cells specific for self antigens

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7
Q

What percentage of the human population is affected by autoimmunity?

A

5-7 %

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8
Q

What resembles immune effector mechanisms?

A

Hypersensitivity reactions II-IV

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9
Q

Mechanisms of autoimmunity

A 
Breakdown of tolerance 
Release of sequestered antigens 
Molecular mimicry 
Inappropriate expression of HLA
Polyclonal B cell activators 
Genetics
AIRE
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10
Q

What is the breakdown of tolerance?

A

Deletion
Anergy
Suppression
The mechanism is compromise (trauma, infection)

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11
Q

HLA-B27

A

Ankolytic spondylitis

however, doesn’t necessary mean your will get it

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12
Q

Infection

A

leads to biological mimicry

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13
Q

Normal T-cell activation

A

MHCII + TCR
CD28 + B7 = activation molecules send the cell to an activated state - Don’t have co-stimulatory molecules

tightly controlled

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14
Q

Anergy

A

Lack of stimulatory signal
CTLA is in the place of CD28 => CTLA-A binds B7 = blocks activation signal
Soluble CTLA can deactivate signal

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15
Q

What does lack of CTLA-4 favor?

A

can spike increase in autoimmunity

Producing less sCTLA4 linked to autoimmune diseases

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16
Q

T cell maturation

A

Any T cell that was very reactive to MHC got deleted in the thymus

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17
Q

Mechanism of Tolerance

A

Thymic epithelium cells present T cells with a wide range of auto antigens
T cells which bind to antigen with high affinity in the thymus are deleted through negative selection
Antigens such as DNA are usually only represent inside cells and if they do escape, are cleared by complement or natural antibodies

Express co-stimulatory molecule

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18
Q

Barriers

A

Some tissues are protected from T cells by physical barriers** e.g. eyes and brain
(A lot of protective spaces where the immune system don’t have access to)

Trauma/inflammation can allow immune cell to pass through - which will mean that the immune system will not recognize environment vs self ?

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19
Q

Breakdown of Tolerance

A

Self antigen is missing from the thymus or MHC is unable to bind antigen
Few auto reactive T cells are deleted and more escape to the periphery
DNA may leak out of dying cells and is not cleared if complement is defective
Physical barriers round cells may become defective
If a tissue becomes infected cells of innate immune response express co-stimulatory molecules and secrete cytokines

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20
Q

Molecular mimicry

A

infection can trigger molecular mimicry

Pathogens express proteins with regions that are similar to self components

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21
Q

when will Intracellular type of antigens will not be sequestered?

A

high cell turnover
intracellular content release
immune response by random association -> immune complex deposition

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22
Q

Lost of T cell suppression

A

T regulatory cells suppress auto reactive CD4 T cells - requires direct contact e.g. IL-4, IL-10 produced = requires them to interact with CD4 T cell that is on the same APC as the Treg cell

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23
Q

What is FoxP3?

A

Treg cells typically have FoxP3
Loss of FoxP3 = less regulation = autoimmunity
a transcriptional repressor
found on X chr.

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24
Q

What kind of signal that CTLA-4 send?

A

inhibitory

suppresses CD4 T cells

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25
Q

Mutation of FoxP3 - a problem with the regulatory cell

A

Defect in suppressor protein

Observed in Chron’s disease and inflammatory bowel disease

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26
Q

Release of sequestered antigens

A

Tissue antigens not seen by developing T cells (sequestered) will not induce tolerance
Exposure of T cells to normally sequestered antigens at a later time may result in their activation

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27
Q

What mechanisms induce the release of sequestered antigens?

A

Trauma

Infectious agents

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28
Q

SLE = systemic lupus

A

T cells exposed to normally sequestered antigen = immune response will occur
Ab against intracellular proteins e.g. histone proteins (nucleosomes)?
Abnormally number of turnover and cells dying
Immune complexes circulate and go wherever they want ****

SLE patients also have increased IFN-y which mediates the ectopic expression of MHC by many different cells

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29
Q

What is one way pathogens escape?

A

Hijack and copy self peptides

-molecular mimicry

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30
Q

Agents that use molecular mimicry with Viral peptides and MBP (myelin basic protein)

A 
Influenza
Adenovirus 
Polio virus 
Epstein Barr virus 
Hepatitis B virus
and associated DISEASES
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31
Q

What diseases associated with molecular mimicry

A 
Post rabies encephalitis 
Polyoma
Rheumatic fever
Rous sarcoma 
Abelson leukemia
-both from viral peptides
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32
Q

In many different cases, pathogens will have quite a few similarities with peptides . What is a classic example?

A

Cytomegalovirus has the similar stretch of peptides as HLA-DR
which causes immune response against Class II MHC

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33
Q

Ectopic expression of MHC

A

MHC Class II are on APCs e.g. macrophages, dendritic cells, B cells

Interferon gamma upregulates or increase MHC II in all different types of cells during extensive infection
These are targeted for the immune system

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34
Q

What are the diseases associated with ectopic expression of MHC?

A

IDDM - insulin-dependent diabetes mellitus

Grave’s disease

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35
Q

what are the different types of cells to which the IFN-yacts to increase or up regulate MHC?

A

pancreatic beta cells
intestinal epithelial cells
melanoma cells
thyroid acinar cells

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36
Q

What can trigger inflammatory response and increase IFN-y

A

Trauma (infection) in organ

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37
Q

Induced expression of MHC

A

Some cells do not normally express MHC II

Trauma (infection) trigger inflammatory response

38
Q

What cells do not normally express MHC II ?

A

Thyroid epithelial cells in Grave’s disease

Pancreaetic beta cells in IDDM

39
Q

What do T cells do in Grave’s disease?

A

Activated T cells recognize thyroid peptides presented by MHC class II and induce autoimmune thyroid disease

40
Q

Polyclonal B cell activation without antigen binding

A

EBV enters B cells through non-tranditional route -> increase production of IgM in B cells?

Other agents that do this are gram negatives and CMV

-cause indiscriminate or non-specific activation (bypass all the specificities)

41
Q

HLA association

A

Association of HLA aerotype with susceptibility to autoimmune disease

42
Q

HLA Class II

A

Mostly indicated e.g. HLA DR3

43
Q

What is the relative risk of just having DR2?

A

4.2

All the Ds are class II HLA

44
Q

Ankylosing spondylitis

A

HLA aerotype B27
Relative risk 87.4 (more than other HLA association)
Sex ratio (male:female) : 0.3
more females affected

45
Q

AIRE

A

Autoimmne regulator
transcriptional activor in the thymus
responsible for inducing the expression of 1200 genes for T cells so the T cells know what is self vs non self

It allows the T cells to see the self antigens and undergo negative selection

46
Q

What happens when the AIRE is lacking?

A

antigens are not present in the thymus, which means that potential self reactive T cells are not removed

-causing autoimmunity in the peripheral organs

47
Q

Autoimmune polyglandular syndrome

A

Lack of AIRE

affected individuals develop a wide rage of autoantibodies against endocrine glands, liver, skin, blood cells, and platelets

48
Q

Thymus education

A

Occurs via extensive gene expression in other tissues

49
Q

What HLA association links to MG?

A

HLA DR3

50
Q

What are the Sx of MG?

A

progressive muscle weakness, droopy eyelids, double vision, eventually other face muscles weaken and similar effects can occur on the chest muscles which can impair breathing

51
Q

How to differentiate between MG and MS

A

MS is spastic because you attack myelin

MG is weakness of muscles

52
Q

What is the early Sx of MG and MS ?

A

Start with vision problems (double vision)
droopy eyes
paralysis

53
Q

MG and inflammation

A

auto-ab specific for Ach rcpt -> activation of complement -> inflammation

54
Q

How to diagnose MG?

A

Anti-Ach ab in the serum

55
Q

How is MG tx?

A

anti-cholinestereases, immunosuppresion. plasmapheresis and thymus removal

56
Q

Type III hypersensitivities

A

Rheumatoid arthritis

Systemic lupus erythematosis

57
Q

Rheumatoid arthritis

A 
cause chronic inflammation of the joints
triggered by a immune complex ; can be hypersensitivity type IV
Affects 1-3 % population 
Females affected 3x more 
20-40 years 
HLA-DR4 association (rr=4.2)
58
Q

Tx for Systemic Lupus Erythematosis

A

Glucocorticoids

59
Q

Why is RH considered type IV?

A

Macrophages + Tcell recruitment = tissue destruction

60
Q

Rheumatoid factor

A

IgM Ab binding specific for Fc of IgG

61
Q

What cells infiltrate the joints in Rheumatoid arthritis ?

A

chronic inflammation:

Leukocytes including CD4, CD8, B cells, plasma cells, neutrophils and macrophages infiltrate into the joint synovium

62
Q

Diagnostic for Rheumatoid arthritis

A

Rheumatoid factor but not always present

Thus, use elevated IgG and IgM

63
Q

Tx for Rheumatoid arthritis

A

NSAIDs (COX-2 inhibitors), corticosterioids, immunosuppresion, gold therapy, anti-TNF-a (infliximab)

64
Q

Presentation for SLE

A

Females 15x affected
20-40 years of age
African American ad Asian women
HLA-DR3 (rr=5.8)

65
Q

What kind of inflammatory disease is SLE?

A

chronic

-involves almost every organ system, Sx depend on organ effected

66
Q

SLE is a multi-system disease. What antigens are targeted

A

Auto-ab to almost every tissue antigen including histones, DNA, RNA, clotting factors

Disease effects dependent on area of complex deposition

67
Q

Mechanism of SLE

A

Immune complexes form and deposit in various tissues
Complement binds
inflammation
necrosis - lumpy bumpy pattern of immune complexes

68
Q

Diagnostic for SLE

A

Anti-DS DNA is specific test

69
Q

Tx of SLE

A

NSAIDs, corticosteriods, immunosuppression, anti-malarial drugs

70
Q

Pathogenesis of SLE

A

Type III HS - lumpy bumpy pattern of deposition
spotty and throughout the kidney
Cause nephritis

Sx : butterfly formation rash on the face

71
Q

Type II HS - Ab deposition

A

Ab deposition fall in a linear fashion in binding to basement membrane of kidneys
SMOOTH

72
Q

Multiple sclerosis

A

Type IV disease

T cells can invade BBB and cause immunity to myelin = attack myelin sheath

73
Q

What does IFN-b do in MS?

A

halt plaques from progressing

74
Q

Diagnostic for MS

A

IgG also seen in CSF

75
Q

Presentation of MS

A 
Females 10x more 
20-30 y/o
HLA-DR2 (rr=4.8)
Motor weakness, impaired vision, lack of coordination, spasticity 
start with double vision
76
Q

Diagnostic for MS

A

MRI - start to see sclerotic plaques

oligoclonal IgG

77
Q

Mechanism of MS

A

Tdth cells infiltrate the CNS (white matter) and react with myelin basic protein

78
Q

What are sclerotic plaques in MS?

A

Contain plasma cells that secrete oligoclonal IgG in CSF

MRI - start to see sclerotic plaques

79
Q

Mechanism Ankylosing spondylitis

A

Antibodies formed in response to Klebsiella, Shigella or Yersinia react with spine, eventual fusion of spine

80
Q

Which HLA associated with ankylosing spondylitis

A

B27

81
Q

Reiter’s syndrome

A

Cross reacting antibodies to many STD’s (Arthritis, conjunctivitis, and fever) also see urethritis

82
Q

What are the pro inflammatory cytokines?

A

IL-1, IL-6, and TNF-a

83
Q

What is the triad for Reiter’s syndrome)?

A
  • post infectious (STD and enteric)
    Chlamydia, Yersinia, Shigella
    are identifying triad for Reiter’s syndrome
84
Q

Presentation of AS

A

Male 3x more
HLA - B27
“bamboo spine”

85
Q

Relationship between AS and TB

A

Suppressing inflammatory response in AS can lead to TB spread

86
Q

Sx of Reiter’s

A

joint stiffness, primarily involving knees, ankles, and feet (WRISTmay be early target)

87
Q

Tx of Reiter’s

A

NSAIDs

COX-2 inhibitors

88
Q

Experimental therapeutic approaches

A

T cell vaccination
Peptide blockage of MHC
Monoclonal Ab

89
Q

T cell activation as experimental therapy

A

Vaccine against the antigens on T cell that attack other type of cells
vaccinate with autoimmune cells
Immune response is directed toward the TCR region of the autoimmune clone

90
Q

Peptide blockade of MHC

A

MHC specific for self peptides
Synthetic peptides with 1 aa changed, binds better to MHC and out competes self peptides

prevent immune response

91
Q

Monoclonal Ab

A

Anti-CD4, Anti-TCR, anti-MHC, and anti-IL-2R

will act to suppress function

92
Q

Rationale for peptide blockage of MHC?

A

Some cells bind self peptide with higher affinity
DR4 – higher affinity than self – outcompete for the protein binding ?
Self peptide will need to compete for space

Musculoskeletal System (27 decks)

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