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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 (92 cards)

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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
Mutation of FoxP3 - a problem with the regulatory cell
Defect in suppressor protein Observed in Chron's disease and inflammatory bowel disease
26
Release of sequestered antigens
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
27
What mechanisms induce the release of sequestered antigens?
Trauma | Infectious agents
28
SLE = systemic lupus
****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
29
What is one way pathogens escape?
Hijack and copy self peptides | -molecular mimicry
30
Agents that use molecular mimicry with Viral peptides and MBP (myelin basic protein)
``` Influenza Adenovirus Polio virus Epstein Barr virus Hepatitis B virus and associated DISEASES ```
31
What diseases associated with molecular mimicry
``` Post rabies encephalitis Polyoma Rheumatic fever Rous sarcoma Abelson leukemia -both from viral peptides ```
32
In many different cases, pathogens will have quite a few similarities with peptides . What is a classic example?
Cytomegalovirus has the similar stretch of peptides as HLA-DR which causes immune response against Class II MHC
33
Ectopic expression of MHC
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
34
What are the diseases associated with ectopic expression of MHC?
IDDM - insulin-dependent diabetes mellitus | Grave's disease
35
what are the different types of cells to which the IFN-yacts to increase or up regulate MHC?
pancreatic beta cells intestinal epithelial cells melanoma cells thyroid acinar cells
36
What can trigger inflammatory response and increase IFN-y
Trauma (infection) in organ
37
Induced expression of MHC
Some cells do not normally express MHC II | Trauma (infection) trigger inflammatory response
38
What cells do not normally express MHC II ?
Thyroid epithelial cells in Grave's disease | Pancreaetic beta cells in IDDM
39
What do T cells do in Grave's disease?
Activated T cells recognize thyroid peptides presented by MHC class II and induce autoimmune thyroid disease
40
Polyclonal B cell activation without antigen binding
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
HLA association
Association of HLA aerotype with susceptibility to autoimmune disease
42
HLA Class II
Mostly indicated e.g. HLA DR3
43
What is the relative risk of just having DR2?
4.2 All the Ds are class II HLA
44
Ankylosing spondylitis
HLA aerotype B27 Relative risk 87.4 (more than other HLA association) Sex ratio (male:female) : 0.3 more females affected
45
AIRE
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
What happens when the AIRE is lacking?
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
Autoimmune polyglandular syndrome
Lack of AIRE affected individuals develop a wide rage of autoantibodies against endocrine glands, liver, skin, blood cells, and platelets
48
Thymus education
Occurs via extensive gene expression in other tissues
49
What HLA association links to MG?
HLA DR3
50
What are the Sx of MG?
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
How to differentiate between MG and MS
MS is spastic because you attack myelin | MG is weakness of muscles
52
What is the early Sx of MG and MS ?
Start with vision problems (double vision) droopy eyes paralysis
53
MG and inflammation
auto-ab specific for Ach rcpt -> activation of complement -> inflammation
54
How to diagnose MG?
Anti-Ach ab in the serum
55
How is MG tx?
anti-cholinestereases, immunosuppresion. plasmapheresis and thymus removal
56
Type III hypersensitivities
Rheumatoid arthritis | Systemic lupus erythematosis
57
Rheumatoid arthritis
``` 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
Tx for Systemic Lupus Erythematosis
Glucocorticoids
59
Why is RH considered type IV?
Macrophages + Tcell recruitment = tissue destruction
60
Rheumatoid factor
IgM Ab binding specific for Fc of IgG
61
What cells infiltrate the joints in Rheumatoid arthritis ?
chronic inflammation: | Leukocytes including CD4, CD8, B cells, plasma cells, neutrophils and macrophages infiltrate into the joint synovium
62
Diagnostic for Rheumatoid arthritis
Rheumatoid factor but not always present | Thus, use elevated IgG and IgM
63
Tx for Rheumatoid arthritis
NSAIDs (COX-2 inhibitors), corticosterioids, immunosuppresion, gold therapy, anti-TNF-a (infliximab)
64
Presentation for SLE
Females 15x affected 20-40 years of age African American ad Asian women HLA-DR3 (rr=5.8)
65
What kind of inflammatory disease is SLE?
chronic | -involves almost every organ system, Sx depend on organ effected
66
SLE is a multi-system disease. What antigens are targeted
Auto-ab to almost every tissue antigen including histones, DNA, RNA, clotting factors Disease effects dependent on area of complex deposition
67
Mechanism of SLE
Immune complexes form and deposit in various tissues Complement binds inflammation necrosis - lumpy bumpy pattern of immune complexes
68
Diagnostic for SLE
Anti-DS DNA is specific test
69
Tx of SLE
NSAIDs, corticosteriods, immunosuppression, anti-malarial drugs
70
Pathogenesis of SLE
Type III HS - lumpy bumpy pattern of deposition spotty and throughout the kidney Cause nephritis Sx : butterfly formation rash on the face
71
Type II HS - Ab deposition
Ab deposition fall in a linear fashion in binding to basement membrane of kidneys SMOOTH
72
Multiple sclerosis
Type IV disease | T cells can invade BBB and cause immunity to myelin = attack myelin sheath
73
What does IFN-b do in MS?
halt plaques from progressing
74
Diagnostic for MS
IgG also seen in CSF
75
Presentation of MS
``` 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
Diagnostic for MS
MRI - start to see sclerotic plaques oligoclonal IgG
77
Mechanism of MS
Tdth cells infiltrate the CNS (white matter) and react with myelin basic protein
78
What are sclerotic plaques in MS?
Contain plasma cells that secrete oligoclonal IgG in CSF | MRI - start to see sclerotic plaques
79
Mechanism Ankylosing spondylitis
Antibodies formed in response to Klebsiella, Shigella or Yersinia react with spine, eventual fusion of spine
80
Which HLA associated with ankylosing spondylitis
B27
81
Reiter's syndrome
Cross reacting antibodies to many STD’s (Arthritis, conjunctivitis, and fever) also see urethritis
82
What are the pro inflammatory cytokines?
IL-1, IL-6, and TNF-a
83
What is the triad for Reiter's syndrome)?
- post infectious (STD and enteric) Chlamydia, Yersinia, Shigella are identifying triad for Reiter's syndrome
84
Presentation of AS
Male 3x more HLA - B27 "bamboo spine"
85
Relationship between AS and TB
Suppressing inflammatory response in AS can lead to TB spread
86
Sx of Reiter's
joint stiffness, primarily involving knees, ankles, and feet (WRISTmay be early target)
87
Tx of Reiter's
NSAIDs | COX-2 inhibitors
88
Experimental therapeutic approaches
T cell vaccination Peptide blockage of MHC Monoclonal Ab
89
T cell activation as experimental therapy
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
Peptide blockade of MHC
MHC specific for self peptides Synthetic peptides with 1 aa changed, binds better to MHC and out competes self peptides prevent immune response
91
Monoclonal Ab
Anti-CD4, Anti-TCR, anti-MHC, and anti-IL-2R | will act to suppress function
92
Rationale for peptide blockage of MHC?
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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