2 - Micro - Autoimmune

Question 1

Explain what is involved in the breakdown of tolerance mechanism of autoimmunity

Answer 1

Some individuals are missing self antigen in the thymus or MHC is unable to bind. As a result, fewer “self-binding” T cells are deleted/caught.

Question 2

Explain the details of “Loss of T Cell Anergy”

Answer 2

Lack of a co-stimulatory signal causes anergy

CTLA-4 (on self-antigen) binds and co-activates T-cell with self-antigen in tolerance process which marks it for deletion.

Autoimmune disease associated with less soluble CTLA-4 (sCTLA-4)?

Basically the absence of these co-stimulators allows the self reactive T-Cells to pass the test because they don’t fully bind self antigens.

Result - Clonal Expansion of self-reacting T Cells

Question 3

Define anergy

Answer 3

Lack of immune reaction to a presented antigen, in this context anergy causes bad T Cells to escape the selection process because they fail to bind dummy self antigens

Question 4

Explain the details of “Loss of T Cell Suppression” in autoimmunity

Answer 4

Key term = LOSS OF FoxP3

Treg cells suppress autoreactive CD4 T cells (requires direct contact), via FoxP3 repressor

Question 5

What are the three processes involved with loss of tolerance in autoimmunity?q

Answer 5

Loss of tolerance period (missing self antigen/MHC)
Loss of Tcell anergy (CTLA-4)
Loss of Tcell repressor (FoxP3)

Question 6

Explain how the release of sequestered antigens can cause T Cell activation/autoimmunity
What disease is this process seen in?

Answer 6

The release of never before seen antigens via trauma or infectious agents can cause unwanted activation (no tolerance is achieved)

Seen in Systemic Lupus Erythematosus

Question 7

Explain how molecular mimicry is involved in autoimmunity

Diseases that show this process of autoimmune rxns?

Answer 7

Pathogens can express proteins that have regions similar to self components, causing activation of a reaction to those self components.

Seen in: Post-Rabies Encephalitis, Rheumatic Fever, Pretty much every virus

Question 8

Explain how ectopic expression of MHC is involved in autoimmunity

Answer 8

Grave’s Disease, SLE, ^IFN-y**
Remember MHC I is expressed on most all nucleated cells, MHC II is much less expressed.

Cytokines released in infection processes can cause the expression of MHC on cells that normally don’t have it, causing a triggering of autoimmunity.

Seen in Grave’s Disease

Question 9

What autoimmune diseases are known to result from the process of ectopic MHC expression?
(2)

Answer 9

Grave’s Disease (on thyroid epithelial cells)

Insulin Dependent Diabetes (pancreatic Beta cells)

Question 10

Explain how polyclonal B cell activation is involved with autoimmune responses

Answer 10

Non-specific polyclonal activation of B Cells i can cause reaction agianst self because it is so agressive, doesn’t require much procoking once active.

Question 11

Where is polyclonal B cell activation seen in autoimmunity? (3)

Answer 11

Gram (-) bacteria –> LPS —> B-Cells go crazy
CMV –> similar to EBV
EBV –> linked to multiple autoimmune diseases, INFILTRATES CD21 and causes non-specific proliferation and autoreactivity

NON-SPECIFIC is the impot thing — crazy B-Cell activation

Question 12

Which class of MHC/HLA are most autoimmune reactions associated with/

Answer 12

Class II

Ankylosing spondylitis B27 = notable class I

Question 13

What is the definition of a type II hypersensitivity?

Answer 13

Antibodies directly bind a cell or tissue, then:

1. kill the cell (cytotoxic)
2. transform (non-cytotoxic)

Question 14

What does autoimmune polyglandular syndrome result from?

SYmptoms?

Answer 14

Results from lacking the AIRE (which is a transcriptional activator that aides in negative selection in the thymus)

Work up involves a wide range of autoantibodies against endocrine glands, liver, skin, blood cells, and platelets

Question 15

What type of hypersensitivity is Myasthenia Gravis?

What does that mean?

Answer 15

Type II (non-cytotoxic), means it directly binds tissues and transforms/changes them for different functions etc.

Question 16

Describe the details of myasthenia gravis? (Code Involved)

Answer 16

HLA DR3 - more common in females
Anti - Ach receptor antibodies in serum
Treated with anti-cholinesterases
Presents with progressive muscle weakness, droopy eyelids, double vision progresses to the chest muscles and can impair breathing

Question 17

What is the differentiation between myasthenia gravis and MS?

Answer 17

MS will normally present with spastic weakness/paralysis

Question 18

What is the key in classifying a class III hypersensitivity

Answer 18

Circulating Immune Complexes

Question 19

Describe the details of Rheumatoid Arthritis

Answer 19

Type III/IV depending
HLA DR4 - more common in women
Chronic inflammation of the joints
Rheumatoid factor binds Fc portion of IgG causing the build up of immune complexes circulating
Known as type 4 as well because it involves the infiltration of T/B cells into the joint along with macrophages and neutrophils
Dx via rheumatoid factor in serum or elevated IgM and IgG, and SYNOVIAL FLUID EXAMINATION for WBCs in the joint.

Question 20

Describe the details of Systemic Lupus Erytematosis (SLE)

Answer 20

HLA DR3 - most common in women
Chronic inflammation of almost every organ, symptoms depend on which organ is effected
C3B is responsible for removing complexes, it gets overwhelmed in disease.

Question 21

What is the new diagnostic mechanism for Rheumatoid Arthritis?

Answer 21

Anti-CCP antibody - look for it in suspected patients, antibodies present in Rheumatoid Arthritis that result from protein transformation to citrulene. BIG DEAL

Question 22

Explain the importance of Renal Implications in SLE.

Answer 22

When complexes reach the kidney, they don’t deposit in a linear pattern, causing many kidney problems such as complex cysts and such..?

Flourescent antibody tests can show a lumpy-bumpy or granular pattern which helps in diagnosis.

Question 23

What is important about flourescent antibody patterns in biopsy of tissue?

Answer 23

If lumpy bumpy or granular, it is indicative of a type III hypersensitivity (type II deposits complexes in a linear pattern)

Could be SLE !!!

Question 24

Describe the details of Multiple Sclerosis (MS)

Answer 24

HLA DR2- more common in females
Type IV hypersensitivity that involves motor weakness, impaired vision, lack of coordination, and SPASTICITY
TH1 cells INFILTRATE the CNS and react with meyelin basic protein which causes symptoms
Dx - MRI to show sclerotic plaques

Question 25

What is the mechanism of MS?

Answer 25

TH1 cells INFILTRATE (type IV) the CNS and react with myelin basic protein

Question 26

Describe the details of Ankylosing Spondylitis

Answer 26

HLA B27 - more common in men

ABs formed in response to Klebsiella, Shigella, Yersinia react in spine and cause eventual fusion “Bamboo Spine”

Question 27

Describe the details of Reactive Arthritis (Reiter’s) syndrome

Answer 27

HLA B27 - more common in men
Infectious hypersensitivity (STD or enteric)
Arthritis, Conjunctivitis, Urethritis
Early signs are peripheral joints (knees, ankles, and feet)

Question 28

What type of autoimmune mechanisms are involved with reactive arthritis and ankylosing spondylitis?

Answer 28

Molecular Mimicry

Question 29

Describe the 3 different new experimental approaches to autoimmunity therapy

Answer 29

1. T Cell Activation - immune response to kill autoreactive T cells
2. Peptide blockade of MHC - creating synthetic peptides that bind MHC better (compete with the autoreactive MHCs) than the self binding peptides that cause the disease
3. Monoclonal antibodies - that give you antibodies for any specific immune something (very expensive