Ch 4: Autoimmune Rubin's

Question 1

What is central tolerance?

Answer 1

Self reactive T and B lymphocytes deleted during their maturation in thymus/bone marrow

Question 2

What is negative selection?

Answer 2

In thymus: self reactive T-cell recognize self-peptides (with compatible self MHC) and are induced to undergo apoptosis
Occurs after + selection (self-MHC restriction)
In bone marrow: called clonal deletion for B-cells

Question 3

What is peripheral tolerance?

Answer 3

Regulating T-cells that escape negative selection

held in check in periphery via anergy, suppression, and/or activation induced cell death

Question 4

What is molecular mimicry? Give an example.

Answer 4

Helper T-cell tolerance is overcome via
Antibodies against foreign antigens that cross reacts with self-antigens.
NO AUTOANTIBODY MADE
Ex: rheumatic fever, anti-S.pyogenes antibody cross-reacts with antigens from cardiac muscle

Question 5

What is a Type I hypersensitivity Response?

Answer 5

Immediate type hypersensitivity rxn

1) IgE binds its Fc domain to mast/basophil cells
2) Subsequent antigen binding = cxrlink IgE and degranulation of histamine etc.

urticaria, asthma, anaphylaxis

Question 6

What is a Type II hypersensitivity Response?

Answer 6

1) IgM or IgG formed against antigen on fixed cell surface or EC antigen
2) Antigen-Ab coupling on fixed cell surface activates complement via the Ig Fc domain= cell lysis (cytotoxicity) or ECM damage (MAC, opsonization)

Question 7

What is a Type III hypersensitivity Response?

Answer 7

1) IgM or IgG response
2) Antigen-Ab coupling in circulation = Immune complex formed in circulation
3) IC deposited in tissue
4) Complement activation at site of IC deposition = wbc recruitment = tissue injury

Question 8

What is a Type IV hypersensitivity Response?

Answer 8

Cell-mediated/delayed type rxn
DOSEN’T INVOLVE Abs
Antigen activation of T-cell and macrophage recruitment = release products = tissue injury

Question 9

What are the 5 THEORIES of the molecular pathogenesis of autoimmunity?

Answer 9

1) Inaccessible Self-Antigens
2) Abnormal T-cell fxn
3) Molecular mimicry
4) Polyclonal B-cell activation
5) Tissue Injury/Hypersensitivity Rxns

Question 10

What is the idea behind inaccessible self-antigens causing autoimmune disease?

Answer 10

Intracellular antigens are not normally exposed
Tissue injury will expose them
Immune response develops

*pathogenic infrequently, remember no evidence that antisperm antibodies cause generalized injury, except for localized orchitis

Question 11

What is the idea behind abnormal T-cell fxn causing autoimmune disease?

Answer 11

Defects in suppressor T-cells described in many autoimmune diseases

Helper T cells may become autoreactive in autoimmune disease (normal job: antigen-specific B-cell activation, T-cell tolerance induced by low doses of antigen then get cray cray autoreactive)

***Drug induced lupus = ex of DNA hypomethylation leads to upreg leukocyte antigen and B-cell activation independent of antigen
T cell autoreactivity and loss of antigen specificity

Question 12

What is the idea behind polyclonal B cell activation causing autoimmune disease?

Answer 12

B-cells directly activated by bacterial cell walls/viruses (with complex and numerous antigenic sites)

Ex = post bacterial, viral, parasitic infections shown dev of Rheumatoid Factor (RA) and anti-DNA antibodies (SLE)

Question 13

What is the prototypical systemic immune complex disease?

Answer 13

SLE

Question 14

What does SLE characteristically affect?

Answer 14

skin, joints, serous membranes, kidneys

Question 15

What are the two autoantibodies that are pathognomonic but not directly cytotoxic in SLE?

Answer 15

Types of anti-nuclear antibodies to:

1) Sm antigen
2) dsDNA

Question 16

Who do we typically see with SLE?

Answer 16

common and severe in AAs/hispanics

over 80% of cases are in women of childbearing age (whatever the hell that means….stupid Rubin)

Question 17

What are some potential etiological factors in SLE?

Answer 17

virus (EBV)
hormones (estrogen)
genetic predispositions (HLA B8)
Drugs (procainamide, hydralazine, isoniazid)

Question 18

What is the pathogenesis of SLE?

Answer 18

1) potential etiological factors
2) loss of tolerance, acquired sensitivity to auto-antigens
3) Autoreactive CD4 T-cells
4) polyclonal B cell hyper-reactivity
5) Autoantibody production (anti-dsDNA ab)
6) Immune complex formation in circulation & tissues
7) Tissue injury: glomerulonephritis, vasculitis, serositis, arthritis

Question 19

How is joint disease (polyarthralgia) in SLE different from that in rheumatoid arthritis?

Answer 19

Joint destruction is unusual in SLE

Question 20

What is the prototypical skin involvement in SLE?

Answer 20

erythematous rash in sun-exposed sites
malar “butterfly” rash

perivascular lymphoid infiltrate & liquefactive degeneration of basal cells

Ig and complement deposition

Question 21

What is the prototypical renal disease seen in SLE?

Answer 21

glomerulonephritis (3/4 of SLE pts)

Immune complexes between DNA and IgG abs to dsDNA deposit in glomeruli

Question 22

What can be a consequence of serous membrane involvement in SLE? Resp system in SLE?

Answer 22

pleuritis and pleural effusion
less frequently: pericarditis, peritonitis

pneumonitis
progressive interstitial fibrosis
pulmonary hypertension

Question 23

What is the cardiac involvement in SLE?

Answer 23

commonly pericarditis (but all layers can be affected)

Question 24

What is Libman-Sacks endocarditis?

Answer 24

Associated with SLE
small nonbacterial vegetations on valve leaflets
diff from larger/bulkier bacterial endocarditis vegetations

Question 25

What is CNS involvement with SLE?

Answer 25

vasculitis&raquo_space; hemorrhage and infarction of brain

Question 26

What are antiphospholipid antibodies associated with in SLE?

Answer 26

1/3 pts

thromboembolic complications, Budd-Chiari, DVT, stroke, PE, spont abortions

Question 27

How is joint disease (polyarthralgia) in SLE different from that in rheumatoid arthritis?

Answer 27

Joint destruction is unusual in SLE

Question 28

What is primary Sjogren Syndrome?

Answer 28

intense lymphocytic infiltrates in salivary and lacrimal glands (CD4 T-cells)
leads to acini destruction&raquo_space; keratoconjunctivitis and xerostomia
w/o other CT disease

Question 29

What is secondary SS?

Answer 29

SS associated with other CT disease

Question 30

What are some clinical features of SS?

Answer 30

dry mouth, dry eyes, dysphagia w/GI tract involvement, lymphoid infiltration&raquo_space; atrophic gastritis

Question 31

Name the disease!
vasculopathy, excessive collagen deposition in skin and lungs (diffuse interstitial fibrosis)/GI tract/heart/kidneys (focal hemorrhage/cortical infarct), lesions in arteries/arterioles/capillaries, thickening and fibrosis of vessels

Answer 31

Scleroderma

Question 32

What is the difference between generalized form of scleroderma and the limited variant?

Answer 32

limited form: a milder disease, usually present with skin involvement, CREST syndrome within this category

Question 33

What are some clinical features of scleroderma?

Answer 33

“stone facies”: tightening of facial skin/restricted motion of mouth
Raynaud phenomenon
painful tendonitis
joint pain
hypomotility and dysphagia of esophagus
intestinal motility problems b/c fibrosis
pulmonary fibrosis
scleroderma renal crisis

Question 34

What is mixed connective tissue disease?

Answer 34

SLE symptoms (rash, Raynaud, arthritis, arthralgias) 
Scleroderma signs (swollen hands, esophageal hypomotility, pulmonary interstitial disease) 
RA

Question 35

What is autoimmune disease?

Answer 35

Immune response against self-antigen
No longer able to differentiate b/t self- and non-self antigens
Loss of immune tolerance