Autoimmune Disorders

Question 1

When does autoimmunity become a disease?

Answer 1

Breakdown in mechanisms that keep benign autoimmunity in check

Question 2

What is central tolerance?

Answer 2

Removal of self-reactive T and B cells in the thymus and bone marrow respectively

Question 3

What is peripheral tolerance?

Answer 3

Anergy inactivation of B and T cells when they bind to self-antigens in the absence of co-stimulatory signals
Fas-mediated apoptosis

Question 4

What has provided direct proof of autoimmunity as a disease?

Answer 4

AI is transmissible from mother to baby via placenta (IgG)
Most AI involves autoreactive T-cells - observed in animal experiments

Question 5

What has provided indirect proof of autoimmunity as a disease?

Answer 5

Disease recreation in animal models via experiments
Spontaneous AI occurrence in animals of AI seen in humans

Question 6

These factors are helpful in diagnosis of autoimmune disease

Answer 6

High IgG and deposition of immune complexes in certain tissues
High number of infiltrating immune cells to affect tissue
HLA molecules presenting self-peptides to T-cells —> no self-tolerance
Decreased symptoms with immunosuppressive therapies

Question 7

What factors contribute to autoimmune disorders?

Answer 7

Genetic
Environmental
Immune regulation

Question 8

How do genetic factors contribute to autoimmunity?

Answer 8

HLA alleles
non-HLA genes (deficiency in pro-apoptosis molecules, overexpression of pro-inflammatory cytokines, complement deficiency)

Question 9

How do environmental factors contribute to autoimmunity?

Answer 9

Drugs modifying self-antigen
Modified environmental antigens
Trauma
Microbial antigens may mimic self-antigens or cause polyclonal B-cell activation

Question 10

This sex is more likely to develop autoimmune disorders

Answer 10

Females
Pregnancy may improve or worsen some AI diseases

Question 11

What is relative risk?

Answer 11

Risk of contracting a disease based on a person having a certain HLA type vs someone who doesn’t have that HLA type

Question 12

This HLA is strongly associated with ankylosing spondylitis and is helpful in diagnosis of the disease

Answer 12

HLA-B27, class I gene

Question 13

How is tolerance to foods (highly antigenic) maintained?

Answer 13

Oral tolerance Immune unresponsiveness to oral or nasally encountered antigens
Initiated when antigen encounters GALT
Dendritic cells most active in GALT
Large antigen dose —> some entering systemic circulation —> T cell anergy when no co-stimulatory interactions
Low dose —> locally induced tolerance r/t cytokines in GALT —> differentiation into TH2 and Treg for specific antigen

Question 14

This condition is related to a failure of oral tolerance to gluten

Answer 14

Celiac disease

Question 15

What sites in the body are immunoprivileged?

Answer 15

Brain
Testicles
Fetus and placenta
Eyes

Question 16

What mechanisms protect immunoprivileged tissues?

Answer 16

Lack of lymphoid drainage
BBB
Presence of immunosuppressive cytokines (TGF-beta, FasL expression)

Question 17

How can immunoprivileged sites be compromised?

Answer 17

Trauma —> antigen from site into circulation —> T-cell presentation by APCs

Question 18

What happens to autoreactive B cells that escape into the periphery?

Answer 18

Deleted or become anergic in absence of T-helper cells

Question 19

What is molecular mimicry?

Answer 19

Epitope of microbial antigen mimics that of self-antigen —> self reactivity

Question 20

What is the mechanism of molecular mimicry? (T and B cell role)

Answer 20

• T-cell cross reactivity with microbial epitope —> self-reactive B cell activation —> anti-self antibody production

Question 21

What causes rheumatic heart disease?

Answer 21

• S.pyogenes cross reactivity with heart valve myosin —> autoimmune response

Question 22

Tell me about Myasthenia Gravis (sensitivity type, target)

Answer 22

Type II hypersensitivity
Ach receptor antagonist

Question 23

Tell me about Graves disease (sensitivity type, target)

Answer 23

Type II hypersensitivity
TSH receptor agonist

Question 24

Tell me about SLE (sensitivity type, mechanism)

Answer 24

Type III hypersensitivity
Immune complex deposition

Question 25

What is the half-life of IgG? Implications for MG and Graves?

Answer 25

IgG half-life = 21-28 days
IgG is the autoantibody in MG and Graves and can cause transient disease in the newborn
Severe disease tx with plasmapheresis

Question 26

Immune complexes in SLE often composed of…

Answer 26

Ab + soluble DNA

Question 27

What is the principal lab test for dx of SLE?

Answer 27

High titer of autoantibodies vs DS DNA

Question 28

Autoimmune diseases are mainly what type of hypersensitivity?

Answer 28

Type IV hypersensitivity - T cell mediated

Question 29

Tell me about rheumatoid arthritis (hypersentitivity, location, cells/cytokines involved)

Answer 29

Type IV
Synovial fluid chronic inflammation
Fluid infiltration by CD4, CD8, B-cells, plasma cells, and macrophages
Cytokines: TNF-am IL-1 —> fibroblast, macrophage, chrondrocyte production of proteinases and other enzymes

Question 30

Tell me about Type I diabetes (hypersensitivity, location, cells/cytokines involved)

Answer 30

Type IV
B-islet cells of pancreas
CD8 cells mainly; CD4, macrophages also
Cytokines: TNF-a, IL 1, IFN-a

Question 31

Tx of AI diseases

Answer 31

NSAIDS
Immunosuppressive drugs
Cytokine production inhibitors
Cytotoxic drugs

Question 32

Immunosuppressive drugs and action

Answer 32

Steroids
Hydroxychloroquine
Anti-inflammatory. Alter Tcell and neutrophil movement and communication; decrease # of immune cells, decrease cytokine production

Question 33

Cytokine production inhibitors and uses

Answer 33

Cyclosporin and Tacrolimus: interfer with IL2 synthesis
Rapamycin: blocks IL2-ILR signal

Question 34

Cytotoxic drugs and action

Answer 34

• Azathrioprine, methotrexate,
• Nucleotide synthesis inhibitors

Question 35

Biologics - mechanism, types, side effects

Answer 35

Function: biological response modifiers or targeted immune modulators
Types:
TNF-a antagonists
IL1 antagonists
MAB
IF-b
- Side effects: TNF-a inhibition may reactivate TB, certain viruses