19: Immunologic Tolerance & Autoimmunity Part II

Question 1

List immune privilege sites

Answer 1

Eye; cornea, anterior chamber, vitreous cavity, subretinal space
Brain - ventricles & striatum 
Pregnant uterus 
Ovary
Testis
Adrenal cortex
Hair follicles

Question 2

How is autoimmunity prevented?

Answer 2

Ignorance: barriers / physical separation (ex. - BBB, blood testis barrier)

Deletion: Fas/FasL mediated apoptosis of autoreactive cells (death receptors)

Inhibition: prevents activation (CTLA-4/CD80/86)

Suppression: decreased activity / responsiveness (Ex. - Treg inhibitory cytokines)

Question 3

Cause of autoimmunity:

Answer 3

Failure of B or T cell self-tolerance

–activation B or T cells in absence of infection or cause

Question 4

T/F: In complete absence of injury or damage, autoimmunity will not manifest.

Answer 4

TRUE - injury must proceed development of autoimmunity bc injury what releases the Ags initiate entire process

Question 5

Genetic components / Non-infectious Triggers:

Answer 5

HLA Class II alleles (DR, DQ)

• -strongest association; bc they control the action of CD4+ T cells
• -Rheumatoid arthritis & T1D

Non-HLA genes polymorphisms (CTLA4)

Question 6

How do genes and environmental triggers confer susceptibility to developing autoimmunity?

Answer 6

Genes / gene loci confer susceptibility via effecting the maintenance of self-tolerance

Environmental triggers confer susceptibility via promoting influx of lymphocytes into tissues & activation of self-reactive T cells

Question 7

Environmental components / Infection-Induced autoimmunity

Answer 7

–Molecular mimicry, Polyclonal (Bystander) Activation, Epitope spreading, Release of cryptic / hidden Ags

Question 8

Molecular Mimicry

Answer 8

1) viruses carrying Ags structurally similar to self-Ags
2) cross reactive response against self & non-self Ags
- –activated autoreactive T cell bind both Ags
- - Rheumatic fever & multiple sclerosis

Question 9

Polycolonal / Bystander Activation

Answer 9

1) Non-specific or overreactive antiviral or antimicrobial response = inflammation
2) self-Ags released from damaged tissue
3) taken up & presented on APC

**More specific activation of autoreactive T cells

Question 10

Epitope Spreading

Answer 10

1) persistent viral infection
2) more tissue damage = release NEW self-Ags

**Non-specific/less specific activation

Question 11

Release of Hidden / Cryptic Ags

Answer 11

intracellular self-Ags hidden during central tolerance & thus T cells specific to these self-Ags are not negatively selected.

Tissue damage causes the release of hidden self-Ags
—commonly infections (lytic virus) cause tissue damage

Question 12

Role of Estrogen in SLE

Answer 12

Exacerbate Systemic Lupus Erythematosus (SLE)

–altering B cell repertoire in absence of inflammation

Question 13

Role drugs in altering immune cell repertoire?

Answer 13

penicillin & cephalosporins – bind RBC membrane & generate neoantigen elicits an auto-Ab results in hemolytic anemia

Question 14

How does TNF-a inhibitors induce autoimmunity?

Answer 14

TNF-a inhibits activated T cells

–induce antinuclear Abs, SLE, & MS

Question 15

Sytemic Lupus Erythmatosus

Answer 15

Type III hypersensitivity - immune complex mediated

• -Anti-DNA Abs form immune complexes
• -Clinical pres: rash, vasculitis, glomerulonephritis, arthritis

Question 16

Rheumatoid Arthritis

Answer 16

Inflammatory disease - joint synovium 
Type IV - T cell mediated
Clinical pres: destruction of cartilage & bone
Rheumatoid Factor (RF) - IgM or IgG autoAbs react hidden carbo structures in Fc region of IgG

Question 17

Multiple Sclerosis

Answer 17

Type IV
Clinical - plaques & loss of white matter in CNS, neurological symptoms
–CYTOKINES trigger inflammatory response against myelin of CNS (TNF-a, IL-6, IL-17, TGF-b, IFN-g)
Treatment - IFN-b

Question 18

Type 1 diabete

Answer 18

immune mediated destruction of pancreatic B cells - insulin deficiency
Type IV
– ketoacidosis, auto-Abs for Beta cell destruction, high risk HLAs, hyperglycemia
– Symptoms manifest after 60-80% beta cells destroyed
–T1D onset associated with insulitis (infiltration of inslet of Langerhans via mononuclear cells & CD8+ T cells)

Question 19

Inflammatory Bowel Disease (IBD)

Answer 19

= 2 type IV chronic inflammatory disease of GI
–increased permeability of GI epithelial barrier = impaired formation of tight jxns & disruption of mucus layer

• -Ulcerative Colitis –> chronic inflammation & ulcers of colon or rectum
• *disruption of barrier function
• -Crohn’s Disease –> GI lining inflammation ANYWHERE in GI tract, spreads deep to underlying tissues, rectum usually spared
• • Dysfunction of microbe sensing