Autoimmunity

Question 1

List the immunologically privileged sites:

Answer 1

• brain
• eye
• testis
• uterus (fetus)
• hamster cheek pouch

Question 2

What constitutes peripheral tolerance?

Answer 2

• regulatory cytokines (IL-10, TGF-beta)
• immunoinhibitory molecules molecules (CTLA-4, PD-1)
• Tregs

Question 3

What are the two main classes of autoimmune disease and give examples of each:

Answer 3

1. Systemic: SLE, rheumatoid arthritis, systemic sclerosis, mixed connective tissue disease
2. Organ specific: T1DM, multiple sclerosis, thyroiditis, Goodpasture, Guillain-Barre syndrome

Question 4

What are the characteristics of autoimmune disease?

Answer 4

• evidence of autoantibodies and/or autoreactive Tcells
• some AI diseases are transmitted from mother to fetus by passage of IgG autoantibodies through placenta
• in animals the disease can be transferred by T cells or antibodies (adoptive or passive transfer)

Question 5

List the postulated etiologies of ADs:

Answer 5

1. molecular mimicry with infectious agents –> rheumatic fever, Guillain-Barre
2. failure of Tregs
3. B cell or T cell polyclonal activation (especially SLE)
4. mutations to key regulatory molecules (AIRE, Foxp3) ex. PTPN-22 polymorphisms
5. tissue damage releasing hidden antigens (ex. sympathetic opthalmia, orchitis)
6. vitamin D deficiency ex. AD more common at high altitudes
7. Drugs and toxins (ex. autoimmune hemolytic anemia, SLE)

Question 6

Name one reason we believe hormones influence ADs?

Answer 6

ADs are more common in females (estrogen related?). ex. SLE 10x more common in Females

Question 7

List the 3 major types of Tregs:

Answer 7

• thymic derived (natural) Foxp3+ (nTreg)
• induced (adaptive) Foxp3+ (iTreg)
• Type 1 regulatory T cells (Tr1); produce IL-10 and TGF-beta

Question 8

What lethal autoimmune/inflammatory condition do Foxp3+ mutations result in?

Answer 8

IPEX Syndrome

Question 9

What Abs are present in SLE?

Answer 9

anti-nuclear antibodies (ANA)

Question 10

What is more specific than ANA for diagnosing SLE?

Answer 10

anti-dsDNA

Question 11

what immune complex diseases are characteristic of SLE?

Answer 11

• skin rash
• glomerulonephritis
• arthritis
• vasculitis
• endocarditis

Question 12

Can SLE be induced by drugs? What drugs?

Answer 12

Yes. By hydralazine and procainamide.

Question 13

What are possible mechanisms of SLE?

Answer 13

• autoantibodies
• immune-complex disease
• deficiency of compliment (ex. C2, C4, C1q)
• exposure to UV light exacerbates SLE

Question 14

What is scleroderma (systemic sclerosis)?

Answer 14

• progressive fibrosis of skin and internal organs
• Raynaud’s phenomenon
• occlusive vascular disease
• renal disease with HTN
• ANAs
• can overlap with other ADs

Question 15

Describe Rheumatoid Arthritis (RA):

Answer 15

• inflammation of synovium with pannus formation and destruction of cartilage
• not just about joints–> inflammation of lungs, heart, m etc possible
• vasculitis
• characterized by RF= rheumatoid factors ie autoantibodies reactive to the Fc segment of IgG.

Question 16

What are two examples of organ-specific ADs caused by T cell activity?

Answer 16

• MS (in mice model= EAE- experimental autoimmune encephalomyelitis)
• T1DM

Question 17

What cells attack pancreatic beta cells in T1DM?

Answer 17

• CD4+ (Th cells)

- CD8+ (CTLs)

Question 18

What autoimmune conditions associated with cancer (PNS)

Answer 18

• neurological diseases: sensory neuropathy, Eaton-Lambert myesthenia syndrome
• systemic diseases (dermatomyositis/polymyositis)
• cancer-associated retinopathy
• skin diseases (paraneoplastic pemphigus)

Question 19

How do tumours initiate autoimmunity?

Answer 19

• anti-cancer immunity is often autoimmune
• mutated tumour antigens break tolerance
• tumours express antigens expressed during embryonic period or in immune-privileged sites
• tumours can secrete mediators that alter immune tolerance

Question 20

What therapies are used in autoimmune disease?

Answer 20

• corticosteroids and immunosuppressive drugs (SLE)
• TNF-alpha or IL-6 cytokine blockade (RA)
• immunomodulatory agents (interferon-beta-MS, IVIG-many ADs)
• mAbs against B cells ex. anti-CD20 (RA)
• mAb against B cell lymphocyte stimulator BLyS (SLE)