Exam 4 Lecture 23: Autoimmunity

Question 1

What is autoimmunity?

Answer 1

• condition where the immune system attacks
  healthy self cells and tissue as if they were foreign
• Autoimmunity is a multifactorial disease caused by the
  interaction of genetics and the environment
• Autoimmunity is typically a progressive disease caused by
  escalation of inflammation and exposure of new antigens that
  can further stimulate the immune system (epitope spreading)

Question 2

What is the most significant genetic factor associated with autoimmune disorders?
What does this tell us about the immune mechanisms that mediate disease?

Answer 2

MHC
* The associations with HLA highlight the important role that T cell tolerance plays in preventing autoimmunity.
* But not all autoimmune diseases are directly mediated by T cells, so why is HLA always involved >
* Autoantibodies that have undergone isotype switching and affinity maturation have received T cell help from CD4+ TFH cells (linked recognition)

Question 3

How and where does immune tolerance happen?

Answer 3

Central Tolerance: Negative selection of lymphocytes
* B cells negatively selected in the bone marrow
* T cells negative selected in the thymus

Peripheral Tolerance: Suppression of autoreactive lymphocytes in the periphery by regulatory T cells

Question 4

How can immune tolerance be broken?

Answer 4

Mutations in AIRE -> APECED
Mutations in FoxP3 -> IPEX
Tissue trauma or infection mediated damage

Question 5

What are the symptoms of Graves’ Disease?
What immune mechanism causes the disease?

Answer 5

Symptoms
Hyperthyroidism: heat intolerance, nervousness, weight loss, thyroid enlargement

Mechanism
Autoantibodies to TSH receptor stimulates overproduction of thyroid hormones (independent
of thyroid-stimulating hormone (TSH))

Normally, TSH binding to TSH receptor leads to breakdown of thyroglobulin from iodide -> stimulates release of T3 & T4 and inhibits pituitary gland from
making any more TSH
During Graves’ disease, there is an uncoupling of TSH and thyroid hormone production

Question 6

What are the hallmark symptoms of Systemic Lupus Erythematosus (SLE)?
What is it caused by?

Answer 6

autoantibodies to nucleoprotein particles
(DNA, snRNP (small nuclear ribonucleoproteins), other
DNA components like histones and ribosomes)

Butterfly rash

Question 7

What is epitope spreading?

Answer 7

the diversification of reactive epitopes beyond the initial acute response leading to new autoreactive T or B cells

Caused by:
1) tissue damage leading to release of new self-antigens
2) enhanced display of antigens under an inflammatory environment
3) B cells as Antigen Presenting Cells

Question 8

What is Hashimoto’s disease? What impact does it have on thyroid hormone?
How is this different from Graves’ Disease?

Answer 8

Causes hypothyroidism
Mediated by CD4+ Th17 cells
that attack the thyroid tissue
Common symptoms: fatigue, weight gain, cold intolerance, joint and muscle pain, enlarged thyroid (goiter)

Question 9

What are the symptoms of rheumatoid arthritis (RA)? What causes RA?

Answer 9

Painful swelling & progressive deterioration of joints

Mechanism
Initiated by autoreactive TFH CD4+ T cells that generate autoreactive B cells and the accumulation of immune complexes in the joints
80% of patients will develop IgM, IgG, or IgA autoantibodies to self-IgG, called rheumatoid factor

Causes
1. Associated with a certain HLA type (HLA- DR4-beta chain)
2. Associated with antibodies against citrullinated proteins (ACPAs)
* Citrullinated proteins = proteins with arginine converted to citrulline
* The cause is unknown, but associated with cell death and inflammation
3. Increased risk with smoking
–> Having all 3 factors dramatically increases your risk

Question 10

What leads to destruction of the pancreatic beta-cells during Type I Diabetes?

Answer 10

Caused by the autoimmune destruction of insulin producing cells (beta cells) in the pancreas (islets of Langerhans) due to lymphocytic infiltration
T cells treat beta cells as if they were an infection

Question 11

What is molecular mimicry?

Answer 11

Infectious agents that express molecules that are cross-reactive with self
Infections or exposure to other environmental antigens stimulate lymphocytes whose receptors cross-react with self-antigens

Question 12

What are two examples of pathogen antigens?

Answer 12

Streptococcus pyrogenes (group A strep)
mimics self proteins in heart, kidney, and joint tissue triggering rheumatic fever

Borrelia burgdorferi (Lyme disease)
expresses an antigen, Outer Surface Protein A (OspA), homologous to an epitope of the adhesion molecule LFA-1