Physiology

Question 1

Mechanisms hypothesized to be involved in the breakdown of tolerance?
5

Answer 1

1. Failure to delete autoreactive lymphocytes
   (Central tolerance failure and
   Peripheral tolerance failure)
2. Molecular mimicry
3. Abnormal presentation of self antigens
4. Epitope spreading
5. Polyclonal lymphocyte activation

Question 2

What are epitopes?

Answer 2

the part of an antigen molecule to which an antibody attaches itself.

Question 3

T cells

1. Derived from where?
2. Important in what process?
3. Induce what to produce antigens?
4. Each programmed to recognize what?
5. Circulate in blood and sequestered in where? 2

Answer 3

1. Derived from the thymus
2. Important in cellular immunity
3. Induce B cells to produce antigens
4. Each programmed to recognize unique processed peptide fragment by T-cell receptor (TCR)
5. Circulate in blood, sequestered in
   - spleen and
   - lymph nodes

Question 4

1. T cell activation: Which cells act as the antigen presenting cells? (APC)
2. Major histocompatibility complex (MHC)— what is it?
3. MHC—human leukocyte antigen (HLA). What are they?
4. When NOT self peptide the APCs interact and present antigen to T-cells– which ones?
5. Normal ratio?

Answer 4

1. Dendritic cells and macrophages
2. a region formed by genetic loci that plays a central role in humoral & cellular immunity
3. group of proteins that participate in antigen presentation (APC)
4. CD4 and CD8:
   CD4 T helper cells CD8 Cytotoxic T cells
5. Normal ratio CD4/CD8—2:1

Question 5

1. CD4 and CD 8 expressing T cells are referred to as what?
2. What do the helper T cells do?
3. Describe what the Class I to III MHC molecules do?
   3

Answer 5

1. CD4+ and CD8+
2. The helper T cells—secrete cytokines & influence all other cells of the immune system
3. • Class I MHC molecules—associated w/ recognition of endogenous antigens
   • Class II MHC molecules—associated w/ recognition of exogenous antigens
   • Class III MHC molecules—involved w/ the complement system

Question 6

B LYMPHOCYTES

1. Derived from where?
2. Present where? 5
3. After stimulation B cells form what?
4. How many circulate?

Answer 6

1. Derived from bone marrow
2. Present in:
   - bone marrow,
   - lymph nodes,
   - spleen,
   - tonsils and
   - nonlymphoid organs such as GI tract (Peyers Patches)
3. After stimulation B cells form plasma cells & secrete immunoglobulins
4. 10-20% circulate

Question 7

IMMUNE SYSTEM REVIEW
Antigen processing:
1. Ag must be taken up by what?
2. Ag is then processed where?
3. Then it is presented to the what?
4. MHC class I/CD8+-- which cell?
5. MHC class II/CD4+-- which cell?

Answer 7

1. APC
2. inside the cell
3. immune system
4. cytotoxic cell
5. helper T cell

Question 8

1. IMMUNOLOGICAL TOLERANCE is what?

2. It prevents the body from doing what?

Answer 8

1. State of unresponsiveness specific for a particular antigen (Ag)
2. It prevents the body from attacking itself—self-tolerance

Question 9

B-Cell Tolerance:
1. Loss of self-tolerance with development of autoantibodies is characteristic of what?

Example:
2. Hyperthyroidism in Grave’s disease is due to what?

3. Filtering autoreactive B-cells out of population. How? 4

Answer 9

1. of a number of autoimmune disease
2. autoantibodies to the thyroid-stimulating hormone receptors
3. • Clonal deletion in bone marrow
   • Deletion of autoreactive cells in spleen or lymph nodes
   • Functional inactivation by anergy
   • Receptor editing- process that changes specificity of a B-cell receptor when autoantigen is encountered

Question 10

T-Cell Tolerance:

Central mechanisms of T-cell tolerance involve the what?

Answer 10

deletion of self-reactive T-cells in thymus

Question 11

1. What is Positive Selection?

2. What is Negative Selection?

Answer 11

1. Immature T cells of a clone that are not auto-reactive T cells are allowed to mature
2. Immature T cell clones that have high affinity for host cells are sorted out and undergo apoptosis

Question 12

1. Many autoantigens are not present in thymus which results in what?
2. Sequestered antigens (immunologically privileged) e.g.—Examples? 3
3. Therefore, there needs to be what available to deal with these?

Answer 12

1. self-reactive cells escaping the process
2. -CNS,
   -eyes,
   -testes
   (if these are released then an immune response ensues)
3. peripheral mechanism

Question 13

Describe the Peripheral mechanism involved with T cell tolerance?
4

Answer 13

Peripheral activation of T-cells requires 2 signals:

1. Recognition of peptide Ag with MHCs on the APCs AND
2. Secondary costimulatory signals which are often absent
3. Apoptosis (Fas receptor + Fas ligand)
4. Suppressor T cells can also down-regulate autoreactive T-cells

Question 14

Peripheral mechanism involved with T cell tolerance: Sometimes, no problem exists because what?

Answer 14

the self-reactive T-cells, remain immunologically ignorant because they can’t “see” Ag (Blood-brain barrier)

Question 15

MECHANISM OF SELF-TOLERANCE

1. What is central tolerance?
2. What is peripheral tolerance? 2
3. What is anergy?

Answer 15

1. Central tolerance – Elimination of self-reactive T cells and B cells in the central lymphoid organs
2. Peripheral tolerance :
   - Some of the T cells will become regulatory T cells (Tr)—products of Tr are cytokines that downregulate the immune response when the pathogen is cleared & help prevent autoimmunity
   - Some escaped T cells won’t recognize MHC-self-antigen and will remain as immature Tc cells
3. “Anergy”= State of immunologic tolerance to Ag

Question 16

MECHANISMS OF AUTOIMMUNITY: Much remains unknown but possibilities have been proposed: (5-7% of the population is affected by autoimmunity)?

4 possibilites

Answer 16

1. Failure of mechanisms that maintain self-tolerance
2. Genetic factors: genes that are involved in the immune response are the major players (MHC & HLA loci)
3. Gender: autoimmune diseases affect females more severely and more often than men—hormonal influences play a role (estrogen)
4. Infection & environmental factors: molecular mimicry*; environmental factors may contribute to or exacerbate (smoking)

Question 17

Autoimmune Disorders: Result from 1 or more mechanisms producing loss of self-tolerance. IN general this involves?

Answer 17

Immunologic cells are involved in tissue injury that results in exposure of self-antigen

Question 18

Possible mechanism of autoimmune dz?

Answer 18

1. Failure of T-cell-mediated suppression
2. Release of Sequestered Antigens
3. Molecular Mimicry
4. Heredity and Gender

Question 19

Possible mechanism of autoimmune dz: Failure of T-cell-mediated suppression: How does this occur? 2

Answer 19

1. Failure to delete autoreactive immune cells

2. Increasing ratio of CD4 to CD8 may be involved

Question 20

Possible mechanism of autoimmune dz: Release of Sequestered Antigens? 2

Example?

Answer 20

1. Normally body does not produce Ab against self Ag
2. Any self Ag sequestered from immune system during development and then reintroduced is considered foreign

Examples: Sperm and ocular Ag following post-traumatic uveitis and orchitis following vasectomy

Question 21

Describe Molecular Mimicry? 2

Examples? 2
describe the PP in these examples

Answer 21

1. Molecular Mimicry:
   - Foreign Ag so closely resembles a self Ag that Ab produced against former attack the later
   - B-cell or T-cell response can be mounted against antigentically altered or injured tissue creating an immune response
2. EXAMPLES:
   -Rheumatic Fever and
   -Acute Glomerulonephritis:
   (A protein in the cell wall of group A Beta hemolytic streptococci has considerable similarity to Ag in heart and kidney)

Question 22

Autoimmune: POSSIBLE mechanisms (Continued)

1. Describe Hereditary and Gender mechanism of action?
   - Example?
2. The exact trigger that causes the autoimmune disease in patients with certain HLA types is unknown although there are some possible theories? 3

Answer 22

1. • Certain inherited HLA types occur more frequently with certain immunological disorders
   • Example: 90% of patient with ankylosing spondylitis carry the HLA-B27 Ag
2. • Certain viral or bacterial infections
   • Chemical substance exposure
   • Self Ag that has been hidden from immune system during development becomes released

Question 23

Almost all autoimmune diseases are more common in women, therefore what may play a big role?

Answer 23

estrogen

Question 24

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)‏

1. Genes?
2. More common in who? 2
3. Produce autoantibody to what?
4. What can be affected?

Answer 24

1. HLA DR2 and DR3
2. -85% of patients are female & More common in blacks (1:250) versus whites (1:1000)
   -Strong familial link:
   If mother has SLE then daughter with 1:40 chance and son 1:250 chance
3. Produce autoantibodies to nuclear Ag
4. Multiple organ systems are affected

Question 25

SLE PATHOGENESIS 1. Many effects are secondary to trapping what? 2. Other effects are autoantibody mediated destruction of what?

Answer 25

1. Ag-Ab complexes in capillaries of visceral structures | 2. host cells (thrombocytopenia)

Question 26

SLE ENVIRONMENTAL FACTORS 1. Estrogen stimulates what? 5 2. Estrogen increases macrophage proto-oncogene expression and reduces what? 3. What are immunosuppressive? 4. What affect immunoreactivity and favor autoantibody production? 2

Answer 26

1. - T cells, - B cells, - macrophages, - releases some cytokines, & - cell adhesion molecules 2. apoptosis in self-reactive B cells 3. Androgens 4. Progesterone and prolactin

Question 27

Other SLE ENVIRONMENTAL FACTORS? 3

Answer 27

1. UV light exacerbates the disease 2. Viruses can stimulate specific cells in the immune network: 3. Some drugs can cause lupus-like syndromes:

Question 28

1. SLE flares can follow what? 2. SLE pts have higher titers of what? 3. What are two drugs that often cause lupus-like syndorme?

Answer 28

1. Lupus flares may follow bacterial infections 2. Patients w/ SLE have higher titers to EBV 3. - Procainamide - Hydralazine

Question 29

RHEUMATOID ARTHRITIS (RA) 1. Associated with what genes? 2. Disease initiated how? 3. Target is what? 4. Autoantibodies are produced against what? 4

Answer 29

1. Genetic predisposition—associated with HLA-DR4 and/or HLA-DR1 2. Disease in initiated by activation of helper T cells responding to some arthritogenic agent (possibly microbial)‏ 3. Target is the synovial lining of joints 4. Autoantibodies are produced against: - Type II cartilage, - Cartilage antigenic glycoprotein-39, - Immunglobulin G, - Citrullinated proteins and peptides

Question 30

RA SYNOVITIS 1. Angiogenic cytokines stimulate growth of what? 2. Results in what into joint? 3. What activate endothelial cells—produce adhesion molecules? 2 4. Together with transmigration of lymphocytes; PMNs enter where? 5. Activated CD4+ cells: Do what? 2

Answer 30

1. new blood vessels 2. transudation of fluid 3. - Tumor necrosis factor (TNF) & - substance P 4. synovial space 5. - Activate macrophages and other cells - Activate B cells producing Abs

Question 31

IMMUNE RESPONSE IN SYNOVIUM 1. Rheumatoid synovium has both what derived cytokines? 2 2. Cytokines (IL-1 and TGF-alpha) also cause what? 2 3. Activated rheumatoid synovium eventually destroys what? 2 4. Simultaneously osteoclasts and osteoblasts are activated by synovial cytokines destroying what?

Answer 31

1. lymphocyte and macrophage 2. synovial and chondrocyte proliferation 3. cartilage and tendons 4. subchondral bone

Question 32

RHEUMATOID FACTOR 1. 70% of patientss w/ RA are what? 2. What are generated that are directed against the Fx portions of IgG? 3. RF and IgG form immune complexes that do what? 2 and lead to? 4. Circulating RF contributes to the what of RA? 2

Answer 32

1. RF+ 2. Autoantibodies (IgM and some IgG) 3. - fix complement, attract neutrophils and - lead to tissue injury 4. - extra-articular manifestations of RA and - the synovial inflammation

Question 33

1. What is scleroderma? 2. What do the autoantibodies in this stimulate? Causing? 3. Which decades? 4. Women or men? 5. Two types? 2

Answer 33

1. Diffuse fibrosis of skin and internal organs 2. platelet derived growth factor receptors (PSGFR) causing fibroblast dysregulation 3. 3rd through 5th decade 4. 3 times more common in women than men 5. Two types: Limited (80%) and Diffuse (20%)

Question 34

LIMITED SCLERODERMA 1. 80% of cases—limited to where? 2 2. What is CREST Syndrome? 5

Answer 34

1. face and hands 2. - Calcinosis cutis - Raynaud’s phenomenon - Esophageal motility disorder - Sclerodactyly - Telangectasias

Question 35

DIFFUSE SCLERODERMA 1. What percent of cases? 2. Main characteristic? 3. Organ involvement of ?2 4. More or less severe that limited?

Answer 35

1. 20% of cases 2. Tendon friction rubs over wrists, ankles, and knees 3. Lung and cardiac involvement 4. The more severe form