Immunology Dr. McMillan

Question 1

Describe immune effector mechanisms that mediate autoimmune disease.

Answer 1

1. antibodies directed against components of cell surfaces or extracellular matrix
   e. g. Grave’s disease: antibodies to TSH receptor activates secretion of T3/T4, but actual TSH levels are low and so negative feedback doesn’t work (hyperthyroidism)
2. soluble immune complies that are deposited in tissues
   e. g. systemic lupus erythematosus
3. effector T cells
   e. g. multiple sclerosis-t cells activated in brain, cause inflammation and demyelination of neurons

Question 2

What genetic loci have been associated with autoimmune disease?

Answer 2

• certain HLA alleles associated with autoimmune disease
• strongest association with Ankylosing spondylitis, other disease have weaker association with HLA
• defective non-MHC genes involved in tolerance can contribute to disease, e.g. Complement associate with lupus

Question 3

How can infection influence autoimmunity?

Answer 3

• certain infections can trigger autoimmunity
• Group A strep elicits antibodies that cross react with epitopes present in human heart, joint, kidney, antibodies activate complement and generate inflammation everywhere=rheumatic fever
• hypothesis: T cells activated by pathogen react with peptides derived from human protein. auto reactive effector t cells become chronically stimulated by cells of body after infection cleared.

Question 4

Why are animal models that mimic human autoimmune diseases important?

Answer 4

• to figure out mechanisms and to develop therapies
  e. g. non-obese diabetic mouse model to research diabetes Type I
• experimental autoimmune encephalomyelitis (EAE) mouse used to mimic multiple sclerosis

Question 5

Compare and contrast peripheral and central tolerance for T and B lymphocytes.

Answer 5

T cells

central: neg selection of immature t cells in thymus
peripheral:
- anergy (no costimulator) or
- inhibitory receptors (CTLA-4 instead of CD28)
- deletion after repeated encounters via Fas/FasL from activation induced death
- from Treg suppression (expression of FoxP3)

B cells:

central: deleted if recognize self in BM or receptor editing of light chain
peripheral: anergy

Question 6

Describe anergy in peripheral B and T lymphocytes.

Answer 6

definition: functional inactivation of T-lymphocytes that occurs when these cells recognize antigens without adequate levels of costimulators that are needed for full cell activation

Question 7

What is activation induced cell death?

Answer 7

• In T-cells, repeated stimulation of activated T cells by self antigen without costimulation involves brief period of cell division followed by apoptosis
• Expression of Fas and FasL-signaling that activates caspases that induce apoptosis

Question 8

Why are Treg cells so important?

Answer 8

• can mediate tolerance
• express FoxP3, CD4, CD25
• arise in réponse to strong recognition of self antigens, they inhibit activation or differentiation of naive t cells

Question 9

Describe the structure and function of chemokines.

Answer 9

• small proteins 60-140 AAs long, named based on location of cysteine bridges
• function: guide lymphocytes to different regions of lymphoid organs, involved in tissue maintenance like wound headlong, and development (angiogenesis e.g.)

Question 10

What is the role of Il-8 in the immune response?

Answer 10

Major effects: mobilizes, activates, and degranulates neutrophils. Angiogenesis.

• produced by monocytes, macrophages, fibroblasts, keratinocytes, endothelial cells.
• Il-8 interacts with receptor on neutrophil and activates integrins for tight binding to endothelial cells that express ICAM
• Macrophages also secrete Il-8 that produce chemokine gradient to attach neutrophils to the point of infection where pathogen was first encountered
• attracted cell moves towards a higher concentration of chemokine

Question 11

How do chemokines assist in the trafficking of leukocytes?

Answer 11

-homing of naive T cells to lymph nodes is mediated by chemokines and cell adhesion molecules, chemokines involved: CCL19 and CCL21
-chemokines important in lymphocytes exiting blood and entering lymph nodes
For B cells:
-CXCL13 chemokine attracts B cells into primary follicle
-CCL21 attacts immature B cells to HEV
-CCL21 and CCL19 attract B cells into lymph nodes

Question 12

What families of adhesion molecules are involved in cell migration?

Answer 12

ICAM, VCAM, E-Selectin which bind to sulfated glycans

Question 13

What are ways in which chemokines can be regulated?

Answer 13

• decoy chemokine receptors prevents cell activation. They will bind chemokines and will not induce signaling in order to dampen chemokine actions.
• Th1 and Tc cell attracting chemokines become epigenetically silenced in stromal cells which encapsulate the fetus and the placenta

Question 14

Describe the role of CCR5, mutant CCR5, and CXCR4 in HIV infections.

Answer 14

• HIV requires CD4 and coreceptor CCR5 and later CXCR4 for infection
• in people with mutant CCR5, there is not infection by HIV virus

Question 15

Describe the structure of chemokine receptors.

Answer 15

• G protein coupled receptors containing 7 transmembrane domains
• activates second messengers

Question 16

What is the role of chemokines in disease?

Answer 16

E.g.
in Tumors, dendritic cells well move up chemokine gradient to lymph nodes
-important receptor is CCR7 on dendritic cell
-Tumor turns off CCR7 receptor in dendritic cell so that dendritic cell can’t move from dendritic cell to tumor so that no immune response is mounted against the tumor.
-Also: blockade of CCR9 can ameliorate crohn’s disease.

Question 17

How do viral pathogens evade immune response using chemokines?

Answer 17

• can produce chemokine mimics

- inhibit chemokine-chemokine receptor interaction