Autoimmunity Objectives

Question 1

Explain central tolerance

Answer 1

induction of T and B cells occurs during maturation in the thymus and bone marrow, respectively

Question 2

Explain peripheral tolerance

Answer 2

deletion (activation induced cell death)
suppression by T cells (T cell derived factors)
lack of T cell help for B cell activation
absence of appropriate major histocompatibility complex (MHC) for antigen presentation
absence of co stimulatory molecules (CD28 on T cells)

Question 3

Describe the reasons for loss of self tolerance

Answer 3

autoimmunity following loss of self tolerance can occur

1. genetic defects leading to defects in lymphocyte regulation
2. antigen related mechanisms

Question 4

what are the two antigen related mechanisms in loss of self tolerance?

Answer 4

1. molecular mimicry/cross reactivity with a microbial epitope
2. release of previously sequestered antigen

Question 5

why does loss of tolerance occur by molecular mimicry?

Answer 5

because host tissues share an antigenic epitope, often identical over only a sequence of a few AA, with an infecting virus or bacteria.

Question 6

why does loss of tolerance occur in cross reactivity?

Answer 6

host tissues display an epitope cross reactive with one present on the microbial antigen surface.

Question 7

why does loss of tolerance occur with previously sequestered antigens ?

Answer 7

tolerance is broken if the immune system comes in contact with previously sequestered antigens. when ocular damage (inflammation) occurs an immune response can develop to this previously sequestered antigen, resulting in ocular pathology

Question 8

Immunopathology generally reflects the presence of autoreactive antibodies, or the activation of what?

Answer 8

T cells secreting type I cytokines, which activates phagocytes.

Question 9

Autoreactive antibodies induced pathogenesis to cell bound antigens, is similar to what hypersensitivity mechanism of action?

Answer 9

Type II

Question 10

Autoreactive antibodies bind to cell surface antigens and activate mechanisms leading to what?

Answer 10

cell destruction

Question 11

There are three mechanisms of cell destruction that are similar whether the cell is in circulation or a component of solid tissues. Describe the first mechanism

Answer 11

1. Antibodies bind to antigen
2. classical complement activated
3. MAC generated and cells destroyed via osmotic lysis
4. complement is overwhelmed due to antigen and antibody

Question 12

what is the second mechanism of action for cell destruction?

Answer 12

1. complement activates C3b and C5a.
2. C3b opsonin facilitates phagocytosis
3. C5a is chemotactic for neutrophils –> releases cytokines, proteases and inflammatory mediators destroy local tissue

Question 13

what is the third mechanism of action for cell destruction?

Answer 13

1. IgG binds to cell surface antigen Fc portion of antibody and Fcgamma receptors on neutrophils and macrophages
2. Macrophages are activated as they attempt to phagocytose cells

Question 14

The next autoreactive antibodies to soluble antigens is similar to what hypersensitivity?

Answer 14

type III

Question 15

When autoreactive antibodies are specific for soluble antigens, large immune complexes are formed in the serum. Under normal conditions what happens to these immune complexes?

Answer 15

the number and size of these immune complexes are sufficiently small that they are eliminated by the clearance mechanisms of the reticuloendothelial system (phagocytic macrophages in the spleen and liver)

Question 16

what happens when these immune complexes are large?

Answer 16

immune complexes are going to overwhelm these clearance mechanisms, complexes are deposited and trapped in tissues.

Question 17

For some autoimmune diseases, cell mediated immunity is the primary cause of what?

Answer 17

the pathology