immunopathy II

Question 1

self antigen to double-stranded DNA

Answer 1

• systemic lupus erythematosus (SLE)

Question 2

self antigen to histones

Answer 2

• SLE

Question 3

Self antigen to topoisomerase I

Answer 3

• Diffuse scleroderma

Question 4

self antigen to centromere protein

Answer 4

limited scleroderma

Question 5

what are the eight mechanisms for tolerance breakdown

Answer 5

• failure of tolerance/immune regulation
• failure of T cell anergy
• failure of apoptosis of self-reactive cells
• failure/dysfunction of regulatory CD4+ T cell
• molecular mimicry
• polyclonal lymphocyte (B and T cell) activation
• emergence of sequestered Ag
• Exposure of cryptic antigenic determinants

Question 6

describe the mechanism of failure of T cell anergy

Answer 6

• auto-reactive T cells that escape central deletion are anergic (functionally inactive) to self Ag without co-stimulation
• if cells are induced by infection/inflammation to express co-stimulatory molecules, autoreactivity occurs

Question 7

describe the mechanism of failure of activation induced cell death

Answer 7

• (apoptosis of self-reactive cells)
• the Fas ligand molecule on the surface of cytotoxic T cells binds to the Fas receptor on target cell surfaces of auto-reactive cells –> apoptosis
• failure of Fas-Fas ligand system enables peripheral persistence and proliferation of auto-reactive cells

Question 8

describe the mechanisms of failure T cell mediated suppression

Answer 8

• regulatory CD4+ T cells can suppress Ag-specific proliferation of other T cells via secretion of immunosuppressive cytokines IL-10, TGF-alpha
• failure of these regulatory cells to suppress such proliferation encourages creation of auto-reactive cells and autoimmune reactions

Question 9

describe the mechanisms of failure T cell mediated suppression

Answer 9

• regulatory CD4+ T cells can suppress Ag-specific proliferation of other T cells via secretion of immunosuppressive cytokines IL-10, TGF-alpha
• failure of these regulatory cells to suppress such proliferation encourages creation of auto-reactive cells and autoimmune reactions

Question 10

describe the mechanisms of molecular mimicry or cross reactivity

Answer 10

• self Ag may share an antigenic determinant (epitope) with microbial Ag so that an immune reaction against the microbe –> damaging tissue reaction

Question 11

describe the mechanisms of polyclonal lymphocyte activation

Answer 11

• polyclonal activation of B cells by microorganisms and their products (eg. bacterial lipopolysaccharide- endotoxin) or activation of CD4+ T cells by superAg may induce/alter immune response that gives rise to auto-reactive cells

Question 12

describe the mechanisms of emergence of sequestered Ag

Answer 12

• normally hidden self Ag that are not exposed to the immune system during development are seen as foreign when they gain entry into the circulation

Question 13

describe the mechanisms of exposure of cryptic antigenic determinants

Answer 13

• during development, many dominant epitopes are processed/presented to T cells while others are not; in circumstances where these hidden epitopes become exposed, self-reactive cells develop and lead to induction of others (epitope spreading)

Question 14

describe how genes influence autoimmune

Answer 14

• expression of certain HLA alleles may increase susceptibility to autoimmunity because Class II HLA alleles influence presentation of auto-Ag and their proteins to T cells

Question 15

describe how microbes influence autoimmunity

Answer 15

• infection, inflammation and tissue necrosis are major factors in the pathogenesis of peripheral tolerance breakdown; mechanisms include…
• -> upregulation of co-stimulatory molecules
• -> molecular mimicry
• -> exposure of cryptic epitopes
• -> non-specific B and T cell activation