Immune Pathology III: Autoimmune Diseases

Question 1

What are the three properties of autoimmune disease?

Answer 1

• presence of autoimmune reaction
• evidence that autoimmune response is primary source of injury, not a secondary reaction to some other source of tissue damage
• absence of other well-defined cause of disease

Question 2

What are four general features of autoimmune diseases?

Answer 2

• failure to recognize self –> immune reaction mounted against self antigens
• tend to be progressive, with sporadic relapses and remissions
• clinical and pathologic features depend on the particular immune response
• -> some dominated by neutrophils, some by macrophages or lymphocytes
• clinical, pathologic, and serologic features may overlap with other autoimmune diseases
• -> complicates diagnosis, treatment

Question 2

What is tolerance?

Answer 2

The usual state in which the body’s immune system does not react to self stimulus.

Question 3

What are the three features of the autoimmune disease spectrum?

Answer 3

• may be very organ specific (ex: Hashimoto’s thyroiditis)
• may involve several defined organs (ex: lung and kidney in Goodpasture’s syndrome)
• may have widespread, protean (changing) targets (ex: SLE)

Question 4

What are the three results of peripheral tolerance?

Answer 4

• anergy
• suppression
• activation induced cell death

Question 5

What are the three results of peripheral tolerance?

Answer 5

• clonal anergy
• peripheral suppression (by T cells)
• activation induced cell death - clonal deletion

also mechanism of immunologic tolerance:
antigen sequestration

Question 6

Molecular mimicry is when the self antigen is molecularly similar to what?

Answer 6

to foreign antigen

Question 7

What are six ways of escape from tolerance?

Answer 7

• FAILURE of anti-self cells to undergo APOPTOSIS (failure of clonal deletion)
• LOSS OF ANERGY (return to immunoreactivity by previously anergic cells)
• LOSS OF SUPPRESSOR T CELLS
• MOLECULAR MIMICRY (self antigen is molecularly similar to foreign antigen)
• POLYCLONAL LYMPHOCYTE ACTIVATION (activation overwhelms or bypasses normal regulatory controls)
• EMERGENCE OF SEQUESTERED ANTIGEN (able to interact with immune system)

Question 8

Polyclonal lymphocyte activation overwhelms or bypasses what controls?

Answer 8

The normal regulatory controls

Question 9

Emergence of antigen that was previously sequestered renders the antigen able to do what?

Answer 9

interact with the immune system

Question 10

Do autoimmune disease cluster in families? What gene?

Answer 10

Yes. This is associated to certan human leukocyte antigen (HLA) types
- HLA-B27: associated with ankylosing spondylitis; induction of autoimmune disease in HLA-B27 transgenic animals

Question 11

How are microbial agents involved in autoimmunity?

Answer 11

• share cross-reactive epitope with self antigen
• modify self antigen or complex with it –> antigen no longer recognized as self
• produce superantigens
• -> cause powerful T and B cell activation and proliferation sufficient to break normal self-tolerance

Question 12

What are autoantibodies?

Answer 12

Antibodies that target self antigens

Question 13

What antigens are recognized by autoantibodies?

Answer 13

• cell surface proteins
• components of cell cytoplasm
• nuclear components

Question 14

How do autoantibodies assist in diagnosis?

Answer 14

• typing of autoantibodies in serum

- may be specific for certain diseases

Question 15

How do autoantibodies assist in current disease?

Answer 15

levels of autoantibodies correlate with disease severity

Question 16

What are antinuclear antibodies (ANA)?

Answer 16

Autoantibodies commonly present in patients with autoimmune disease.
They are directed against nuclear antigens.

Question 17

What types of ANA exist?

Answer 17

Antibodies to

• DNA
• histones
• non-histone proteins bound to RNA
• nucleolar antigens

Question 18

What are the limitations associated with ANA?

Answer 18

False-positive ANA is detected in up to 15% of population.
In these people, levels of ANA are low.
In this case, people test positive for ANA, but have no autoimmune disease.

Question 19

ANAs are characterized by immunofluorescence staining of inflammatory cells. What are the staining patterns?

Answer 19

• homogeneous: non-specific
• rim (peripheral): think SLE
• speckled: think SLE
• nucleolar: think systemic sclerosis (scleroderma)

Question 20

Contrast clonal anergy with clonal deletion (both mechanisms of immunologic tolerance)

Answer 20

Clonal anergy: (anti-self lymphocytes are rendered non-reactive to antigen stimulation)

• lack of activation of a lymphocyte which it needs in order to be active and an effector of the immune system
• occurs due to lack of costimulation when a lymphocyte reacts with self antigen

Clonal deletion: (anti-self lymphocytes undergo apoptosis)
- removes any lymphocyte (T cell) that reacts with self through apoptosis

Question 21

How can superantigens break tolerance?

Answer 21

• microbial agents share a cross-reacting epitope with self antigen; modify self antigen or complex with it to change recognition as self
• cause a nonspecific activation of T cells that produces a powerful response

Question 22

What are two common laboratory tests for SLE?

Answer 22

• testing for antibodies (antinuclear antibody ANA) via immunofluorescence; if rim or speckled, likely SLE
• -> antibody to double stranded DNA: ds-DNA antibody
• -> antibody Smith antigen: anti-Sm antibody
• renal biopsy (look for glomerular disease)
• direct immunofluorescence of skin (look for immune complexes at dermal-epidermal junction)

Question 23

What abnormalities of facial skin and renal glomeruli are present in SLE?

Answer 23

• kidney develops glomerulonephritis
• -> glomerulus becomes inflamed and the basement membrane becomes defective due to deposits (type III hypersensitivity mechanism)
• face develops butterfly rash
• -> red rash on nose, cheeks, forehead
• -> deposition of antibody complexes at dermal/epidermal junction

Question 24

What are three non-genetic factors which may act as triggering events for clinically apparent SLE?

Answer 24

• drugs
• ultraviolet light
• estrogens (sex hormones; pregnancy)
• injury/trauma (including surgery)