Type II Autoimmunity

Question 1

What are the 4 types of Immunopathology?

Answer 1

Think of the pneumonic ACID

• Anaphylactic & Atopic - Type I
• Cytotoxic - Type II
• Immune complex - Type III
• Delayed (cell mediated) - Type IV

Question 2

What is the general method of Type II immunopathology?

Answer 2

• Type II causes cell destruction (cytotoxicity) by the action of immunoglobulin with complement or cytotoxic cells.
  
  • IgM, IgG bind to fixed antigen on “enemy” (what the body thinks is enemy anyways) -> cell destruction

Question 3

What are the 3 main mechanisms for Type II tissue damage?

Which of the three is the most common mechanism?

Answer 3

1. Complement-Mediated Damage (Major)
2. Stimulatory hypersensitivity (uncommon)
3. Neutralization

Question 4

Describe Complement-Mediated Damage

Answer 4

• Most common mechanism
  
  • Pearl: Normal cells that are bound by antibody should alert you to complement
• Activation of complement leads to
  
  • Lysis (C6-9 i.e. autoimmune hemolytic anemia)
  • Opsonization for phagocytosis
  • Phagocytic lysosomal enzymes and ROS
  • Release of histamine specific for C5a, 4a, 3a
    
    • Attraction of neutrophils which can damage tissue

Question 5

Describe the mechanism for Stimulatory Hypersensitivity

Answer 5

• Mimicry of hormone that normally activates the receptor –> agonism of the receptor by the autoantibody
  
  • Antibodies look like the ligand for a particular receptor. CONSTANT activation with none of the normal regulation methods
• E.g. - IgG autoantibody to TSH receptor leads to long-acting thyroid stimulation -> hyperthyroidism
  
  • Normal feedback doesn’t work on releasing IgG (Graves disease)

Question 6

Neutralization rxns

1. Define
2. Mechanism (general)

Answer 6

• Definition: Binding of antibody to an epitope resulting in inactivation, neutralization or abnormal activation
• Mechanism: Ab binding to a protein (e.g. toxin) can inhibit binding to substrate or alter conformation, resulting in loss of activity
  
  • e.g. - Autoimmune Abs against hormone or neurotransmitter receptors can either block or activate the receptor

Question 7

What is an example of a type II disease that effects muscle?

Give a general outline of disease

Answer 7

Myasthenia Gravis - muscle (Only disease that starts with an M)

• Characterised by progressive muscle weakness
  
  • Body has an Ab against AChR (Acetylcholine Receptor)
  • Specifically the alpha subunit - likely low yeild?
• Complement and neutrophil mediated

Question 8

What is an example of a type II disease that effects the Lung & Kidney?

Answer 8

Goodpasture Syndrome: AutoAb to lung and kidney basement mebrane (BM) - form of vasculitis

• Type IV collagen antigen is shared between these to organs (we know b/c no other organs involved)
• Characterized as linear/sharp (not lumpy & bump) floresence slide

Recall: BM is collagenous non-living connective tissue framework upon which the endothelial cells of capillaries sit

Question 9

Name two Type II diseases that affect the heart and give brief mechanism

Answer 9

Dressler Syndrome: After M.I. people make some autoAb against their heart - improves as heart heals

• Manifests as persistent cardiac pain, fever, malaise

Rheumatic Heart Disease (RHD): heart disease occurring shortly after a streptococcal infection

• Cross-rxn between a Group A Streptococcus M-protein antigen and heart’s laminin endothelial lining

Rheumatic fever is the same disease with more widespread manifestations, including in the skin and CNS

Question 10

What type II disease effects RBC’s?

Answer 10

Autoimmune Hemolytic Anemia

• May follow viral infxtn, other autoimmune syndromes or cancer
• Many drugs can induce AIHA
• For paroxysmal cold hemoglobinuria the autoAbs bind to red cells only at 15⁰C

Question 11

What type II disease effects Platelets?

Answer 11

Autoimmune Thrombocytopenic Purpura (ATP)

• General: Bleeding abnormalities due to platelet destruction by autoAbs
  
  • Platelets opsonized for destruction in the spleen
• Treatment: splenectomy and immune suppression

Question 12

What type II disease effects normal Thyroid fxn?

Answer 12

Grave’s Disease

• IgG antibody to TSH receptor on thyroid cells.
• Not enough TSH receptors close enough to activate C1q, so no complement activation.
• Mimics TSH and causes cells to secrete thyroid hormones (T3, T4)
• Normal feedback doesn’t work because it isn’t TSH doing the stimulating

Question 13

What type II disease effects Pancreatic islets?

Answer 13

Juvenile diabetes (Type I Diabetes)

• AutoAbs to islet-associated antigens
• Technically diabetes is considered Type IV immunopathology

Question 14

When would you use a direct antibody test for Good Pasture’s Syndrome

Answer 14

• Direct antibody test: if you have the patient’s tissues (and hopefully a control normal tissue!)
  
  • Use antisera to detect presence of attached IgG on patient’s kidney
  • Control normal kidney should NOT have attached IgG
  • Where IgG is present, it should be linear (sharply defined) and attached to all of the exposed surface (BM)

Question 15

When would you u se an indirect antibody test to diagnose Goodpasture’s Syndrome?

Answer 15

• Indirect antibody test: if you ONLY have the patient’s serum
  
  • Expose the normal kidney (no Ab in it), to the patient’s serum
  • Wash off unbound antibody
  • Use antisera to detect the IgG now bound to the normal kidney

Question 16

1. Which immunopathology is characterised by “lumpy-bumpy” as it relates to an immunoflorescent pattern

Answer 16

Lumpy-bumpy: represents clusters of antigen-Ab complexes stuck in the BM b/c they are too big to be filtered. They are non-uniform and are representative of Type III immunopathology

Question 17

What immunopathology is characterized by linear immunoflorescence patterns?

Answer 17

• Linear: Ab that directly attack BM (basement membrane) and so they can uniformly distribute along the membrane. These indicate Type II immunopathology

Question 18

What Ab would you use in immunofloresence patterns to determine if either a Type II or Type III immunopathology was involved?

Answer 18

Anti-IgG:To see the IgG that is bound to the BM

Question 19

What is the innocent bystander phenomenon?

Answer 19

Innocent Bystander Phenomenon

• Common mechanism
• Damage occurs because the normal tissue happens to be in proximity to or infected by the REAL slim-shady (foreign antigen)
• Ex: A drug adheres to red cells and you make Ab against the drug. Complement lyses the red cell, not the drug.

Question 20

How can antibody-mediated tissue damage result from Cross-rxn of a foreign antigen with self?

Answer 20

Cross-reaction of a foreign antigen with self: (rheumatic fever, ATP)

• Damage results from Abs binding to self-cells
• Researchers can’t identify the antigens that get things started because once you have clinical symptoms, the initiator is gone.

Question 21

How can antibody-mediated tissue damage result from Hybrid (foreign+self) antigen formation? aka - “Illicit Help Model”

PDF SPECIFICALLY STATES TO MAKE SURE YOU KNOW THIS MECHANISM. YOU HAVE BEEN WARNED.

Answer 21

• We have normally occuring anti-self B cells that have yet to be deleted

1. Issue comes if a foreign antigen couples to self antigen
2. Anti-self B cell could binds self antigen w/ coupled foreign antigen
3. Foreign epitopes is presented to Tfh on Class II MHC
4. TfH -> cytokines engages coreceptors
5. B-cell is ctivated and secretes Ab against itself

Question 22

How can antibody-mediated tissue damage result from exposure of a sequestered antigen?

Answer 22

Exposure of a sequestered antigen:

• There are self-antigens that the immune system doesn’t generally see (they are sequestered)
• If these get into the bloodstream, they can trigger an immune response because the system hasn’t negatively selected against those self-antigens
• E.g.: some men who get mumps end up sterile. The mumps break down the blood/testis barrier, and allowes immunization to normally sequestered sperm antigens.

Question 23

How can antibody-mediated tissue damage result from Inadequency of regulatory T cells?

Answer 23

Inadequacy of regulatory T cells:

• Need a proper balance between 5 types of helper/regulatory T cells (do you remember them all?) for appropriate immune response
  
  • Th1, Th2, Th17, Tfh, Treg
• May have this balance perturbed and cause the breakdown of self/non-self discrimination

Question 24

How can antibody-mediated tissue damage occur from the emergence of a forbidden clone?

Answer 24

Emergence of a forbidden clone:

• “forbidden clone” - a clone that escapes normal clonal deletion. It matures and has reactivity with self.
• Seen in myasthenia gravis.

Question 25

What is Rheumatoid Factor?

Answer 25

Rheumatoid Factor: It is IgM anti-IgG and is found in the joints of patients with rheumatoid arthritis.

• RA is linked to the gene PADI4
• Molecular nature: IgM antibodies made against the Fc portion of the IgG antibodies - essentially antibody against an antibody

Question 26

What is the name of the condition in which the antibody stimulates that than inhibits/harms its target cell?

Hint: It stimulates constantly

Answer 26

Graves’ Disease!

• Classic example is the “Long-acting thyroid stimulator” (LATS).
• LATS is IgG antibody to TSH receptor on thyroid cells
• LATS mimics TSH and causes the cell to secrete thyroid hormones and normal feedback controls don’t work –> hyperthyroidism

*Note that another example is autoAb to the beta-adrenergic receptor which is stimulatory. This leads to inappropriate tachycardia*

Question 27

Why is the Aire gene important in preventing autoimmune disease?

Answer 27

Aire (Auto-immune regulator) gene:

• Autoimmune disease if issues w/ Aire itself or genes it regulates.
• Thymus does not express certain [self] tissue types
  
  • Without a full profile of what self antigens are, negative selection is incomplete and allows passage of autoAb leading to autoimmune diseases