Exam 2: Autoimmunity

Question 1

Autoreactive Lymphocytes

Answer 1

• Low levels of autoreactive T and B cells common
  
  • Usually harmless due to regulatory mechanisms
• In 2-5% of population ⇒ anti-self-response robust enough to cause clinically significant damage ⇒ autoimmune disease

Question 2

Autoimmune Diseases

Characteristics

Answer 2

Adaptive immunity inappropriately targets self-antigens due to loss of self-tolerance.

Chronic, progressive, and self-perpetuating

• Persist because auto-Ag cannot be removed
• If autoreactive reaction crosses threshold, resulting tissue damage can further up-regulate immune response

Question 3

Autoimmune Diseases

Susceptibility

Answer 3

• Generally multifactorial
  
  • Genetics
  • Environmental factors
  • Stochastic events
• Few are due to single gene disorders

Question 4

Factors Leading To

Autoimmunity

Answer 4

• Breakdown or failure of tolerance mechanisms
• Genetic susceptibility
• Uncontrolled or misdirected response to foreign antigen
• Injury
• Hormonal influences

Question 5

Genetic Susceptibility

Answer 5

• MHC Alleles
  
  • Most associated with MHC class II
  • Alkylosing spondylitis shows strongest correlation (HLA-B27)
  • Most encode residues in the peptide binding groove or regions near the groove
    
    • Determines peptide binding, T cell recognition, and selection during thymic maturation
• Non-MHC Alleles
  
  • Role in development and regulation of immune responses
  • Many in non-coding regions
• Few single-gene abnormalities identified that cause autoimmunity
  
  • High penetrance

Question 6

Infection

&

Autoimmunity

Answer 6

1. Release of sequestered self-Ag
   
   • Break cell/tissue barriers
   • ↑ concentration of specific self-Ag
   • Triggers activation of un-tolerized (ignorant) lymphocytes
2. Triggering a bystander effect
   
   • Infection upregulates costimulators on APCs
   • Naive non-tolerant T-cells accidently provided both signals by APC presenting self-Ag
3. Altering self-proteins
   
   • Infectious agents bind to self-Ag making them appear foreign
   • As immune response develops, epitope spreading could lead to autoimmunity
4. Triggering a cross-reactive response due to molecular mimicry
   
   • Foreign-Ag induces T/B cells with cross-reactivity to self-Ag
   • Causes naive cells to expand to autoreactive effector cells
5. Overcoming anergy by the polyclonal activation of lymphocytes
   
   • T-cell activation by superantigen
   • B-cell activation by LPS or Epstein-Barr virus
   • Can activate previously tolerized or anergized autoreactive cells

Question 7

Changes in Anatomical Structures

&

Autoimmunity

Answer 7

Inflammation, ischemia, or trauma can result in the release of self-Ag.

• Post-traumatic uveitis and orchitis
  
  • Follows damage to an immunoprivileged site of the eye
• Sympathetic ophthalmia
  
  • Rare bilateral granulomatous uveitis
  • Follows ocular trauma or surgery to one eye
  • Both eyes affected once tolerance or clonal ignorance lost

Question 8

Gender Differences

Answer 8

Most autoimmune diseases have high incidence in women.

Thought to be secondary to hormonal changes.

Theories include:

• ♀ have more vigorous immune responses overall
• ♀ with more T_H1 like responses
• Immunostimulatory role of estrogen and prolactin
• Fetal cells in maternal circulation
• Maternal cells in male circulation

Question 9

Self-Tolerance Failure

Answer 9

• Defects in deletion
  
  • ∆ central tolerance
• Defects in apoptosis
  
  • ∆ central tolerance and AICD
• Defects in anergy
  
  • Breakdown of T-cell anergy
• Inadequate T_reg cell generation
  
  • Ex. IPEX

Question 10

Autoimmune Disease

Progression

Answer 10

1. Predisposition of an individual to autoimmunity
2. Autoimmune event initiated by an environmental trigger or stochastic event
   
   • Loss of self tolerance
   • Stimulation of autoreactive lymphocytes
3. Autoimmune attack releases additional self-Ag which are not eliminated in an efficient manner
   
   • Propagation of autoimmune response
   • Response against ↑ # of self-Ag
   • Epitope spread ⇒ recognition of additional epitopes within the recognized self-Ag
   • Development of clinical features

Question 11

Organ-specific

vs

Systemic Disease

Answer 11

Determined in part by distribution of auto-antigen.

• Organ specific autoimmune diseases
  
  • Often involve autoreactivity against a single antigen or target cell
  • Can result in systemic symptoms
• Systemic Disease
  
  • Tends to be immune complex mediated
  • Involves autoreactivity against multiple self-antigens

Question 12

T vs B

Mediated Damage

Answer 12

Various effector mechanisms responsible for tissue injury.

Most autoimmune diseases have varying roles for T-cells and B-cells in pathogenesis.

Diseases classified as B cell or T cell mediated but…

Most B-cell responses are T-cell dependent.

B-cells can act as important APC for T-cell activation.

Question 13

Multiple Sclerosis

Pathophysiology

Answer 13

Prominent T-cell activity.

Considered a type IV hypersensitivity.

• Mediated by autoreactive CD4⁺ T-cells
• Inflammatory process upregulates Fas on oligodendrocytes making them targets for FasL expressing T-cells
• Auto-Ag includes PLP, MBP, and others
• IL-17 involved suggesting T_H17 cell involved
• Results in demyelination or destruction of myelin sheaths in CNS
• Relapsing-remitting course or chronic progressive form
• Hypothetical triggers:
  
  • Release of sequestered myelin Ag s/p infection or trauma
  • Molecular mimicry d/t immune response to virus with “neuro-epitope”

Question 14

Daclizumab (Zenapax)

(MS)

Answer 14

• Humanized mAb for IL-2R α-subunit
• Shown to ↓ lesions
• ? impact on T cell ± NK cell

Question 15

Natalizumab (Tysabri)

(MS)

Answer 15

• Humanized mAb for VLA-4 on activated T cells
• VLA-4 : VCAM on BBB for firm adhesion
• Reduces progression of MS
• But ↓ CNS T cell immunity ⇒ reactivation of latent viruses
• Can lead to development of progressive multifocal leukoencephalopathy (PML)

Question 16

Fingolimod (Gilenya, Norvartis)

(MS)

Answer 16

Blocks exit of lymphocytes from LN to CNS

Question 17

IFN-β

(Betaseron (Beyer), Avonex (Biogen Idec), and Rebif (Merck Serono)

(MS)

Answer 17

• Released at the end of an immune attack
• Blocks the action of interferon gamma
• Helps to reduce inflammation and the body’s immune reaction

Question 18

Type I DM

Answer 18

Prominent T-cell activity.

Considered a type IV hypersensitivity.

• Pancreatic β-cells destroyed by CTL-mediated killing
• Also involves CD4⁺ T-cells and macrophages
  
  • Secrete proinflammatory cytokines
• Many develop autoAb against islet Ag
  
  • Unclear if involved in disease pathogenesis or develop d/t β-cell destruction
  • Usually develop years before clinical disease ⇒ ? use as prognostic indicator
• Results in insulin deficiency or absence
• Treatment includes:
  
  • Insulin
  • Immunosuppresion

Question 19

Graves’ Disease

Answer 19

Prominent B-cell activity.

Considered a non-cytotoxic type II hypersensitivity.

• Auto-Ab causes constitutive activation of TSH receptor
• Can be transmitted from mother to infant via placental IgG
• High T₃ and T₄ but low TSH
  
  • ↑ in general metabolic activity, sweating, hot flashes, nervousness, weight loss, goiter, exophthalmos
• Serum contains autoAb to thyroid components
  
  • Thyroglobulin, cell surface Ag, microsomes, TSH receptor
• Possible triggers:
  
  • Aberrant expression of MHC class II d/t viral infection
  • Ag cross-reactivity between TSH receptor & Yersinia enterolytica
• Treatment includes:
  
  • Anti-thyroid drugs ⇒ reduce production of thyroid hormones
  • Thyroidectomy
  • Radioiodine ablation

Question 20

Pernicious Anemia

Answer 20

Prominant B-cell activity.

Considered a type II hypersensitivity.

• Auto-ab against intrinsic factor
• IF needed for absorption of Vit B₁₂
• Erythropoiesis deficient leading to macrocytic anemia
• Treatment with Vit B₁₂ supplementation

Question 21

Goodpasture Syndrome

Answer 21

Prominent B-cell activity.

Classic type II hypersensitivity.

• Auto-Ab bind Ag epitope in basement membranes
• Results in:
  
  • Recurrent alveolar hemorrhage
    
    • For Ab deposition, additional lung injury must occur which increases alveolar-capillary permeability
    • Events that induce lung inflammation ↑ risk
  • Rapidly progressive severe glomerulonephritis
• Treatment includes:
  
  • Plasmapheresis
  • Prednisone
  • ACE inhibitors

Question 22

Systemic Lupus Erythematous

(SLE)

Answer 22

Combined T and B cell activity.

Considered a type III hypersensitivity.

• High titers of antinuclear auto-Ab and nuclear debris form immune complexes
  
  • Often also auto-Ab against platelets, WBCs, RBCs
• Complexes deposit & activate complement components
  
  • Kidney
    
    • Directs accumulation of granulocytes within glomeruli
    • Destruction of blood vessel wall and nephron
    • “Lumpy bumpy” morphology with immunofluorescence
    • Glomerulonephritis most damaging
  • Skin
    
    • Butterfly rash on face
• Auto-reactive T-cells play a critical role
  
  • Can activate auto B cells with more wide range of reactivities
• Abnormalities in macrophage scavenger function ↑ likelihood of SLE
  
  • Poor clearance of apoptotic cells
  • Normally hidden Ag in blebs released
  • Stimulates autoreactive cells
• Treatment with immunosuppresive drugs

Question 23

Rheumatoid Arthritis

(RA)

Answer 23

Combined T and B cell activity.

• Inflammatory process in joints results in dysfunction and deformity
• T_h1 cells and macrophages play dominant role in RA development
• AutoAb Rheumatoid factor (RF) with role in inflammation and neutrophil recruitment but likely not causative
  
  • Binds IgG allowing ↑ complement activation
• Early stage:
  
  • Synovial membrane and cavity contains infiltrating neutrophils, lymphocytes, and plasma cells
• Advanced stage:
  
  • Highly vascular inflammatory tissue ⇒ pannus
  • Mostly lymphocytes, plasma cells, macrophages, and fibroblasts
  • Eventually undergoes calcification

Question 24

Tofacitinib

(Xeljanz)

Answer 24

Question 25

Myastenia Gravis

Answer 25

Combined T and B cell activity.

Type II Hypersensitivity

• Auto-Ab bind Ach receptor at NMJ
  
  • Block interaction of ACh with receptor
  • Interacts with regions near the receptor and physically hinder ACh access
• Bound Ab fix complement
  
  • Induces destruction of the folding membrane
• IgG can cross placenta
  
  • Cause transient disease in newborn
• T-cells can transfer disease in animal models
• Treatment includes:
  
  • Plasmapheresis
  • Exchanges with normal plasma
  • Thymectomy
  • Acetylcholinesterase inhibitors

Question 26

Auto-Ab

Clinical Uses

Answer 26

• Diagnosis
• Determining disease subtype
• Monitor disease progression
• Monitor treatment effectiveness

Question 27

Autoimmune Diseases

Therapeutic Approaches

Answer 27

1. Corticosteroids
   
   • Reduce tissue injury
   • Block inflammatory process
2. Immunosuppressive drugs
   
   • Cyclosporine
     
     • Blocks T cell activity
   • Used to treat severe exacerbations
3. Immune mediators
   
   • Antagonists of pro-inflammatory cytokines IL-1 and TNF-α
   • Anti-integrins
   • Inhibit pathologic immune reactions
4. Costimulator antagonists
   
   • B7
   • CD40 ligand
   • Block T-cell activation
5. Plasmapheresis
   
   • Reduce the amount of circulating Ab
6. Induce tolerance
   
   • Oral administration of self proteins
   • Administration of altered self proteins