HC31: HLA and autoimmunity

Communication

Communication between 2 cells takes place via surface contact. This is made possible by:

• Neurons
• Muscles
• Immune cells

Many processes use synapses to communicate. This communication is specific → HLA molecules (MHC molecules) are present on antigen-presenting cells. There are many different HLA-molecules and the T-cell receptors know exactly which molecule it is.

Myasthenia gravis

In case of myasthenia gravis (MG), there is a defect of neuro-muscular synapses where the motor neuron informs the muscle whether or not to contract. 99% of myasthenia gravis cases are caused by an auto-immune disease → develop during life. Several subtypes of myasthenia gravis exist, each caused by autoantibodies against the neuromuscular synapse.

Process:

Normally, there are 2 important signal transduction cascades in the synapse, where

vesicles with acetylcholine play an important part:

• Voltage gated calcium channels (VGCC) release acetylcholine → binds to the acetylcholine receptors on the post-synaptic membrane → depolarization
• Muscle specific kinase (MuSK) and lipoprotein-related protein 4 (Lrp4) bind acetylcholine to the receptor
  1. The nerve secretes argin
  2. Argin binds to Lrp4
     • The muscle knows that there is a nerve
  3. Lrp4 interacts with MuSK
     • Gives feedback to the nerve
  4. MuSK dimerizes → autophosphorylation
  5. A signaling cascade to the clustering acetylcholine receptor (AChR)

Myasthenia gravis is caused by acetylcholine receptors not clustering.

Symptoms:

Myasthenia gravis is characterized by fluctuating muscle weakness which improves during rest. Patients with myasthenia gravis have antibodies against AChR, MuSK or Lrp4, which cause different symptoms:

• AChR myasthenia gravis
  • 80% of myasthenia cases
  • Asymmetric
    • One eye is more affected than the other
  • Fluctuating ptosis
  • Ophtalmoplegia with diplopia
  • Descending weakness
    • Starts in the upper body parts and slowly spreads downwards
  • May ultimately affect all skeletal muscles
• MuSK myasthenia gravis
  • 4% of myasthenia cases
  • Asymmetric
  • Bulbar weakness
    • Speaking problems
    • Swallowing problems
    • Neck weakness
  • Up to 50% have respiratory insufficiency at some point
• Lrp4 myasthenia gravis
  • 2% of myasthenia cases

Epidemiology:

AChR myasthenia gravis mainly occurs in:

• Young women
  • A non-tumor and early onset is more common
• Old men
  • A non-tumor and late onset is more common
  • A small cell lung carcinoma is more common

The disease is associated with a tumor in the thymus:

• 15% of myasthenia gravis cases are paired with a thymoma
  • The thymus may also be enlarged
• 40% of thymoma cases are paired with myasthenia gravis

MuSK myasthenia gravis only occurs in women. In this case, there is no tumor-association.

Lambert-Eaton Myasthenia

4% of Myasthenia patients have Lambert-Eaton Myasthenia (LEMS). In this case, antibodies for the voltage gated calcium channels (VGCC) are present.

Symptoms:

LEMS is characterized by ascending weakness → starts in the legs and slowly spreads upwards. For instance, patients have trouble standing up without using their hands. There mainly is an autonomic dysfunction.

Epidemiology:

Similar to normal myasthenia gravis, LEMS is more common among young women and old men. It is associated with small cell lung cancer (SCLC):

• 50% of LEMS cases are paired with SCLC
• 3% of SCLC cases are paired with LEMS
  • 3% of cases are also paired with neuropathy, degeneration and encephalomyelitis

Tumors and autoimmune diseases

Tumors often correlate with autoimmune diseases. Antigen presenting cells lead to an immune response → tumors express proteins present on muscles or neurons → cross react with antigens doing their normal function in the neuromuscular synapse.

Disease mechanism

The IgG subclass of autoantibodies dictates the disease mechanism:

• IgG1, IgG2 and IgG3: have 2 “arms” → can bind 2 antigens at the same time and are very easily triggered
  • Are linked with AChR myasthenia gravis and LEMS
  • There are 3 mechanisms that cause disease:
    • Antibodies bind to the AChR on the neuromuscular synapse → activate the complement system → cause complement mediated damage and internalization of autoantigens at the neuromuscular junction → AChR are also damaged
    • The 2 arms crosslink the antigens and internalize them → there aren’t sufficient receptors at the cell surface to transmit the signal anymore
    • Antibodies bind to the site where acetylcholine normally binds → block acetylcholine from binding
• IgG4: has 1 arm that can bind an antigen and 1 arm that binds something else → functional motivated binding
  • Is linked with MuSK myasthenia gravis
  • Has >90% sequence homology with other IgG’s
  • Does not bind complements and does not activate Fc receptor-mediated cytotoxicity → very anti-inflammatory
  • Interacts with other IgG4’s through its heavy chain
  • Undergoes Fab-arm exchange → becomes functionally monovalent
    • Does not crosslink antigens → there is only 1 arm to link an antigen
    • Instead of forming sulfide-bridges between heavy chains, sulfide-bridges in heavy chains are formed
  • The IgG4 MuSK antibodies make the patient sick

1. There are certain residues in the MuSK protein that are critical for the interaction between Lrp4 and MuSK
2. Antibodies bind to Lrp4
3. Lrp4 cannot bind MuSK anymore → loss of acetylcholine receptor clustering

Hereditary factors

Hereditary factors of auto-immune diseases are auto-immunity in the family and HLA-genes. These diseases are often inherited through the maternal line.

Patients with myasthenia gravis often have a second auto-immune disease:

• HLA B8-DR3 is linked with auto-immune diseases like myasthenia gravis and LEMS
  • Early-onset female patients have a strong HLA association
• HLA type DR14-DQ5 is linked with MuSK myasthenia gravis