Acetylcholine receptor (AChR) antibody-positive myasthenia gravis, from antibody to complement

Both antibodies and complement play important roles
in the pathogenesis of AChR-gMG.

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies with impaired neuro-muscular junction transmission[1].

Patients with MG mainly present with skeletal muscle fluctuation weakness and easy fatigue, and extraocular muscles are often the first to be affected, which can affect the whole body [1].

Autoantibodies are of great value in elucidating the pathogenesis and diagnosis of MG, and the subgroup classification of MG in the Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gvis (2020 Edition) is mainly based on the patient's autoantibodies [1].

At present, we are already very familiar with the autoantibodies produced by MG patients, in fact, for the largest proportion of acetylcholine receptor (AChR) antibody positive MG patients, complement-related pathological mechanisms are also worthy of attention and understanding
.

Ancient rare disease, prone to relapse

The incidence of MG is low, but its clinical symptoms are obvious and have been recognized
for a long time.
MG has been discovered for a long time, as early as 1672 as described by Thomas Willis in his book, as an ancient rare disease [2].

With the development of medicine, people's understanding of MG has been deepening, from the beginning of symptomatic description, to gradually in-depth study of its pathological mechanism
.
AChR antibodies were discovered and elaborated in the 70s of the 20th century [2,3], and it is now known that AChR antibodies are the most common pathogenic antibodies
for MG.
The discovery of AChR antibody has advanced people's understanding of MG to the level of molecular biology, which is of great value to the diagnosis and treatment of MG, and is considered a milestone event
in the field of MG.
Subsequently, the researchers found other possible autoantibodies
in MG patients.

The adult-age- and sex-adjusted incidence rate of MG patients in China was 0.
74/100,000 person-years, and the incidence rate was slightly higher in women, and the ratio of female and male incidence was 1.
3:1 [4].

The course of MG includes remission, relapse, exacerbation, and death, with a high rate of
relapse in patients.
A study in China showed that 29.
6% of patients had relapse during follow-up [5].

It can be seen that the treatment management and recurrence prevention of MG are still challenging
at this stage.

In the new classification of MG, AChR-gMG accounts for the largest proportion

In 2021, the Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gvis (2020 Edition) issued by China updated the subgroup classification
of MG.
The previous Osserman classification is no longer used
.
The new subgroup classification is mainly divided according to the characteristics and clinical characteristics of serum antibodies in MG patients, which is helpful for precise treatment
of MG after diagnosis.
There are six major categories of MG subgroups[1], namely:

(1) Ocular MG (OMG): The patient's muscle weakness is limited to the eye muscle

(2) AChR-gMG (generalized MG, gMG): The patient's serum acetylcholine receptor antibody is positive

(3) MuSK-MG: serum muscle-specific receptor tyrosine kinase (MuSK) antibody is positive, and about 1%-4% of MG patients can be detected

(4) LRP4-MG: positive for serum low-density lipoprotein receptor-related protein 4 (LRP4).

(5) Antibody negative MG: The above antibody test is negative, accounting for a small proportion

(6) Thymoma-related MG: belongs to paraneoplastic syndrome

AChR antibodies are detectable in approximately 85 percent of patients and have been the most studied [6].

Clinically, AChR-gMG has the highest proportion of patients, which can be further divided into early-onset (< 50 years) and late-onset (> 50 years) according to the age of onset, and some patients with OMG may also transition to systemic [1].

AChR antibodies are specific antibodies to AChR-gMG

Every contraction of skeletal muscle requires successful signaling
at the neuro-muscular junction.
ACh is released at the axon ends of motor neurons, and AChR
is present on the postsynaptic membrane.
Physiologically, the main role of AChR is to bind to ACh released by presynaptic membrane vesicles, complete signaling at the neuro-muscular junction, and trigger depolarization of myocyte membranes and muscle contraction [6].

If any step in this process is disrupted, signaling at the neuro-muscular junction cannot be completed, resulting in muscle weakness
in the patient.

AChR-gMG patients produce antibodies against postsynaptic membrane acetylcholine receptors, known as AChR antibodies [6].

AChR antibodies are a class of autoantibodies that are considered specific to
patients with AChR-gMG.
In patients with AChR-gMG, the combination of AChR antibodies with AChR eventually leads to the development of muscle weakness, a pathological process that has been widely known
.
Clinically, AChR antibody detection on patients is an important basis for
diagnosing AChR-gMG.
For AChR-gMG, if you only know AChR antibodies, you only know the tip
of the iceberg.

In fact, AChR antibodies impede neuro-muscular junction signaling by three mechanisms [7]:

(1) Block the binding of ACh and AChR: This is the easiest to understand that AChR antibodies bind to the extracellular domain of AChR, which may directly bind to the ACh binding site on AChR, thus hindering the binding
of ACh and AChR.
(2) Accelerate the internalization and degradation of AChR and reduce the number of AChR: AChR is the main antigen of the posterior membrane at the neuro-muscular junction, and AChR antibody is a bivalent antibody, which can bind two antigens at the same time and produce an antigen modulation process, resulting in endocytosis and degradation of AChR on the surface of myocytes [7,8].

(3) Complement activation: This mechanism is considered to be the most important mechanism of action of AChR antibody binding to AChR and causing muscle weakness [7].

Moreover, the role of complement in MG has attracted much attention in recent years, and it is an indispensable mechanism
of action in the pathogenesis of AChR-gMG.

Complement plays an important role in the pathogenesis of AChR-gMG

The complement system is an important member of the human immune system, and under normal circumstances, complement plays a role in both innate and humoral immunity [7].

The complement system is complex and precise, with more than 30 proteins involved in the regulation of complement, ensuring the "smooth operation" of the complement system, which can not only play an immunological role, but also avoid damage
to its normal components.

Complement activation pathways include the classical pathway, the alternative pathway, and the lectin pathway
.
These three pathways activate the complement system and regulate a cascade of reactions
.
It should be noted that the three pathways share a common terminal pathway: complement factor C5 cleaves to form C5a and C5b, and C5b continues to undergo cascade reactions, forming membrane attack complexes (MAC) with C6, C7, C8, and C9 [7] (Figure 1).

MAC can lyse target cells and help the body remove foreign microorganisms as well as apoptotic cells
.
If the complement system is overactivated, MAC may attack its own cells, causing immunological damage and leading to disease
.

Figure 1 Complement activation process

In patients with AChR-gMG, AChR antibodies bind to AchR to form antigen-antibody complexes, which in turn activate complement through the classical pathway
.
After that, the complement cascade occurs sequentially, forming MAC
through the final pathway.
Animal studies suggest that the formation of MAC after complement activation in MG animal models is a necessary condition for damage to the postsynaptic membrane at the neuro-muscular junction [7].

Results from human trials have found autoantibodies and MAC at the neuromuscular junction in patients with AChR antibody-positive MG [7].

The final MAC formed after complement activation attacks the postsynaptic membrane, and this process is thought to play an important role in the pathogenesis of AChR antibody-positive MG [7].

At the neuro-muscular junction, MAC destroys its normal components, resulting in damage
to the postsynaptic membrane.
Complete signaling at the nerve-muscular junction is disrupted, which in turn hinders muscle contraction
.

It can be seen that for AChR-gMG patients, after AChR antibody binds to AChR, there are a series of complex pathological mechanisms
such as complement activation.
The exploration of pathological mechanisms will bring people a deeper understanding
of AChR-gMG.

MG is an ancient class of neurological autoimmune rare diseases, and MG patients have a high disease burden
due to their disability and high recurrence rate.
For AChR-gMG, which accounts for the largest proportion, it is well known
that AChR antibodies are produced in patients.
The antigen-antibody complex in the patient activates complement, leading to a cascade that attacks the postsynaptic membrane at the neuro-muscular junction, leading to clinical signs
of skeletal muscle weakness.
Complement also plays an important role in the pathogenesis of AChR-gMG, and the exploration of the pathogenesis of AChR-gMG will bring more new thinking
to clinicians and researchers.

References

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