Page 917 - Clinical Immunology_ Principles and Practice ( PDFDrive )

886 PARt SEVEN Organ-Specific Inflammatory Disease

MG. 27,28 The risk of developing MG has also been linked to a and the development of EOMG and human MG. An interesting
polymorphism in the promoter region of CHRNA1, the previously story has emerged concerning miR150-P. Increased levels of this
mentioned gene that encodes the α subunit of AChR and CHRND, miRNA were found in the serum of patients with MG, and
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the gene that encodes the δ subunit. It has been proposed these levels fell in association with the clinical improvement that
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that such polymorphisms in genes encoding autoantigens cause followed thymectomy. A decrease in miR320a was observed in
reduced expression of AChRα on thymic medullary epithelial the peripheral blood mononuclear cells of a cohort of Chinese
22
cells, thereby impairing central deletion of autoantigen-specific patients. This finding was associated with increased levels of a
thymocytes. Additional MG-associated risk factors include number of proinflammatory cytokines. Further studies of the role
polymorphisms in CTLA4, type II, IFNII, IL12, CD86, AKAP12, of miRNAs will need to be conducted to elucidate whether they
VAV1, BAFF, TCF19, and TNIP genes. 22,23 contribute to the immunoregulatory abnormalities seen in MG.
Exogenous Factors TREATMENT OF MYASTHENIA GRAVIS
Whether or not sensitization to AChR occurs in the thymus or
the periphery, the stimulus for this autoimmune response remains tHERAPEUtIC PRINCIPLES
a conundrum. Moreover, it remains to be determined whether
the stimulus is a self-antigen (AChR) or a foreign antigen that • Anticholinesterase agents
mimics the receptor’s molecular structure. In this regard, several • Corticosteroids
examples of molecular mimicry between AChRα chain and other • Thymectomy
• Plasmapheresis
molecules have been reported. Studies carried out with certain • Immunosuppressive agents
monoclonal anti-AChR antibodies demonstrated epitope sharing • Intravenous immunoglobulin
between the receptor and several bacteria, including Klebsiella
pneumoniae, Escherichia coli, Proteus vulgaris, and Yersinia Therapeutic intervention in MG usually proceeds in a stepwise
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enterocolitica. However, for the most part, no difference was manner, beginning with anticholinesterase agents. Most of the
observed in the binding of polypeptides from these organisms experience dealing with therapeutic modalities is based on treating
by either sera from patients with MG or control sera. A computer patients with anti-AChR-associated MG.
search of protein banks revealed a sequence homology between
AChRα chain and a short peptide in herpes simplex glycoprotein Anticholinesterases
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D, although the significance of this finding is unknown. Finally, Anticholinesterases are the mainstay of treatment. These agents
similarities were reported between idiotypic determinants on protect acetylcholine from hydrolysis by cholinesterase, thereby
anti-AChR antibodies and antibodies reactive with α1,3-dextran. increasing the amount of neutrotransmitter and the number of
Interestingly, antidextran antibodies were detected in approxi- contacts with the reduced number of receptors at the postsynaptic
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mately 13% of patients with MG but rarely in normal controls. junction. This, in turn, raises the probability of attaining the
α1,3-Dextran is found in the cell walls of several common enteric necessary threshold for neuromuscular transmission. In addition,
pathogens and thus represents a potential ubiquitous source of some of the anticholinesterase agents have a direct agonist effect
immunogen. This type of idiotypic network connectivity led at the postsynaptic junction. The three most popular agents in
the investigators to postulate that an unregulated antiidiotypic this group are neostigmine bromide (Prostigmin), pyridostigmine
response to anti-α1,3-dextran antibodies might lead, in certain bromide (Mestinon), and ambenonium chloride (Mytelase).
individuals, to an anti-AChR antibody response. Unfortunately, Although there are only slight differences between these agents,
there has been no follow-up to these observations. Mestinon remains the most commonly used. It has an onset of
A striking association has been reported between the develop- action of 30–60 minutes, peak action at about 2 hours, and loss
ment of MG and treatment with the drug penicillamine, 32,33 of activity after 4 hours. Adverse effects of these agents are caused
particularly in individuals with HLA-DR1. MG developed in by excessive stimulation of nicotinic and muscarinic receptors.
patients with rheumatoid arthritis and patients with Wilson Auxiliary drugs that have been purported to have a salutary
disease treated with this agent. After discontinuation of penicil- effect on neuromuscular transmission are ephedrine and xanthine
lamine, resolution of MG symptoms was reported in some patients derivatives (theophylline), which are thought to increase the
but not others. Penicillamine treatment was associated with the presynaptic release of ACh. The minimal effect of their added
development of anti-AChR antibodies that appeared to have the benefit has not warranted their common usage. As mentioned
same type of specificity profile as found in idiopathic myasthenia. previously, anticholinesterase agents often are not beneficial in
Additional evidence suggests that penicillamine may directly patients with anti-MuSK-antibody–associated MG and may even
interfere with neuromuscular transmission. Although penicil- exacerbate weakness. These agents neither induce sustained
lamine has been shown to have diverse effects on the immune remission of symptoms nor impede disease progression.
response in the normal host and has reactive sulfhydryl groups
capable of modifying self-antigens, its role in the development Thymectomy
of MG remains to be determined. Another mainstay in the therapy of the adult with generalized
Currently, considerable attention is being focused on the role MG is thymectomy. 36,37 The benefit is greatest in younger patients
of epigenetic mechanisms to explain how environmental factors and those with thymic hyperplasia, although many centers include
may promote the development of autoimmune diseases. Although older patients as well. Over many years, despite the absence of
some key epigenomic mechanisms, such as DNA methylation, a controlled study, there was general agreement that removal of
histone acetylation, and microRNAs, have been demonstrated to the thymus leads to clinical improvement, particularly in young
possibly play a pathogenic role in several autoimmune disorders, patients with follicular hyperplasia. In one study, 90% of patients
the analysis of these factors is at a rudimentary stage in MG. To were asymptomatic or in complete remission within a few years
date, there is evidence to support an association between miR155 of thymectomy, and 46% were off all medications. An international