Effector Mechanisms of Anti-AChR Antibodies (Anti-AChR Abs)

Anti-AChR Abs affect NMT by at least three mechanisms [2]: (i) complement binding and activation at the NMJ, (ii) antigenic modulation (accelerated AChR endocy- tosis of molecules cross-linked by antibodies), (iii) and functional AChR block—preventing normal ACh from attaching and acting on the AChR.

Role of CD4+ T Cells in MG

Pathogenic anti-AChR Abs are high-affinity IgGs, and their synthesis requires activated CD4+ T cells to interact with and stimulate B cells. Thymectomy is believed to benefit patients with MG by removal of these AChR-specific CD4+ T cells [20]. Treatment with anti-CD4+ antibodies has also been shown to have a positive therapeutic impact. AIDS patients with reduction in CD4+ T cells notice myasthenic symptom improvement.

Role of CD4+ T-Cell Subtypes and Cytokines in MG and EAMG (Experimental Autoimmune MG)

CD4+ T cells are classified into two main subtypes: Th1 and Th2 cells. Th1 cells secrete pro-inflammatory cytokines, such as IL-2, IFN-y, and TNF-a, which are important in cell-mediated immune responses. Th2 cells secrete anti-inflammatory cytokines, like IL-4, IL-6, and IL-10, which are important inducers of humoral immune responses. IL-4 further stimulates differentiation of Th3 cells that secrete TGF-p, which is involved in immunosuppressive mechanisms [17].

MG patients have abundant anti-AChR Th1 cells in the blood that recognize many AChR epitopes and are capable of inducing B cells to produce high-affinity anti-AChR antibodies. Th1 cells are indispensible in the development of EAMG as proven in animal models. Therapies against Th1 cytokines (TNF-a and IFN-y) have been proven in animal models to improve EAMG symptoms [22, 23].

Anti-AChR Th2 cells have a complex role in EAMG pathogenesis. They can be protective, but their cytokines IL-5, IL-6, and IL-10 may also facilitate EAMG development [2]. CD4+ T cells that express CD25 marker and transcription factor Foxp3 are called “Tregs” and are important in maintaining self-tolerance. Tregs in MG patients may be functionally impaired and have been shown to increase after thymectomy with concomitant symptom improvement. Natural killer (NK) and natural killer T (NKT) cells also have important roles in MG and EAMG. Natural killer T (NKT) cells with Tregs help in regulating anti-AChR response. Mouse models have shown inhibition of EAMG development after stimulation of NKT cells [23]. IL-18, secreted by antigen-presenting cells (APCs), stimulates NK cells to produce IFN-y, which permits and enhances Th1 cells to induce EAMG. IL-18- deficient mice are resistant to EAMG, and pharmacologic block of IL-18 suppresses EAMG. MG patients have been shown to have increased serum level of IL-18, which tends to decrease with clinical improvement [15].

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