Complement-Sensitive Cells Display Significant Change in Patients With NMOSD

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Expression of CD16 and activation markers in natural killer and natural killer-T cells may be responsible for the escalating autoimmune activity in NMOSD.

Shuhei Nishiyama, MD, PhD, research fellow, the Neuroimmunology Clinic and Research Laboratory, Massachusetts General Hospital and Harvard Medical School

Shuhei Nishiyama, MD, PhD

A recent study published in the Journal of Neuroinflammation showed that the expression of CD16 and activation markers in natural killer (NK) and natural killer-T (NKT) cells significantly changed in patients with neuromyelitis optica spectrum disorder (NMOSD) compared with the controls.1 These results support an immunopathogenesis model in which complement pathway activation in NK and NKT cells upregulate CD16, expression which binds to complexes with antibodies and antigens.

The number of NKT cells increased in NMOSD (P <.001) from baseline, although the proportion of those who were CD16 positive was lower compared with normal controls (NCs) and disease controls (DCs) (P = .0012). The NK cell count was normal, even though the ratio of CD16 positive individuals was also significantly lower (P <.001). In both NK cells and NKT cells from the disease, C5 complement receptor expression was much higher than normal rates and disease controls (both P <.001).

“The C5 inhibitor eculizumab [Soliris; Alexion] was thought to have a mechanism of action [MoA] to prevent astrocytic necrosis by inhibiting the formation of membrane attack complexes [MAC] starting from C5b. However, clinical trial results have indicated that the annual recurrence rate is also significantly lowered, suggesting that eculizumab's MoA may be broader than we thought,”2 lead author Shuhei Nishiyama, MD, PhD, research fellow, the Neuroimmunology Clinic and Research Laboratory, Massachusetts General Hospital and Harvard Medical School, told NeurologyLive®. “Since eculizumab inhibits forming C5a and C5b from C5, another product—C5a—may be a key factor. Although C5a can activate immune cells via its receptor CD88, we still need to understand how C5a acts on the immune system.”

Samples of peripheral blood mononuclear cell (PBMC) were extracted from 45 patients with NMOSD with aquaporin 4 (AQP4)-IgG antibodies, as well as 18 DCs, and 19 NCs, which were then analyzed for CD16 expression and complement receptors in vitro. The disease controls included 8 patients with myelin-oligodendrocyte glycoprotein (MOG)-IgG associated disease (MOGAD), 4 patients with multiple sclerosis (MS) who were seronegative for both AQP4 and MOG-IgG, and other diagnoses. As for analysis with CD16, encoded by FCGR3A, 45 patients had V/V, V/F, with F/F genotypes in 11, 22, and 12 patients, respectively.

“Our recently published data show that NK and NKT cells are reduced in patients with NMOSD. Their respective CD16 expression levels are also decreased compared to normal controls CD16 is a receptor that binds to the Fc portion of IgG. We hypothesize that the reduction of this receptor on the surface of NK and NKT cells results from their binding and internalization of immune complexes. The internalization may trigger the immune system to initiate an attack against self-antigens,” Nishiyama said.1

Investigators also evaluated activation markers in CD69 and CD83. The CD69 expression significantly increased in NMOSD compared with NCs, while an increase in CD69 + NK was also observed in DCs compared with NCs (NMOSD: 12.96 ±7.721; DCs: 11.55 ±8.765; NCs: 4.543 ±2.873; P <.0001). Notably, a significant increase was observed in CD83-positive cells in NMOSD and DC in NK cells (NMOSD: 23.49 ±13.83; DCs: 24.14 ±15.06; NCs: 9.744 ±7.248; P = .0001).

>> READ MORE: Beneficial Response Observed With Satralizumab After Switching From Other NMOSD Treatments

The effect of FCGR3A p158 polymorphism on NK cell ratio and its surface markers in patients with NMOSD was additionally further analyzed. The ratio of NK cells among all PBMCs in the V/V genotype group was significantly lower than that in the F/F group (P =.0400). Also, the number of CD69-positive NK cells significantly increased in the F/F group compared with the V/V group (p = 0.0388). Notably, the expression of CD88 on NK cells was significantly upregulated in the V/V group compared with the V/F group (p = 0.0175).

Limitations of the study include that the disease control group was heterogeneous, collecting a wild variety of autoimmune diseases, limited the ability to observe results are specific to NMOSD. Secondly, the samples were all from the remission phase and may not accurately reflect events that occurred in the acute phase with the NK and NKT cells. In addition, the sample size of each group was different and the authors noted that the analysis might be skewed because of this.

FCGR3A, also known as CD16A, was previously reported to have a significant therapeutic effect from anti-CD20 antibody rituximab depending on its genetic polymorphism. Recently, a similar analysis was performed in the inebilizumab [Uplizna; Horizon] trial,” Nishiyama said.3,4 “Interestingly, NMOSD patients with the FCGR3A p158 V/V polymorphism in its placebo arm had a significantly higher relapse rate than patients with the F/F polymorphism. This means that patients with p158 V/V polymorphism may be more severely affected in the natural course of the disease. A possible pathogenetic mechanism is that the immune complex of the AQP4 antibody and AQP4 peptide binds to CD16A more strongly, leading to more activation of NK and NK cells.”

REFERENCES
1. Nishiyama S, Wright AE, Lotan I, et al. Upregulated complement receptors correlate with Fc gamma receptor 3A-positive natural killer and natural killer-T cells in neuromyelitis optica spectrum disorder. J Neuroinflammation. 2022;19(1):296. Published 2022 Dec 12. doi:10.1186/s12974-022-02661-1
2. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019;381(7):614-625. doi:10.1056/NEJMoa1900866
3. Kim SH, Jeong IH, Hyun JW, et al. Treatment Outcomes With Rituximab in 100 Patients With Neuromyelitis Optica: Influence of FCGR3A Polymorphisms on the Therapeutic Response to Rituximab. JAMA Neurol. 2015;72(9):989-995. doi:10.1001/jamaneurol.2015.1276
4. Paul F, Bennett J, Weinshenker B, et al. P 4 The impact of low affinity immunoglobulin gamma Fc region receptor III-A gene polymorphisms in neuromyelitis optica spectrum disorder and implications for treatment outcomes: results from the N-MOmentum study. Clin Neurophysiol. 2022;137:e16–7.

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