Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons at the motor cortex, bulbar, and spinal levels, leading to muscle weakness, progressive paralysis, and respiratory failure and death within 3–5 years after disease onset [1]. Whilst the aetiology and pathology of ALS remains unclear, current evidence suggests that oxidative stress, glutamatergic toxicity, ribonucleic acid (RNA) processing dysfunction, abnormal protein aggregation, mitochondrial dysfunction, axonal transport dysfunction, neuroinflammation, and immunomodulation might play important roles in the pathogenesis of ALS [2, 3].
Recently, evidence indicating that there is a significant contribution of inflammatory and immune responses to the progression of ALS has emerged [4]. The activation of astrocytes and microglia and the infiltration of T cells and monocytes have been observed in the central nervous system (CNS) of patients with ALS and animal models [5–8]. Immunoglobulin deposits were observed in motor neurons from the spinal cord of patients with ALS [9], and upregulated complements were found in the cerebrospinal fluid (CSF), spinal cord, and motor cortex of patients with ALS and transgenic mice [10–12]. In addition to the dysregulation of immune responses in the CNS, immune aberrations within the peripheral nervous system have been reported in patients with ALS. The levels of circulating chemokines and cytokines, such as IL-7, IL -6, and TNF-alpha and its soluble receptors, TNF-R1 and TNF-R2, were found to be increased in patients with ALS [13–15]. Increased levels of complement C3 and C5a, C reactive protein (CRP), and erythrocyte sedimentation rate (ESR) as well as T cell abnormalities and immunoglobulin alterations were found in the blood of patients with ALS [16–21]. However, some results regarding serum immunoglobulin and complement are inconsistent. Some studies have demonstrated significantly higher IgG levels, not IgM or IgA levels, in patients with ALS than in controls [22, 23]. Other studies have reported normal serum levels of IgG, IgA, and IgM [24, 25], or increased IgM levels and normal IgG level at the early stage of ALS, with a decrease in IgG levels and serum IgM level normalization with disease progression [26]. Additionally, although there is strong evidence of complement upregulation in ALS, normal C3 and C4 levels were also observed in patients with ALS [24, 27], and the specific genetic deletion of C3 and C4 in ALS mouse models did not show any beneficial effects on the disease progression [12, 28].
Neuroinflammation and immunomodulation have been hypothesized to play roles in the pathogenesis of ALS as well as other neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple system atrophy (MSA) [29–36]. Important differences in the immunological processes occurring in ALS, PD, and AD involving microglial function have been reported. Furthermore, although the contribution of adaptive immune cells to AD seems to be modest, T cells can influence microglial phenotypes and induce neuroprotection in PD, and especially in ALS models [33]. In addition, an increasing number of studies on peripheral immune component levels in patients with other neurodegenerative diseases, such as AD and PD, have been conducted [37, 38]; however, few studies have explored whether the contribution of peripheral immune components is similar among patients with ALS and other neurodegenerative diseases.
To evaluate these conflicting findings, resolve any discrepancies, and explore the relationships between ALS clinical characteristics and peripheral immune components as well as determine whether ALS shares similar peripheral immune abnormalities with other neurodegenerative diseases, the current study was designed: (1) to detect differences, if any, in the serum levels of IgG, IgM, IgA, and complement C3 and C4 among patients with ALS, patients with other neurodegenerative diseases, and healthy controls (HCs); (2) to systematically review the results of previous studies using the meta-analysis methodology; and (3) to compare the serum immune component levels between different ALS patient groups established by age at onset, site at onset, disease duration, or disease severity, and analyse the correlations of serum immune components with age at onset, disease duration, and the revised ALS functional rating scale (ALSFRS-R) score.