Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that involves the selective loss of the upper and lower motor neurons (MNs). Neuroinflammation has been implicated in the pathogenesis of the sporadic form of the disease. We earlier developed immune-mediated animal models of ALS and demonstrated humoral and cellular immune reactions in the nervous system and in the sera of patients and animals. The accumulation of immunoglobulin G (IgG), an elevated intracellular level of calcium, ultrastructural alterations in the MNs, and activation of the microglia were noted in the spinal cord of ALS patients. Similar alterations developed in mice inoculated intraperitoneally with IgG from ALS patients or from an immune-mediated goat model.MethodsWe have now examined whether the intraperitoneal injection of mice with IgG from sporadic ALS patients or from immunized goats with the homogenate of the anterior horn of the bovine spinal cord is associated with changes in the pro-inflammatory (TNF-α and IL-6) and anti-inflammatory (IL-10) cytokines in the spinal cord and serum of the mice. The levels of cytokines were measured by ELISA.ResultsIntraperitoneally administered IgG from the ALS patients induced subclinical signs of MN disease, while the injection of IgG from immunized goats resulted in a severe respiratory dysfunction and limb paralysis 24 h after the injections. Significantly increased levels of TNF-α and IL-10 were detected in the spinal cord of the mice injected with the human ALS IgG. The level of IL-6 increased primarily in the serum. The IgG from the immunized goats induced highly significant increases in the levels of all three cytokines in the serum and the spinal cord of mice.ConclusionsOur earlier experiments had proved that when ALS IgG or IgG from immune-mediated animal models was inoculated into mice, it was taken up in the MNs and had the ability to initiate damage in them. The pathological process was paralleled by microglia recruitment and activation in the spinal cord. The present experiment revealed that these forms of IgG cause significant increases in certain cytokine levels locally in the spinal cord and in the serum of the inoculated mice. These results suggest that IgG directed to the MNs may be an initial element in the damage to the MNs both in human ALS and in its immune-mediated animal models.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that involves the selective loss of the upper and lower motor neurons (MNs)
Behavior of the injected mice Each of the mice injected ip with the immunoglobulin G (IgG) from the ALS patients developed slightly sluggish movements generally. This slight, but noticeable deficit is comparable with the altered ultrastructure and increased calcium content in the MNs of mice inoculated with IgG from ALS patients described previously [26]
The mice injected with the preimmune IgG from the same goats, or with the IgG from a normal human individual, from the Parkinson disease patient or from the patient with multifocal motor neuropathy, or with vehicle did not appear to exhibit any change in movement or behavior
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that involves the selective loss of the upper and lower motor neurons (MNs). Many hypotheses have been put forward to explain the selective degeneration of the MNs in ALS, including excitotoxicity [3,4,5,6], oxidative stress [7, 8], cytoskeletal abnormalities [9, 10], and the aggregation of abnormal proteins [2, 11]. These pathogenic mechanisms can be accounted in part by the genetic defects in fALS patients. Reactive astrocytes in ALS can produce pro-inflammatory mediators, including interleukin-6 (IL-6) [16] and tumor necrosis factor-alpha (TNF-α) [17, 18]
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