Sensitization and tolerization to brain antigens in stroke

Abstract

Despite encounter of novel brain antigens by the systemic immune system following stroke, autoimmune responses to these antigens do not seem to occur. In rats, a systemic inflammatory response at the time of stroke, however, provokes changes that increase the likelihood of developing detrimental autoimmunity. These findings may help to explain why infections in the post-stroke period are associated with worse outcome. In addition, data suggest that the immune response can be manipulated in an antigen specific fashion to improve stroke outcome. Together these data argue that the nature of the post-ischemic immune response influences neurological recovery from stroke.

Figure 1. Immune response to MBP in brain and spleen following MCAO

Individual animal data are presented. For each animal, the response of brain lymphocytes to MBP is depicted by open black circles; the response of splenocytes to MBP is depicted by open gray triangles. The ratio of the number of MBP-specific IFN-γ secreting cells to the number MBP-specific TGF-β1 secreting cells is depicted on the Y-axis; the time from MCAO is depicted on the X-axis. A ratio ≥ 1.48 is considered indicative of a Th1(+) response (solid gray line); a ratio ≤ 0.68 is considered indicative of a Th3/Treg response (dotted gray line). There is no demonstrable immune response to MBP following MCAO.

Figure 2. The immune response to MBP in spleen among naïve animals and animals “sensitized” to MBP

The ratio of the number of MBP-specific IFN-γ secreting cells to the number MBP-specific TGF-β1 secreting cells in spleen is depicted on the Y-axis. The box plots display the median and interquartile ranges; the lower interquartile range of MBP sensitized animals (1.48) effectively excludes naïve animals. *P<0.01 using the t-test.

Figure 3. Rotarod performance following MCAO based on tolerization status and immune response to MBP

Animals tolerized to MBP prior to MCAO performed better than those tolerized to OVA (a). Animals that developed a Th1(+) response to MBP fell more quickly from the rotarod than those that did not (b). Animals with a Treg response to MBP performed better than those with either a Th1(+) response or no response (c). The box plots display the median and interquartile ranges. *P≤0.05, ** P≤0.01 using the t-test or ANOVA, as appropriate.

Figure 4

There are multiple perforin positive cells (stained with FITC) within the infarcted tissue of this LPS treated animals sacrificed one month after MCAO (a). These perforin positive cells are seen in close juxtaposition to DAPI positive cells (40x). The DAPI positive cells were shown to be neurons using a Texas-red conjugated antibody for neuron specific enolase (100x) (b).