Figure 6

Scheme summarizing the changes in the immunophenotype associated with MHE and hypotheses on how this may affect the brain and lead to MHE. The main alterations associated with MHE are: (1) Increased activation of all subtypes of CD4⁺ T-lymphocytes, as indicated by the increased expression of CD69. (2) An increased amount of CD4⁺CD28⁻ T lymphocytes, associated with increased levels of CX3CL1 (fractalkine) and of IL-15, which may promote their infiltration into the brain. (3) Increased differentiation of CD4⁺ T lymphocytes to Th follicular and Th22, which may promote the formation of tertiary lymphoid organs in brain. (4) Increased activation of B lymphocytes and serum IgG. These four main alterations may contribute separately or jointly to alter cerebral function and to the appearance of the neurological alterations associated to MHE in cirrhotic patients. Some possible mechanisms by which changes in peripheral inflammation in patients with MHE may contribute to the appearance of the neurological alterations are: (a) infiltration into the brain of CD4⁺CD28⁻ T lymphocytes, leading to neuroinflammation and neurological impairment; (b) activation by peripheral interleukins (TNFα, IL-1b, IL-6) of their receptors in endothelial cells, triggering the release of inflammatory factors into the brain, neuroinflammation and neurological alterations; (c) infiltration of Tfh cells and formation of tertiary lymphoid organs with B lymphocytes germinal centers, leading to neurological alterations.