Introducing Molecular Chaperones into the Causality and Prospective Management of Autoimmune Hepatitis

Molecular chaperones influence the immunogenicity of peptides and the activation of effector T cells, and their pathogenic roles in autoimmune hepatitis are unclear. Heat shock proteins are pivotal in the processing and presentation of peptides that activate CD8⁺ T cells. They can also induce regulatory B and T cells and promote immune tolerance. Tapasin and the transporter associated with antigen processing-binding protein influence the editing and loading of high-affinity peptides for presentation by class I molecules of the major histocompatibility complex. Their over-expression could enhance the autoimmune response, and their deficiency could weaken it. The lysosome-associated membrane protein-2a isoform in conjunction with heat shock cognate 70 supports the importation of cytosolic proteins into lysosomes. Chaperone-mediated autophagy can then process the peptides for activation of CD4⁺ T cells. Over-expression of autophagy in T cells may also eliminate negative regulators of their activity. The human leukocyte antigen B-associated transcript three facilitates the expression of class II peptide receptors, inhibits T cell apoptosis, prevents T cell exhaustion, and sustains the immune response. Immunization with heat shock proteins has induced immune tolerance in experimental models and humans with autoimmune disease by inducing regulatory T cells. Therapeutic manipulation of other molecular chaperones may promote T cell exhaustion and induce tolerogenic dendritic cells. In conclusion, molecular chaperones constitute an under-evaluated family of ancillary proteins that could affect the occurrence, severity, and outcome of autoimmune hepatitis. Clarification of their contributions to the immune mechanisms and clinical activity of autoimmune hepatitis could have therapeutic implications.