Isoaspartyl post-translational modification triggers autoimmune responses to self-proteins

Area of Science:

• Immunology
• Biochemistry
• Autoimmunity

Background:

• The immune system normally distinguishes self from non-self, maintaining tolerance to self-proteins.
• Mechanisms breaking self-tolerance in autoimmunity are not fully understood.
• Isoaspartyl modifications occur in proteins under physiological conditions, particularly in aging and stressed cells.

Purpose of the Study:

• To investigate if isoaspartyl-modified self-peptides can break immune tolerance and induce autoimmune responses.
• To explore the potential role of isoaspartyl peptides as triggers for autoimmune diseases.

Main Methods:

• Mice were immunized with either the normal or isoaspartyl form of specific peptides, including murine cytochrome c peptide 90-104 and a human systemic lupus erythematosus (SLE) autoantigen peptide.
• B and T cell responses, as well as antibody cross-reactivity, were assessed following immunization.

Main Results:

• Immunization with the isoaspartyl form of murine cytochrome c peptide induced strong B and T cell autoimmune responses, unlike the normal form.
• Antibodies generated against the isoaspartyl peptide cross-reacted with both peptide isoforms and native cytochrome c.
• Immunization with the isoaspartyl form of an SLE autoantigen peptide also elicited strong autoimmune responses, while the normal form did not.

Conclusions:

• Isoaspartyl modification of self-peptides can break immune tolerance and elicit significant B and T cell autoimmune responses.
• These post-translationally modified peptides may act as crucial early immunologic stimuli in the initiation of autoimmune diseases like SLE.
• The findings highlight a potential mechanism for autoimmunity triggered by physiologically occurring protein modifications.