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Mechanism and regulation of antigen processing by cathepsin B
N Katunuma1, Y Matsunaga, T Saibara
1Institute for Health Sciences, Tokushima Bunri University, Japan.
Abstract:
Cellular and humoral immune responses to vaccines of hepatitis B and rabies as antigens were suppressed by specific inhibitors of cathepsin B, anti-cathepsin B antibody and the specific substrate of cathepsin B. The antigenic peptides of these vaccines are processed by cathepsin B and the fragments are capable of binding with the desetope of MHC class II, beta-chain, because one of the active sites of cathepsin B (14, 15) VN217-222 shares high homology with a part of the desetope, VN57-62, of MHC class II, beta-chain. Rechallenge of the synthesized antigenic peptides of these vaccine molecules shows a strong proliferative response to the splenocyte primed by these vaccines. However, the response to these antigenic peptides was not inhibited by cathepsin B inhibitors. These findings suggest that cathepsin B inhibitors do not inhibit any other processes of immune responses than the proteolytic processing of antigens. Some investigators reported recently that the Ii-chain is degraded by purified cathepsin B in vitro (23-25). However, we showed that the suppression of these immune responses by cathepsin B inhibitors is not due to the inhibition of invariant chain degradation. We found that the invariant chain shares about 40% homology with the cystatin family which are the endogenous inhibitors of cysteine proteases (23, 24). Therefore, the Ii-chain is one of the members of the cystatin superfamily and may participate in the regulation of presentation of antigenic peptides and also antigen processing by cathepsin B.
Insights
Cathepsin B inhibitors suppress immune responses by blocking the processing of vaccine antigens. This protease is crucial for antigen presentation, but does not affect invariant chain degradation.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Cellular and humoral immune responses are critical for vaccine efficacy.
- Antigen processing and presentation are key steps in initiating adaptive immunity.
- Cathepsin B is a cysteine protease implicated in various cellular functions.
Purpose of the Study:
- To investigate the role of cathepsin B in the immune response to hepatitis B and rabies vaccines.
- To determine if cathepsin B inhibitors affect antigen processing and presentation.
- To clarify the mechanism by which cathepsin B influences immune responses.
Main Methods:
- Utilized specific cathepsin B inhibitors and antibodies to block protease activity.
- Synthesized antigenic peptides from hepatitis B and rabies vaccines.
- Assessed splenocyte proliferation in response to vaccine antigens and peptides.
- Analyzed the homology between cathepsin B active sites and MHC class II beta-chain desetopes.
- Investigated the effect of cathepsin B inhibitors on invariant chain degradation.
Main Results:
- Cathepsin B inhibitors suppressed immune responses to hepatitis B and rabies vaccines.
- Antigenic peptides processed by cathepsin B bind to MHC class II beta-chain.
- Rechallenged splenocytes with synthesized peptides showed a strong proliferative response, unaffected by cathepsin B inhibitors.
- Cathepsin B inhibitors did not inhibit invariant chain degradation.
Conclusions:
- Cathepsin B plays a critical role in the proteolytic processing of vaccine antigens.
- The observed suppression of immune responses by cathepsin B inhibitors is due to impaired antigen processing, not invariant chain degradation.
- The invariant chain, a member of the cystatin superfamily, may regulate antigen processing by cathepsin B.