Immunological Interaction of HLA-DPB1 and Proteinase 3 in ANCA Vasculitis is Associated with Clinical Disease Activity

Dhruti P. Chen; Elizabeth A. McInnis; Eveline Y. Wu; Katherine G. Stember; Susan L. Hogan; Yichun Hu; Candace D. Henderson; Lauren N. Blazek; Simon Mallal; Edita Karosiene; Bjoern Peters; John Sidney; Eddie A. James; William W. Kwok; J. Charles Jennette; Dominic J. Ciavatta; Ronald J. Falk; Meghan E. Free

doi:10.1681/ASN.2021081142

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Visual Abstract

Significance Statement

In a longitudinal, prospective cohort study, we observed that patients with PR3-ANCA vasculitis and HLA-DPB1*04:01 are more likely to experience disease flares, which informed our hypothesis that HLA has an immunopathogenic role. We found that an epitope of PR3 (PR3_225-239) has high affinity for HLA-DPB1*04:01. By examining patient peripheral blood mononuclear cells, we demonstrated that PR3_225-239 presentation by HLA-DPB1*04:01 stimulates PR3_225-239–specific autoreactive T cells. This may explain the associated increased relapse risk. However, in patients who are in long-term remission off therapy, HLA-DPB1⁺ cells bind PR3_225-239 at levels seen in healthy controls. The diminished interaction between HLA-DPB1 and autoantigen in long-term remission signals immunological nonresponsiveness, creating a foundation to define immunological remission.

Abstract

Background PR3-ANCA vasculitis has a genetic association with HLA-DPB1. We explored immunologic and clinical features related to the interaction of HLA-DPB1*04:01 with a strongly binding PR3 peptide epitope (PR3_225–239).

Methods Patients with ANCA vasculitis with active disease and disease in remission were followed longitudinally. Peripheral blood mononuclear cells from patients and healthy controls with HLA-DPB1*04:01 were tested for HLA-DPB1*04:01 expression and interaction with a PR3 peptide identified via in silico and in vitro assays. Tetramers (HLA/peptide multimers) identified autoreactive T cells in vitro.

Results The HLA-DPB1*04:01 genotype was associated with risk of relapse in PR3-ANCA (HR for relapse 2.06; 95% CI, 1.01 to 4.20) but not in myeloperoxidase (MPO)-ANCA or the combined cohort. In silico predictions of HLA and PR3 peptide interactions demonstrated strong affinity between ATRLFPDFFTRVALY (PR3_225–239) and HLA-DPB1*04:01 that was confirmed by in vitro competitive binding studies. The interaction was tested in ex vivo flow cytometry studies of labeled peptide and HLA-DPB1*04:01-expressing cells. We demonstrated PR3_225–239 specific autoreactive T cells using synthetic HLA multimers (tetramers). Patients in long-term remission off therapy had autoantigenic peptide and HLA interaction comparable to that of healthy volunteers.

Conclusions The risk allele HLA-DPB1*04:01 has been associated with PR3-ANCA, but its immunopathologic role was unclear. These studies demonstrate that HLA-DPB1*04:01 and PR3_225–239 initiate an immune response. Autoreactive T cells specifically recognized PR3_225–239 presented by HLA-DPB1*04:01. Although larger studies should validate these findings, the pathobiology may explain the observed increased risk of relapse in our cohort. Moreover, lack of HLA and autoantigen interaction observed during long-term remission signals immunologic nonresponsiveness.

View Full Text

If you are:

an ASN member, select the "ASN Member" login button.
an individual subscriber, login with you User Name and Password.
an Institutional user, select the Institution option where you will be presented with a list of Shibboleth federations. If you do not see your federation, contact publications@asn-online.org.

Log in through your institution

Purchase access

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$34.00

In order to get access to the article, you must have an account. If you have an account, enter your user name and password into the boxes above. If you do not have an account, follow the instructions below to create one. Once you have purchased the article, you will have access to it for 24 hours.

Steps for Creating an Account:

Click the "Purchase Access" button. The page will redisplay with the following message at the top of the screen. In the message, click to create an account.

When you create the account, you will be asked to register a user name, email address and you will need to create a password that is at least eight characters in length. You do not need an ASN Member number to complete the form. As you move through the registration page, you will have to verify you are a person by completing a Captcha request. Lastly, your first and last name will be required.

Once your information is successfully saved, the system will redisplay the home page of the journal. From there, navigate back to the article to purchase. Select the article and at the bottom of the page, use the credentials you just created to login. The article will be added to your shopping cart. You can continue to navigate across JASN and CJASN adding to your cart from both journals. When you are ready to complete your purchse, select the Shopping Cart from the upper right hand corner of the page and follow the onscreen instructions.