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Granulomatosis with polyangiitis (GPA) is a B-cell-mediated, relapsing, autoimmune disease. There is a need for novel therapeutic approaches and relapse markers to achieve durable remission. B cells express immune regulatory molecules that modulate their activation and maintain tolerance. While recent studies show dysregulation of these molecules in other autoimmune diseases, data on their expression in GPA are limited. This study aimed to map the expression of surface immune regulatory molecules on circulating B-cell subsets in GPA and correlate their expression with clinical parameters. Immune regulatory molecule expression on circulating B-cell subsets was comprehensively examined in active GPA (n = 16), GPA in remission (n = 16), and healthy controls (n = 16) cross-sectionally using a 35-color B-cell-specific spectral flow cytometry panel. Our supervised and unsupervised in-depth analysis revealed differential expression of inhibitory and stimulatory immune molecules on distinct B-cell populations in GPA, with the most notable differences observed in active GPA. These differences include the upregulation of FcγRIIB on nonmature B cells, downregulation of CD21 and upregulation of CD86 on antigen-experienced B cells, and elevated CD22 expression on various populations. Additionally, we found a strong association between FcγRIIB, BTLA, and CD21 expression on specific B-cell populations and disease activity in GPA. Together, these findings provide novel insights into the immune regulatory molecule expression profile of B cells in GPA and could potentially form the foundation for new therapeutic approaches and disease monitoring markers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

ANCA-associated vasculitis (AAV) is characterized by inflammation and destruction of small and medium-sized vessels. Current management strategies for AAV have been validated in large groups of patients. However, recent insights indicate that distinct patient subsets may actually exist within AAV, thereby justifying the development of more personalized treatment strategies. In this review, we discuss current evidence for a better classification of AAV based on ANCA type. We describe how thus defined categories of AAV patients may differ in genetic background, clinical presentation, immune pathology, response to treatment and disease outcome. We also explore how these insights may provide a rationale for targeted treatments in different categories of AAV patients. Finally, we provide recommendations on how to further establish precision medicine in AAV.

Background: Both the role of inducible nitric oxide synthase (iNOS) in the development of inflammatory bowel disease (IBD) as well as the molecular details governing its mucosal induction remain unclear., Methods: In the present study we evaluated the role of the residing intestinal microflora in the induction of epithelial iNOS upon transfer of CD45RB(high) CD4(+) T cells to SCID mice. CB-17 SCID mice were reared with conventional flora (CNV) or germfree CB-17 SCID mice were monoassociated with Helicobacter muridarum, act A(-) mutant Listeria monocytogenes, segmented filamentous bacteria (SFB), or Ochrobactrum anthropi., Results: Within 2 weeks CNV SCID mice injected with CD45RB(high) CD4(+) T cells showed a focal, epithelial iNOS expression on the apical site of villi that preceded the infiltration of CD4(+) T cells and cytokine production followed by extension of this expression to the entire surface along the whole crypt axis as the colitis progressed. SCID mice monoassociated with H. muridarum developed a severe colitis and showed high epithelial iNOS expression. CNV-SCID mice without T cells and SCID mice monoassociated with SFB did not show any iNOS expression, whereas SCID mice monoassociated with act A(-) mutant L. monocytogenes and O. anthropi showed some scattered epithelial iNOS staining on the apical site of a few villi, but none of these mice developed colitis., Conclusions: These findings demonstrate that the expression of epithelial iNOS is highly bacterium-specific and correlates with the severity of disease, suggesting an important role for this enzyme in the development of IBD.

Objectives: Nasal carriage of Staphylococcus aureus constitutes a risk factor for disease exacerbation in Wegener's granulomatosis (WG). We hypothesized that staphylococcal superantigens (SAg) are a determinant of S. aureus-related risk for disease relapse in WG., Methods: In a retrospective longitudinal cohort study in 62 WG patients, we investigated the presence of the staphylococcal SAg genes sea, seb, sec, sed, see, tsst-1 and eta in S. aureus strains isolated from WG patients during an observation period of seven years. Subsequently, we assessed whether relapses of WG were associated with the presence of SAg-positive staphylococci., Results: Of 1718 swab cultures analysed, 709 (41.2%) were S. aureus-positive. Fifty-one patients carried S. aureus, of whom 37 (72.5%) patients carried at least one SAg-positive S. aureus strain. Of the 709 S. aureus-positive cultures, 326 (46%) contained at least one SAg gene. Except for see, all assessed SAg genes were detected. sea was found most frequently, followed by sec, tsst-1 and eta and finally, by sed and seb. Using a multivariate, time-dependent Cox regression analysis we found that the presence of S. aureus was associated with relapses of WG (RR 3.2; 95% CI 1.2-8.4). The risk for relapse was modulated by the presence and type of SAg, with tsst-1 being associated with an increased risk for relapse (RR 13.3, 95% CI 4.2-42.6)., Conclusion: The risk for relapse of WG increases with the presence of tsst-1-positive S. aureus. Eradication of tsst-1-positive S. aureus in WG may show whether disease relapses can be prevented.

Background: Earlier studies have suggested that complexes of the human IgA receptor FcalphaRI/CD89 with mouse IgA are pathogenic upon deposition in the renal mesangium. Transgenic mice expressing FcalphaRI/CD89 on macrophages/monocytes developed massive mesangial IgA deposition and a clinical picture of IgA nephropathy (IgAN). Based on these findings, the purpose of this study was to design an experimental model of IgAN by injection of human CD89 in mice. The interaction of mouse IgA with CD89 was investigated further., Methods: Recombinant human soluble CD89 and a chimeric CD89-Fc protein were generated, produced, purified and injected in mice. Renal cryosections were stained for IgA and CD89. The interaction of mouse IgA with CD89 was analysed by fluorescence-activated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA) and plasmon resonance technology., Results: Injection of recombinant human CD89 did not result in significant IgA or CD89 deposition in the renal mesangium. However, CD89 staining in the liver was found to be positive. CD89 was rapidly cleared from circulation without signs of complex formation with IgA. FACS analysis, ELISA and plasmon resonance techniques all revealed a dose-dependent binding of human IgA to recombinant CD89, while no detectable binding was seen of mouse IgA, either of serum IgA or of different monoclonal mouse IgA preparations., Conclusions: An experimental model for IgAN in mice could not be obtained by injection of recombinant CD89. This is compatible with our in vitro biochemical data showing a lack of binding between recombinant human CD89 and mouse IgA.

In Wegener's granulomatosis (WG), a form of autoimmune systemic vasculitis, chronic carriage of Staphylococcus aureus constitutes a risk factor for the development of exacerbations. Circulating T cells in this disease are persistently activated, suggesting the presence of a chronic stimulus. A causal link between chronic carriage of S. aureus and chronic T cell activation in WG is conceivable, because S. aureus produces superantigens (SAg), which are potent T cell stimulators. Superantigenic stimulation of T cells results in expansion of T cell subsets expressing SAg-binding T cell receptor V-beta (Vbeta) chains. In the present study we hypothesized that in WG the presence of staphylococcal SAg is accompanied by expansion of SAg-reacting T cell subsets. We tested our hypothesis in a cross-sectional and a longitudinal study in which the association between seven staphylococcal SAg genes [typed by poplymerase chain reaction (PCR)], eight SAg-binding Vbeta chains and four SAg-non-binding Vbeta chains (assessed by flow-cytometry) was assessed. Both studies showed that T cell expansions were present at a significantly higher rate in WG patients than in healthy individuals, but were not associated with the presence of either S. aureus or its SAg. Moreover, T cell expansions were generally of small extent, and did not appear simultaneously in both CD4 and CD8 subsets. We conclude that in WG S. aureus effects its supposed pathogenic function by a mechanism other than superantigenic T cell activation.