The neutrophil: A key resourceful agent in immune-mediated vasculitis.

The term "vasculitis" refers to a group of rare immune-mediated diseases characterized by the dysregulated immune system attacking blood vessels located in any organ of the body, including the skin, lungs, and kidneys. Vasculitides are classified according to the size of the vessel that is affected. Although this observation is not specific to small-, medium-, or large-vessel vasculitides, patients show a high circulating neutrophil-to-lymphocyte ratio, suggesting the direct or indirect involvement of neutrophils in these diseases. As first responders to infection or inflammation, neutrophils release cytotoxic mediators, including reactive oxygen species, proteases, and neutrophil extracellular traps. If not controlled, this dangerous arsenal can injure the vascular system, which acts as the main transport route for neutrophils, thereby amplifying the initial inflammatory stimulus and the recruitment of immune cells. This review highlights the ability of neutrophils to "set the tone" for immune cells and other cells in the vessel wall. Considering both their long-established and newly described roles, we extend their functions far beyond their direct host-damaging potential. We also review the roles of neutrophils in various types of primary vasculitis, including immune complex vasculitis, anti-neutrophil cytoplasmic antibody-associated vasculitis, polyarteritis nodosa, Kawasaki disease, giant cell arteritis, Takayasu arteritis, and Behçet's disease.

Data quality and patient characteristics in European ANCA-associated vasculitis registries: data retrieval by federated querying.

OBJECTIVES: This study aims to describe the data structure and harmonisation process, explore data quality and define characteristics, treatment, and outcomes of patients across six federated antineutrophil cytoplasmic antibody-associated vasculitis (AAV) registries. METHODS: Through creation of the vasculitis-specific Findable, Accessible, Interoperable, Reusable, VASCulitis ontology, we harmonised the registries and enabled semantic interoperability. We assessed data quality across the domains of uniqueness, consistency, completeness and correctness. Aggregated data were retrieved using the semantic query language SPARQL Protocol and Resource Description Framework Query Language (SPARQL) and outcome rates were assessed through random effects meta-analysis. RESULTS: A total of 5282 cases of AAV were identified. Uniqueness and data-type consistency were 100% across all assessed variables. Completeness and correctness varied from 49%-100% to 60%-100%, respectively. There were 2754 (52.1%) cases classified as granulomatosis with polyangiitis (GPA), 1580 (29.9%) as microscopic polyangiitis and 937 (17.7%) as eosinophilic GPA. The pattern of organ involvement included: lung in 3281 (65.1%), ear-nose-throat in 2860 (56.7%) and kidney in 2534 (50.2%). Intravenous cyclophosphamide was used as remission induction therapy in 982 (50.7%), rituximab in 505 (17.7%) and pulsed intravenous glucocorticoid use was highly variable (11%-91%). Overall mortality and incidence rates of end-stage kidney disease were 28.8 (95% CI 19.7 to 42.2) and 24.8 (95% CI 19.7 to 31.1) per 1000 patient-years, respectively. CONCLUSIONS: In the largest reported AAV cohort-study, we federated patient registries using semantic web technologies and highlighted concerns about data quality. The comparison of patient characteristics, treatment and outcomes was hampered by heterogeneous recruitment settings.

Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicentre retrospective case-control study.

OBJECTIVE: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV. METHODS: We performed a retrospective multicentre study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with four controls by gender and year of diagnosis. RESULTS: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in six (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%) and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in seven (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in four (11%). ATD were reintroduced in seven cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs 25%, P = 0.007), but less frequent kidney (38 vs 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95% CI 0.01, 0.65, P = 0.019). CONCLUSION: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 195 GCA patients.

OBJECTIVES: Giant cell arteritis (GCA) is one of the most common forms of vasculitis. There is an abundance of studies which are conducted in a randomised controlled trial setting but limited with respect to cohort size and follow-up time. GeVas is the first large-scale registry for vasculitides in German-speaking countries that enables to evaluate this rare disease. Herein we focus on the subgroup of GCA patients including follow-up data up to one year. METHODS: GeVas is a prospective, web-based, multicentre registry for the documentation of organ manifestations, outcomes, and therapy regimens in vasculitides. Recruitment started in June 2019. By April 2023, 15 centres were initiated and have started to enrol patients. RESULTS: After 4 years, 195 GCA-patients were included in the registry, of which 64% were female and 36% were male. The average age was 76 years at the time of recruitment (IQR=69-82). Seventy-nine percent were included in the registry because of a newly diagnosed GCA and 21% because of a relapse. At the first assessment most of the patients (89%) described general symptoms. Thirty-one percent stated ocular symptoms. Cranial symptoms were documented in 78% of the cases. All patients were documented with immunosuppressive treatment at start, of whom 95% received prednisolone, 16% cyclophosphamide, 20% methotrexate, and 48% tocilizumab. After three months 62% and after one year 91% of the patients achieved remission. CONCLUSIONS: Regarding demographics, clinical manifestations and diagnostics, our study showed a similar composition compared to other studies. However, our data differed in terms of treatment regimens.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 266 AAV patients.

OBJECTIVES: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry. METHODS: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. RESULTS: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry: 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%). CONCLUSIONS: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.

[Granulomatosis with polyangiitis and microscopic polyangiitis]. / Granulomatose mit Polyangiitis und mikroskopische Polyangiitis.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are two entities of ANCA-associated vasculitis (AAV). Both diseases are characterised by systemic necrotising small-vessel vasculitis, which can affect any organ. In GPA, extravascular necrotising granulomatous inflammation, usually affecting the respiratory tract, is found in addition. In the majority of cases, the clinical presentation is dominated by a pulmonary-renal syndrome with alveolar haemorrhage and rapidly progressive glomerulonephritis. Other organ involvement is found as well. In GPA, the upper respiratory tract is commonly affected. GPA is associated with anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase 3 (PR3-ANCA) and MPA with specificity for myeloperoxidase (MPO-ANCA). Immunosuppressive therapy depends on disease activity and the severity of organ involvement.

Spectrum of ANCA-specificities in eosinophilic granulomatosis with polyangiitis. A retrospective multicentre study.

OBJECTIVES: To determine the spectrum of anti-neutrophil cytoplasmic antibody (ANCA) antigen-specificities in eosinophilic granulomatosis with polyangiitis (EGPA), an ANCA-associated vasculitis (AAV) entity. METHODS: We conducted a retrospective analysis of 73 EGPA patients from three German tertiary referral centres for vasculitis. In addition to in-house ANCA testing, pentraxin 3 (PTX3)- and olfactomedin 4 (OLM4)-ANCA were determined using a prototype cell-based assay for research (EUROIMMUN, Lübeck, Germany). Patient characteristics and clinical manifestations were evaluated and compared based on ANCA status. RESULTS: Myeloperoxidase (MPO)-ANCA positive patients (n=8; 11%) significantly more frequently displayed peripheral nervous system (PNS) and pulmonary involvement and less frequently heart involvement compared to MPO-ANCA negative patients. PTX3-ANCA positive patients (n=5; 6.8%) had a significantly higher prevalence of ear, nose and throat, pulmonary, gastrointestinal and PNS involvement, and a lower prevalence of renal and central nervous system involvement compared to PTX3-ANCA negative patients. Proteinase 3 (PR3)-ANCA and OLM4-ANCA were detected in 2 patients (2.7%) each with multiorgan involvement. One PR3-ANCA positive patient was also positive for bactericidal permeability increasing protein (BPI)-ANCA. CONCLUSIONS: In addition to MPO, the spectrum of ANCA antigen specificities includes various other target antigens such as PR3, BPI, PTX3, and OLM4, potentially segregating further EGPA subgroups. A lower prevalence of MPO-ANCA was detected in this study compared with other studies. OLM4 is reported as novel ANCA antigen-specificity in EGPA, and thus AAV.

[Update on etiopathogenesis of small vessel vasculitis]. / Update Ätiopathogenese der Kleingefäßvaskulitis.

Small vessel vasculitis is characterized by a necrotizing inflammation of the vessel wall predominantly with involvement of small intraparenchymal arteries, arterioles, capillaries and venules. Medium-sized and occasionally large vessels can also be involved. Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis) are differentiated from immune complex vasculitides based on immunopathological and serological aspects. Immune complex vasculitides include IgA vasculitis, cryoglobulinemic vasculitis, hypocomplementemic urticarial vasculitis (anti-C1q vasculitis) and anti-glomerular basement membrane disease. Epidemiological and next-generation sequencing-based studies have significantly contributed to the identification of predisposing environmental factors and genetic risk factors in recent years. Under specific conditions ANCA and immune complexes can induce premature intravascular activation of neutrophilic granulocytes with degranulation and release of enzymes and reactive oxygen species, which leads to vascular damage. In granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis various factors, such as barrier dysfunction and dysbiosis of the microbiome contribute to extravascular granuloma formation predominantly affecting the respiratory tract.

[Granulomatous vasculitides and vasculitides with extravascular granulomatosis]. / Granulomatöse Vaskulitiden und Vaskulitiden mit extravaskulärer Granulomatose.

Vasculitides are inflammatory diseases of blood vessels caused by autoimmune or infectious processes, which are associated with alterations and destruction of the vascular wall. From a histopathological point of view, granulomatous vasculitides can be distinguished from necrotizing vasculitides with respect to the pattern of inflammation. Granulomatous vasculitides are characterized by intramural, predominantly lymphohistiocytic infiltrates with the formation of giant cells. They include giant cell arteritis (GCA) and Takayasu arteritis (TAK). By contrast, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) belongs to the group of necrotizing vasculitides. AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In addition to systemic necrotizing small vessel vasculitis, GPA and EGPA are characterized by extravascular granulomatous necrotizing inflammation mainly affecting the upper and/or lower respiratory tract, in EGPA with eosinophilic infiltrates. These granulomatous lesions are part of the autoimmune process and associated with tissue damage.

New insights into the epidemiology of ANCA-associated vasculitides in Germany: results from a claims data study.

OBJECTIVE: ANCA-associated vasculitides (AAV) are rare, potentially life-threatening autoimmune diseases characterized by systemic inflammation and organ damage. AAV prevalence rates reported in Europe vary considerably and robust data sources are often lacking. This study aimed to examine the feasibility of claims data analysis as a complementary method to registry-based studies to assess the epidemiology of AAV. METHODS: In this retrospective observational study, anonymized longitudinal claims data from years 2013-2016 from German statutory health insurance companies (data source: InGef, Institute for Applied Health Research) have been analysed on an age- and gender-stratified cohort of ∼3 million persons representative of the German population. In this cohort, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients were identified. RESULTS: The study cohort revealed a prevalence for GPA and MPA of 210 and 46 cases per million people, respectively. The annual incidence comprised 34 GPA cases and 13 MPA cases per million people per year. Hence, 17 500 AAV patients (GPA and MPA) are estimated to live in Germany, with an annual increase of 3200 patients. According to their demographic and disease-specific characteristics, AAV patients identified in this claims data approach are representative. CONCLUSION: This is the first study using claims data to assess the epidemiology of AAV. In Germany, AAV was diagnosed more frequently than it was estimated by previous self-reporting registry-based studies. The findings indicate that epidemiological data of AAV may have been underestimated but may also reflect improved diagnostic methods and disease recognition.

Granulomatous Inflammation in ANCA-Associated Vasculitis.

ANCA-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). While systemic vasculitis is a hallmark of all AAV, GPA is characterized by extravascular granulomatous inflammation, preferentially affecting the respiratory tract. The mechanisms underlying the emergence of neutrophilic microabscesses; the appearance of multinucleated giant cells; and subsequent granuloma formation, finally leading to scarred or destroyed tissue in GPA, are still incompletely understood. This review summarizes findings describing the presence and function of molecules and cells contributing to granulomatous inflammation in the respiratory tract and to renal inflammation observed in GPA. In addition, factors affecting or promoting the development of granulomatous inflammation such as microbial infections, the nasal microbiome, and the release of damage-associated molecular patterns (DAMP) are discussed. Further, on the basis of numerous results, we argue that, in situ, various ways of exposure linked with a high number of infiltrating proteinase 3 (PR3)- and myeloperoxidase (MPO)-expressing leukocytes lower the threshold for the presentation of an altered PR3 and possibly also of MPO, provoking the local development of ANCA autoimmune responses, aided by the formation of ectopic lymphoid structures. Although extravascular granulomatous inflammation is unique to GPA, similar molecular and cellular patterns can be found in both the respiratory tract and kidney tissue of GPA and MPA patients; for example, the antimicrobial peptide LL37, CD163+ macrophages, or regulatory T cells. Therefore, we postulate that granulomatous inflammation in GPA or PR3-AAV is intertwined with autoimmune and destructive mechanisms also seen at other sites.

Changes in the composition of the upper respiratory tract microbial community in granulomatosis with polyangiitis.

Dysbiosis¸ i.e. changes in microbial composition at a mucosal interface, is implicated in the pathogenesis of many chronic inflammatory and autoimmune diseases. To assess the composition of the microbial upper respiratory tract (URT) community in patients with granulomatosis with polyangiitis (GPA), we used culture-independent high-throughput methods. In this prospective clinical study, nasal swabs were collected from patients with GPA, patients with rheumatoid arthritis (RA, disease control), and healthy controls. Nasal bacterial taxa were assessed using V3-V4 region 16S rRNA amplicon sequencing. Staphylococcus aureus, Haemophilus influenza, and entero- and rhinoviruses were detected using qPCR. Unbiased metagenomic RNA sequencing (UMERS) was performed in a subset of samples to determine the relative abundance of bacterial, fungal, and viral species. A trend toward reduced microbiome diversity was detected in GPA samples compared with healthy controls. The abundance of bacterial taxa and microbial richness were significantly decreased in GPA samples compared with RA samples. The relative abundance of bacterial families shifted, with increased Planococcaceae and decreased Moraxellaceae, Tissierellaceae, Staphylococcaceae, and Propionibacteriaceae in GPA and RA. Further, decreased abundance of Corynebacteriaceae, and Aerococcaceae was observed in GPA samples. Significantly more colonization of S. aureus was seen in the nasal microbiome of GPA compared with RA and healthy control samples. H. influenzae colonization was also observed in GPA samples. UMERS detected the presence of rhinoviral sequences in some GPA samples. Thus, our study uncovered changes in the URT microbial composition in patients with GPA and RA, suggesting that both immunosuppression and disease background affect the URT microbiome. Complex alterations of host-microbiome interactions in the URT could influence chronic endonasal inflammation in GPA.

Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease.

OBJECTIVES: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. METHODS: In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. RESULTS: Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. CONCLUSIONS: Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. TRIAL REGISTRATION NUMBER: NCT02398435.

In situ detection of PR3-ANCA+ B cells and alterations in the variable region of immunoglobulin genes support a role of inflamed tissue in the emergence of auto-reactivity in granulomatosis with polyangiitis.

Circulating anti-neutrophilic cytoplasmic autoantibodies targeting proteinase 3 (PR3-ANCA) are a diagnostic and pathogenic hallmark of granulomatosis with polyangiitis (GPA). It is, however, incompletely understood if inflamed tissue supports presence or emergence of PR3-ANCA+ B cells. In search of such cells in inflamed tissue of GPA, immunofluorescence staining for IgG and a common PR3-ANCA idiotype (5/7 Id) was undertaken. Few 5/7 Id+/IgG+ B cells were detected in respiratory and kidney tissue of GPA. To gain more insight into surrogate markers possibly indicative of an anti-PR3-response, a meta-analysis comprising IGVH and IGVL genes derived from respiratory tract tissue of GPA (231 clones) was performed. Next generation sequencing-based IGHV genes derived from peripheral blood of healthy donors (244.353 clones) and previously published IGLV genes (148 clones) served as controls. Additionally, Ig genes of three murine and five known human monoclonal anti-PR3 antibodies were analyzed. Primary and probably secondary rearrangements led to altered VDJ usage and an extended complementarity determining region 3 (CDR3) of IGHV clones from GPA tissue. Selection against amino acid exchanges was prominent in the framework region of IGHV clones from GPA tissue. The comparison of V(D)J rearrangements and deduced amino acid sequences of the CDR3 yielded no identities and few similarities between clones derived from respiratory tissue of GPA and anti-PR3 antibodies, arguing against a presence of B cells that carry PR3-ANCA-prone Ig genes among the clones. In line with the scarcity of 5/7 Id+ B lymphocytes in GPA tissue, the results suggest that with respect to a local anti-PR3 response, methods detecting rare clones are required.

Circulating CD4+CD8+ double-positive T-cells display features of innate and adaptive immune function in granulomatosis with polyangiitis.

OBJECTIVES: To examine functional features of CD4+CD8+ double-positive T-cells in patients with granulomatosis with polyangiitis (GPA) using phenotypic and transcriptomic analysis. METHODS: Staining of cellular surface marker was performed using freshly collected whole blood. For intracellular cytokine staining freshly collected whole blood was stimulated with phorbol myristate acetate and ionomycin. Multicolor flow cytometric analysis was performed on a FACSCanto II cytometer using FACSDiva software. Lymphocytes were gated on CD3, CD4, and CD8 staining. FACS-sorted CD4+CD8+ double-positive T-cells of GPA-patients and HC (n=3 each) were subjected to transcriptional profiling using an Affymetrix Human Genome 2.0 microarray. Differently expressed genes were analysed using biological databases. RESULTS: Frequency of CD4+CD8+ double-positive T-cells was increased within the total CD3+ T-cell population in GPA, but no difference was detected between patients with active disease and remission. Percentages of interferon γ (Th1-type), interleukin 17 and interleukin 22 (Th17-type) producing CD4+CD8+ double-positive T-cells exceeded the percentage of interleukin 4 (Th2-type) producing cells. There were no significant differences in the percentages of the respective cytokine-positive CD4+CD8+ double-positive T-cells between GPA and HC. Up-regulated genes of CD4+CD8+ double-positive T-cells in GPA were enriched within Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to nuclear factor kappa-lightchain-enhancer of activated B cells signalling, toll-like receptor signalling, nucleotide-binding oligomerisation domain-like receptor signalling as well as major histocompatibility complex class-II antigen presentation. CONCLUSIONS: Employing a combined phenotypic and transcriptomic approach we disclosed a Th1/Th17 phenotype as well as innate and adaptive functions of CD4+CD8+ double-positive T-cells in GPA.

Nomenclature of cutaneous vasculitides - German translation of the dermatologic addendum to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.

The nomenclature system agreed upon by the Chapel Hill Consensus Conference (CHCC) with respect to the terminology and precise definition of the various types of vasculitis has gained widespread interdisciplinary and international acceptance. As the revised version from 2012 (CHCC 2012) does not address the special features of vasculitis of the skin, it has recently been supplemented with an addendum containing the nomenclature of cutaneous vasculitides (D-CHCC). The present article provides the German translation of the terms and defintions of the D-CHCC as well as additional explanatory comments. The goal is to enable German-speaking health care providers to more readily apply these defined terms - which are based on interdisciplinary consensus - in everyday clinical practice and to facilitate assessment of their practicability and relevance in patient care. If the majority of cutaneous vasculitides diagnosed can be matched with any of the defined entities presented herein, it might subsequently be possible to develop a classification system and diagnostic algorithms.

Environmental factor and inflammation-driven alteration of the total peripheral T-cell compartment in granulomatosis with polyangiitis.

Autoimmune diseases are initiated by a combination of predisposing genetic and environmental factors resulting in self-perpetuating chronic inflammation and tissue damage. Autoantibody production and an imbalance of effector and regulatory T-cells are hallmarks of autoimmune dysregulation. While expansion of circulating effector memory T-cells is linked to disease pathogenesis and progression, the causes driving alterations of the peripheral T-cell compartment have remained poorly understood so far. In granulomatosis with polyangiitis (GPA), a prototypical autoimmune disorder of unknown aetiology, we performed for the first time a combined approach using phenotyping, transcriptome and functional analyses of T-cell populations to evaluate triggers of memory T-cell expansion. In more detail, we found increased percentages of circulating CD4+CD28-, CD8+CD28- and CD4+CD161+ single-positive and CD4+CD8+ double-positive T-cells in GPA. Transcriptomic profiling of sorted T-cell populations showed major differences between GPA and healthy controls reflecting antigen- (bacteria, viruses, fungi) and cytokine-driven impact on T-cell populations in GPA. Concomitant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) - positivity was associated with a significant increase in the percentage of CD28- T-cells in GPA-patients compared to sole CMV- or EBV-positivity or CMV- and EBV-negativity. T-cells specific for other viruses (influenza A virus, metapneumovirus, respiratory syncytial virus) and the autoantigen proteinase 3 (PR3) were infrequently detected in GPA. Antigen-specific T-cells were not specifically enriched in any of the T-cell subsets. Altogether, on a genetic and cellular basis, here we show that alterations of the peripheral T-cell compartment are driven by inflammation and various environmental factors including concomitant CMV and EBV infection. Our study provides novel insights into mechanisms driving autoimmune disease and on potential therapeutic targets.