Can We Cure Vasculitis?

Abstract

As with all autoimmune diseases, anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis cannot be cured by a singular approach. This complexity arises because autoimmune conditions typically result from multiple hits to the immune system—including genetic predisposition, environmental exposures, infections, perturbations in adaptive and innate immunity. However, these multiple hits also offer opportunities to develop targeted, multi-pronged strategies aimed at achieving lasting remission or even cure. The field of ANCA vasculitis is unique because a subset of patients has successfully discontinued immunosuppression while maintaining remission. This challenges the long-standing belief and paradigm that autoimmunity necessitates lifelong immunosuppression therapy characterized by cycles of relapse and remission. These patients embody the potential for cure. By exploring theoretical pathways—such as early intervention to modulate innate immunity, restoring normal autoantigen production, enhancing immunoregulatory mechanisms, and eliminating autoreactive cells—we can begin to chart a detailed molecular and cellular roadmap. This approach aims to develop combination therapies that restore immune balance and ultimately transform the management of autoimmune vasculitis, moving toward the goal of durable remission and cure.

Introduction

A cure for anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is no longer a distant dream—it is achievable on the horizon of medical innovation. While the question of “when” remains open, decades of research have revealed key autoantigens targeted by ANCA, critical immune cells driving disease progression, and epigenetic factors fueling autoimmunity. This knowledge lays the foundation for transformative breakthroughs. A remarkable subset of patients—those in long-term remission off therapy (LTROT)—offer compelling proof that a cure is possible.[1] These individuals have maintained health for years, even decades, without ongoing treatment, demonstrating that the immune system can reestablish balance and self-tolerance. While the specter of relapse persists in these patients, their disease remission suggests that restoring immune health is possible. By studying these resilient patients, we are uncovering the immune mechanisms and regulatory pathways that can be harnessed to develop definitive cures—or at least provide the substrate for preventing a relapse of disease.

The future holds exciting and dynamic possibilities. Rapid advancements in immunology, genomics, and personalized medicine are propelling us beyond merely managing ANCA vasculitis toward achieving cures. Every breakthrough brings us closer to transforming countless lives—converting hope into tangible reality.

Understanding ANCA Vasculitis

ANCA vasculitis is a systemic, relapsing and remitting autoimmune disease that can be divided clinically and pathologically into four diagnoses: renal-limited disease, microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis.[2] Patients typically produce ANCA against either myeloperoxidase (MPO) or proteinase 3 (PR3) found in neutrophils and monocytes. In a model of “indirect” autoimmunity, ANCA do not target the affected organs directly, but rather target MPO or PR3 in neutrophils and monocytes, leading to cellular activation and degranulation with release of proteases and enzymes that damage the blood vessel endothelium. In small vessel vasculitis, the affected vessels are typically capillaries, small venules, and arterioles. There is great heterogeneity in the range of tissues and organs affected, but are typically those highly vascularized by small vessels (kidneys, lungs, upper respiratory, etc.).[3] ANCA vasculitis is the result of multiple factors, including genetic predisposition, immune disturbances, infections, and environmental exposures.[4] However, many of the putative immunopathogenic factors that may have initiated the disease are long gone by the time disease is diagnosed.

What is a cure?

Much debate surrounds the definition of “cure,” as disease eradication does not always equate to complete health; residual damage or sequelae can remain. However, our LTROT patients demonstrate a remarkable phenomenon: many have regained health comparable to their pre-disease state. This does not mean that all signs or symptoms have vanished, but these patients no longer require immunotherapy to maintain health and function—indicating an immunologic, and possibly epigenetic, remission. Biologically, this subgroup exemplifies the immune system’s capacity to re-establish immune tolerance and proper immunoregulation. Consequently, current research is shifting toward studying LTROT patients separately from those with active or relapsing disease, or those in remission but still on immunosuppressive therapy. A granular understanding of cellular and molecular distinctions within these patients are instrumental in developing a blueprint for curing ANCA vasculitis.

We have gained fascinating insights from LTROT patients. 1) Their regulatory T cells (Tregs) are often chronically exposed to autoantigens and express HLA-DR on their surfaces (unpublished data). This raises an interesting question: have these Tregs become primed to specifically downregulate autoreactive immune cells? 2) Antigen-presenting cells in LTROT no longer present key autoantigen peptides,[5] which could suggest shifts in immune behavior. 3) Autoreactive B cells are significantly reduced (unpublished data). 4) Autoantigen gene expression is generally lower when patients are in remission compared to active disease.[6,7]. 5) Stable remission correlates with increased DNA methylation at the PRTN3 promoter,[8] and persists in LTROT patients (unpublished data). These findings shed light on cellular, molecular, and epigenetic mechanisms that can guide more balanced and potentially curative therapies.

Prevention Strategies

“An ounce of prevention is worth a pound of cure.” Before restoring health in active disease, we must focus on prevention. Imagine pinpointing key factors that trigger loss of tolerance to MPO or PR3 in susceptible individuals, or identifying a unique genetic signature to screen and educate at-risk people. To this end, polygenic scores (PGS) have been developed to identify individuals at risk for a wide range of quantitative traits.[9] The PGS Catalog features 5,000 polygenic scores for 656 traits, including several autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome.[10,11] Unfortunately, ANCA vasculitis is not among them.

A secondary analysis of the PGS catalog suggests that while polygenic risk scores are promising, they often fall short for population screening, individual risk prediction, and population risk stratification.[12] This raises questions about the effectiveness of PGS for predicting ANCA vasculitis. Nevertheless, genome-wide association studies (GWAS) focused on ANCA vasculitis have provided valuable insights, and ongoing research keeps hope alive for future breakthroughs.

A GWAS of European patients highlighted genetic differences between MPO-ANCA or PR3-ANCA vasculitis.[13] Meanwhile, a GWAS involving North American patients took things a step further by pinpointing functional variants that encode MHC molecules and other select proteins linked to these conditions.[14] In fact, the latter study found that these variants accounted for a substantial 77% of the risk among patients.[14] It is not surprising that human leukocyte antigen (HLA) variants were the most significant variants linked to ANCA vasculitis, given their crucial role in many autoimmune diseases.[15] Since HLA is responsible for antigen presentation and downstream activation of the immune system to a specific antigen, it is logical that certain HLA alleles with select antigenic predilections would be associated with a particular disease. For instance, in cases of ANCA vasculitis, HLA-DPB1 has been associated with PR3-ANCA disease, while HLA-DQ1 is linked to MPO-ANCA disease.[13,14,16] An intriguing study that found that HLA-DRB1*15 alleles were significantly more common in African Americans with PR3-ANCA, with the DRB1*15:01 variant binding a PR3 peptide.[17] Beyond HLA, additional genetic variants have been associated with ANCA vasculitis. The most prominent non-HLA variants associated with GPA were at the SERPINA1 locus and linked to α₁-antitrypsin deficiency.[13,14,18] The gain-of-function R620W variant in PTPN22, which is correlated with autoimmunity, was more frequent in patients with granulomatosis with polyangiitis (GPA),[19] and the association with PR3-ANCA was confirmed by GWAS.[13,14] Two closely linked variants located upstream of the PRTN3 gene function as expression quantitative trait loci (eQTL) for PRTN3 and predict risk of relapse in patients with PR3-ANCA.[7] This connection between PRTN3 expression, disease susceptibility, and relapse highlights the importance of autoantigen regulation in disease pathogenesis.

The timing and triggers behind pathogenic autoantibody production present some of the most fascinating questions in the realm of autoimmune disease. If we could pinpoint when these autoantibodies first emerge and how they contribute to the onset of disease, we might be able to carve out new avenues for early intervention and prevention.

It is essential to understand that not all autoantibodies are created equal. Natural or asymptomatic autoantibodies are present in healthy individuals and serve a role in the body’s immunoregulatory network. Conversely, pathogenic autoantibodies interfere with normal physiologic functions and fuel disease processes.[20] This leads to a key question: What moves the needle from harmless natural autoantibodies to harmful pathogenic ones? Could it be molecular mimicry, epitope drift, or perhaps the exposure to previously hidden cryptic epitopes? Deciphering this transition holds the potential to open the door to enable early intervention and prevent disease before it takes hold.

Recent studies are starting to shed light on these critical timelines. One longitudinal investigation examined serum samples from soldiers, some of which were collected before they developed ANCA vasculitis.[21] Remarkably, anti-PR3 ANCA could be detected more than 1.5 years before the first symptoms appeared.[21] This finding underscores that significant immune alterations can happen years before clinical symptoms, suggesting a window for preventative strategies. Additionally, advanced epitope mapping through innovative mass spectrometry revealed that anti-MPO ANCA can target different epitopes based on disease activity—whether during active disease, in remission, or even in healthy individuals.[22]

These insights highlight the need to combine epitope-specific analyses with large biobanks, like the Department of Defense serum repository. Doing so could help unravel the mechanisms behind the emergence and evolution of autoantibodies. Ultimately, by understanding how natural autoantibodies morph into pathogenic agents, we could pave the way for early diagnostics and targeted interventions that might halt disease progression at its inception.

This genetic landscape is complemented by environmental factors that can predispose individuals to autoimmune disease,[23–25] such as silica and silica dust exposure,[26–29] certain infections (likely through mechanisms like molecular mimicry),[30,31] and medications. Additionally, certain medications are known to act as catalysts for disease onset.[32,33] We recently found that some patients treated with hydralazine develop autoantibodies against hydralazine-reacted antigens. A sequential process involving carbonylation of the target antigen creates hydrazone adducts on carbonyl groups, which unfolds the molecule and exposes new epitopes, ultimately driving autoimmune responses and disease development.[34] Other drugs with similar biochemical properties may operate through comparable, yet not fully understood, mechanisms. Given that many patients are prescribed medications like hydralazine and propylthiouracil—both linked to vasculitis—it raises an intriguing question: Do genetic predispositions influence susceptibility to these triggers? Identifying these genetic factors could enable personalized prevention strategies.

Imagine a future where, by understanding a patient’s genetic milieu, we can effectively mitigate environmental risks—such as silica dust exposure, particular infections, or specific medications—that might trigger diseases like ANCA vasculitis. This approach could completely change how we prevent these conditions, moving from waiting to treat after problems appear to proactively managing risk before symptoms develop. In such a scenario, people with high-risk genotypes or known environmental exposures could be routinely monitored for early signs, such as the presence of IgM and IgG ANCAs, helping catch the disease before it fully takes hold.

Early Targeting of Innate Immunity

Early silencing of the innate immune response is key to preventing glomerular and interstitial scarring. As highlighted in studies of rats and humans, quick action to calm the innate immune response can make a big difference.[35,36]

The innate system acts rapidly when defending against infections. [37–39] Central to this are the complement system and pattern recognition receptors,[40] including Toll-like receptors,[41] and NOD-like receptors[42] that detect conserved microbial structures and launch immune responses. Complement proteins promote opsonization, inflammation, and destroy pathogens by forming membrane attack complexes. Meanwhile, cells like neutrophils are among the first to respond, performing phagocytosis, releasing antimicrobial peptides, and forming neutrophil extracellular traps (NETs) to contain threats.[43] Collectively, these innate components act swiftly to contain infections, shape subsequent adaptive immunity, and determine the outcome of immune responses.

In the context of ANCA vasculitis, targeting these early immune responses may prevent the harmful cascade that leads to blood vessel damage. For example, when neutrophils are aberrantly activated by ANCA, they degranulate and produce reactive oxygens species that damage vessel walls.[44] Intervening early—by halting neutrophil activation or NET formation—could reduce autoantigen exposure that drives further autoantibody production. Moreover, blocking innate pathways such as TLR signaling might decrease cytokine release and inflammation, preventing the recruitment of further immune cells and tissue injury.

For individuals with genetic risks or early biomarkers suggesting imminent disease, early modulation of innate immunity could serve as a preventative strategy—potentially stopping vasculitis before it fully develops. Early targeting of innate immunity in ANCA vasculitis aims to intercept the disease process at its inception, reducing immune activation, autoantigen presentation, and tissue injury.[45] This approach could improve outcomes, decrease reliance on broad immunosuppression, and open avenues for preventive strategies.

Early targeting of the innate immune response holds the promise of transforming how we prevent and manage ANCA vasculitis, shifting the focus from treatment after damage occurs to intercepting the disease at its very start.

Reversing Autoantigen Dysregulation | Restoring Normal Antigen Production

ANCA vasculitis is a complex disease in which both the innate and adaptive arms of the immune system go awry. To truly cure it, we need to fix immune disturbances and restore tolerance. At the core, there is a failure to maintain immune tolerance against MPO and PR3, leading the body to initiate and perpetuate autoimmune responses resulting in vasculitis.

There are several theories about why and how these proteins become targets. Some suggest molecular mimicry—where infections produce proteins similar enough to MPO or PR3 to induce an immune response against these proteins that subsequently react to self antigens. Others point to changes in how these autoantigens are expressed or regulated.[46] Normally, in mature circulating neutrophils, the genes for MPO and PR3 are kept quiet—silenced through epigenetic mechanisms. But in patients with ANCA vasculitis, these genes are abnormally active, with higher levels of MPO and PRTN3 mRNA compared to healthy individuals.[47,48] This abnormal expression might be due to disrupted epigenetic silencing and neutrophil heterogeneity with higher frequency of low-density granulocytes.[6,8,49–51] Research in both mice and humans shows that higher autoantigen gene expression correlates with more severe disease and heightened neutrophil activation.[6] Interestingly, LTROT patients exhibit autoantigen gene expression and DNA methylation patterns that are closer to normal, hinting that restoring control over the level of gene expression could be a key to curing the disease (unpublished data).

What is the way forward? One promising idea is gene therapy—using engineered molecules to suppress either MPO or PRTN3 gene expression directly. This could eliminate the target for autoantibodies and reset the immune system. However, gene therapy remains technically challenging and expensive. Alternatively, we can focus on small molecules that specifically block the production of MPO and PR3. These would be easier and faster to implement. Another avenue involves targeting the epigenetic mechanisms that regulate these genes. Since epigenetic disruptions are documented in patients, correcting these could decrease autoantigen expression and tamp down the autoimmune response.[8,49].

On a different note, it is not just how much of these proteins is present that matters—how they look to the immune system could be just as important. Recent studies show that post-translational modifications (PTMs) of MPO differ between patients and healthy people, affecting how the immune system recognizes these proteins.[34,52] Blocking or masking such modifications could prevent the immune system from reacting to the autoantigens in the first place.

Reversing the aberrant gene expression or pattern of protein modifications would remove the antigenic target, restore neutrophil MPO and PRTN3 expression to a normal silent state, and functionally cure patients of the antigenic portion of autoimmunity.

Enhancement of Immunoregulatory Mechanisms: A Path Toward Restoring Balance

Understanding the need to rebuild immune regulation is critical, especially given the persistent evidence that Tregs in ANCA vasculitis do not function effectively.[54,55] Since Tregs are top players in maintaining peripheral tolerance, their ability to suppress unwarranted immune activation is vital in preventing full-blown autoimmune responses. Over the years, scientists have explored various ways to boost Treg numbers and functionality—not only in ANCA vasculitis but in conditions like type 1 diabetes, transplant rejection, and other autoimmune diseases—with mixed results.[56–58] [59]

The discovery in 2001 of FOXP3 as a defining marker and regulator of Tregs sparked a surge in efforts to harness these cells for restoring immune balance.[60–62] Recent technological advances, such as CyTOF, spectral flow cytometry, and single-cell RNA-sequencing, have shed light on the remarkable heterogeneity within Treg populations. Recognizing that different Treg subsets have distinct roles and varying capacities to suppress effector immune cells has been transformative.[63] Specifically, identifying how these subsets change across different autoimmune diseases, is key to tailoring targeted therapies that boost immunoregulation.

A fascinating development comes from detailed analyses comparing Treg subsets in healthy individuals, patients with active disease, those in remission on therapy, and LTROT patients. Using single-cell RNA (scRNA) sequencing of Tregs from these groups, we have found that a particular Treg subset is expanded uniquely in LTROT patients (unpublished data). This suggests that LTROT is not simply a return to “healthy” immunity, but rather a distinct state where the immune system has effectively reset and re-established immunoregulation. These biological signatures could become powerful biomarkers or therapeutic targets in the future.

While in vitro expansion of Tregs for autologous infusion is promising—allowing for precise manipulation through genetic editing or cytokine priming—it is inherently labor-intensive and time-consuming. Despite these challenges, this method offers the advantage of personalized adjustments to enhance Treg stability and function. Emerging strategies also aim to modify Treg activity directly within the patient’s body, using drugs, cytokines, or small molecules. For instance, cytokines such as IL-233 (which combines elements of IL-2 and IL-33) have shown potential to selectively expand functional Tregs.[64] Another interesting path is that of nanoparticles encapsulating key autoantigen peptides which expand antigen-specific Tregs.[65] These ideas represent just the beginning of promising therapeutic modalities designed to restore immune regulation in autoimmune disease.

At the pinnacle of research efforts toward curing autoimmune diseases is the concept of immunotherapy that re-educates the immune system to self-antigens. One strategy involves delivering autoantigens in a tolerogenic environment—using specialized dendritic cells to promote development of Tregs.[66] Successful examples from other fields include oral tolerance in children with peanut allergy, which has induced desensitization and remission,[67,68] and nasal peptide immunotherapy that prevented development and worsening of glomerulonephritis (GN) in a mouse model of autoimmune anti-MPO GN.[69] These findings inspire hope for similar approaches in humans, but several hurdles exist.

In ANCA vasculitis, the complexity increases because patients may present a diverse range of pathogenic epitopes, influenced by individual genetic backgrounds—particularly variations in HLA genes—that affect the nature of the peptides presented to T cells. This means that a “one-size-fits-all” peptide therapy might not be effective globally. Customizing antigen-specific immunotherapy that accounts for each patient’s unique genetic and immunological profile remains a major challenge but also an exciting frontier.

Restoring immune regulation through a combination of boosting key Treg subsets and reestablishing antigen-specific tolerance offers a promising pathway toward durable remission or even cure. By deciphering the nuanced characteristics of Tregs in different disease states and leveraging innovative delivery methods, we move closer to transforming autoimmune disease management from symptomatic suppression to fundamental immune re-education.

Selective Elimination of Autoreactive Cells

When all else fails and achieving LTROT is out of reach, resetting the adaptive immune system in ANCA vasculitis will likely require a dual approach: specifically targeting and removing the harmful antigen-specific T and B cells while also restoring immune regulation through functional Tregs. Advances in epitope-mapping for MPO and PR3 suggest that personalized, antigen-specific therapies may become a reality for patients in the future.

Drawing inspiration from cancer treatments, chimeric antigen receptor (CAR)-T cells have revolutionized our ability to target specific cell populations. Similarly, the development of chimeric autoantigen receptor (CAAR)-T cells in diseases like pemphigus vulgaris showcases what can be achieved when the autoantigen is well understood.[70] Bispecific T cell engagers (BiTEs), another oncology breakthrough, have been adapted into autoimmune contexts as bispecific autoantigen T cell engagers (BiAATEs), such as in membranous nephropathy.[71] Another innovative approach involves Siglec-engaging tolerance-inducing antigenic liposomes (STALs). These liposomes combine autoantigens with the inhibitory co-receptor CD22 to induce immune tolerance.[72]

Together, these scientific advances demonstrate that selectively eliminating autoreactive immune cells is not just a hope but an achievable goal. By removing these key initiators, we can halt disease progression while preserving the rest of the immune system’s functionality.

A Cure Is Within Reach

The future of autoimmune disease treatment demands nothing less than a bold, relentless pursuit of both prevention and cure. We must envision a world where autoimmune diseases are not just managed but eradicated—where we actively prevent their onset in susceptible individuals and completely eliminate them in those already afflicted. Autoimmune diseases, like ANCA vasculitis, are complex biological puzzles—akin to a lock that requires multiple tumblers to align perfectly. There is no master key, no silver bullet; instead, success depends on a comprehensive, multifaceted strategy that addresses every stage of disease development.

Preventing autoimmune disease must be approached with both urgency and precision. This involves rigorous genetic screening to identify associated risk variants so that we can identify vulnerable individuals before symptoms emerge. Prospective monitoring of low level ANCAs and their targeted epitopes will serve as early warning systems, allowing for preemptive interventions. Documenting environmental and infectious exposures is also crucial, as these can act as triggers that set the cascade in motion. The vision is clear: leverage these insights to develop a dynamic risk score, empowering clinicians to stratify individuals by their susceptibility and intervene proactively.

Prevention alone is not enough. Achieving a cure requires a revolutionary approach that combines targeted immunotherapies to reset tolerance, precision strategies that block disease pathways at their root, and innovative technologies to restore immune balance. We must rally every scientific, clinical, and technological resource to accelerate progress. Incremental steps are no longer sufficient; we stand at the brink of a new era where autoimmune diseases are not just controlled but completely eliminated.

Our mission is unwavering: to pursue this goal with relentless innovation, determination, and a commitment to transforming the landscape of autoimmune disease treatment. Together, we can move from management to eradication, making a cure the reality for all who suffer.

Figure Legend:

Infographic depicting the hurdles necessary to achieve a cure, or restoration of health, in ANCA vasculitis. Prevention of disease could be attained with screening for risk alleles, knowledge of environmental and infectious triggers, and monitoring of early immune system aberrancies. Upon disease onset, quick targeting of the innate immune system with complement or NET inhibitors could blunt organ damage. Restoration of antigen tolerance rests on the ability to restore normal antigen expression, normal protein modifications, and antigen desensitization. Lastly, bolstering immunoregulation through means of restoring optimal Treg function and selective elimination of autoreactive cells with targeted therapies would modulate the adaptive immune system. Overall, a multi-pronged approach is necessary to cure autoimmune disease.