---
title: "IRF5 Risk Variants in SLE Presenting as aHUS: Case Report and Clinical Course"
id: "frontiers-in-immunology-12-case-report-a-young-female-with-co-morbid-sle-and-atypical-hemolytic-uremic"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-12-case-report-a-young-female-with-co-morbid-sle-and-atypical-hemolytic-uremic"
content_type: "clinical_feed_article"
specialty: "Nephrology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1966450"
published_at: "2026-10-14T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# IRF5 Risk Variants in SLE Presenting as aHUS: Case Report and Clinical Course
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-12-case-report-a-young-female-with-co-morbid-sle-and-atypical-hemolytic-uremic
- **Specialty:** [Nephrology](https://medichelpline.com/clinical-feed/nephrology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1966450)
- **Published At:** 2026-10-14T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- A 21-year-old female developed concurrent **SLE** and **aHUS** after a diarrheal illness; presentation included oliguria, hypertension, edema, anemia, profound thrombocytopenia, and acute kidney injury progressing to ESRD. - Laboratory evidence at admission showed severely elevated creatinine, marked hemolysis (LDH 897 U/L), platelets 8 ×10^9/L, low C3/C4, and plasma **sC5b-9** >1580 ng/mL, indicating terminal complement activation. - Whole-exome sequencing found no pathogenic variants in canonical complement genes (CFH, CFI, C3, CFB, CD46, THBD, DGKE). Investigators reported two heterozygous **IRF5** variants: rs2004640 (c.-12+198G>T) and rs201487893 (c.179A>G, p.Asp60Gly). - The rs2004640 intronic variant is a recognized susceptibility allele for SLE linked to increased type I interferon signaling; rs201487893 was classified as uncertain with in silico predicted toxicity but no functional data reported. - Treatment included high-dose methylprednisolone, oral prednisone taper, hydroxychloroquine, and weekly **eculizumab**; hematologic remission occurred rapidly while renal function failed to recover, resulting in initiation of maintenance hemodialysis for ESRD. - The authors hypothesize (unproven) a two-hit sequence: IRF5-driven interferon-high susceptibility followed by an environmental trigger (diarrhea/viral infection) leading to amplified complement activation and clinical aHUS. - The case supports using plasma **sC5b-9** to confirm terminal complement activation when genetic testing is negative and justifies complement inhibition for acute TMA in SLE. - Limitations noted by the authors: single-patient observation, lack of functional validation of IRF5 variants, missing ADAMTS13 measurement during earlier thrombocytopenia episode, absent fundoscopy, and no routine long-term sC5b-9 monitoring after discharge.
## Clinical Analysis & Structured Key Points
Frontiers | Case Report: A young female with co-morbid SLE and atypical hemolytic uremic syndrome carrying IRF5 risk variants T) in the IRF5, who presented with concurrent manifestations of SLE and aHUS following diarrhea. The uniqueness of this case lies in the fact that comprehensive whole-exome sequencing revealed no known pathogenic mutations in complement genes (such as CFH, CFI, C3, etc.), yet identified two heterozygous variants in IRF5, a core gene of the interferon pathway (the c.-12 + 198G>T risk variant and the c.179A>G missense variant). Following targeted therapy centered on eculizumab, the patient achieved hematologic remission, but the kidney disease progressed to end-stage renal disease (ESRD), and maintenance hemodialysis was initiated. This case suggests that the genetic susceptibility underlying aHUS occurring in the context of SLE may extend beyond the classical complement pathway, and that excessive activation of the interferon pathway may be a key factor in triggering a complement activation ‘storm’ that manifests as aHUS. This observation suggests a possible link between IRF5-related interferon signaling and complement-mediated TMA, and highlights the need for further functional studies. It also emphasizes the importance of early recognition of aHUS and initiation of complement-inhibiting therapy in cases of SLE complicated by TMA."> CASE REPORT article Front. Immunol. , 14 October 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1966450 Published in Frontiers in Immunology Autoimmune Disorders 7 impact factor 11.3 citescore Part of a Research Topic Lupus unraveled: from biological insights to therapeutic innovations Submission open 9733 views 6 articles Editor & Reviewers Edited by E M Eric Morand Reviewed by Y M Yoshinori Matsumoto G K Ghalia KHELLAF Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Biological and immunological analysis at admission for acute renal injury. View in article Table 2 Risk variants explicitly associated with SLE. View in article CASE REPORT article Front. Immunol. , 14 October 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1966450 Case Report: A young female with co-morbid SLE and atypical hemolytic uremic syndrome carrying IRF5 risk variants H Z Huili Zhou W L Wei Liu T S Tingting Sun L Z Li Zhang W S Weixia Sun W W Wanning Wang * Nephrology Department of the First Hospital of Jilin University, Changchun, Jilin, China Article metrics View details Abstract Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy and primarily caused by abnormalities in the regulation of the alternative complement pathway, with triggers including infection, pregnancy, surgery and autoimmune disorders like systemic lupus erythematosus (SLE). This paper presents a case of a 21-year-old female carrying a SLE susceptibility variant (c.-12 + 198G>T) in the IRF5 , who presented with concurrent manifestations of SLE and aHUS following diarrhea. The uniqueness of this case lies in the fact that comprehensive whole-exome sequencing revealed no known pathogenic mutations in complement genes (such as CFH, CFI, C3 , etc.), yet identified two heterozygous variants in IRF5 , a core gene of the interferon pathway (the c.-12 + 198G>T risk variant and the c.179A>G missense variant). Following targeted therapy centered on eculizumab, the patient achieved hematologic remission, but the kidney disease progressed to end-stage renal disease (ESRD), and maintenance hemodialysis was initiated. This case suggests that the genetic susceptibility underlying aHUS occurring in the context of SLE may extend beyond the classical complement pathway, and that excessive activation of the interferon pathway may be a key factor in triggering a complement activation ‘storm’ that manifests as aHUS. This observation suggests a possible link between IRF5-related interferon signaling and complement-mediated TMA, and highlights the need for further functional studies. It also emphasizes the importance of early recognition of aHUS and initiation of complement-inhibiting therapy in cases of SLE complicated by TMA. Introduction Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) caused by abnormalities in the regulation of the alternative complement pathway; pathogenic variants in complement regulatory genes such as CFH , CFB , CFI and C3 can be detected in approximately 50–60% of patients ( 1 , 2 ). However, in cases of aHUS that occur in the context of autoimmune diseases, particularly systemic lupus erythematosus(SLE), the genetic basis often differs from that of classic hereditary aHUS: patients typically do not carry single-gene mutations in complement genes, but rather carry genetic variants associated with susceptibility to autoimmune diseases, which indirectly lead to complement system dysfunction through immune dysregulation when triggered by specific environmental factors ( 3 , 4 ). IRF5 (interferon regulatory factor 5) is one of the most important susceptibility genes for SLE; the intronic single nucleotide polymorphism (SNP) rs2004640 (c.-12 + 198G>T) has been shown by genome-wide association studies (GWAS) to be significantly associated with the risk of developing SLE, a mechanism involving the excessive activation of the type I interferon pathway ( 5 ). However, there are currently no published reports indicating whether IRF5 risk variants are associated with the occurrence of aHUS in patients with SLE. Here we report a severe female patient with SLE complicated by aHUS, and genetic testing identified a risk variant in the IRF5 gene. Taking the genetic test results as our starting point, we retrace the progression of her clinical symptoms, explore how a genetic predisposition to SLE may have provided a ‘fertile ground’ for the development of aHUS, and analyze the implications of this finding for clinical diagnosis and management. Case presentation A 21-year-old unmarried female was admitted due to oliguria, generalized edema for more than two weeks after diarrhea. Two weeks prior to admission, the patient developed diarrhea (5–10 times per day) for 4 days after ingestion of unclean food, followed by oliguria (minimum urine volume 90 Immunological analysis C3 (g/L) 0.3 0.7-1.4 C4 (g/L) 0.03 0.1-0.4 Anti-dsDNA (IIF) 1:10 positive 1580 75-219 Others LDH (U/L) 897 120-250 Shiga toxin-producing Escherichia coli – – Biological and immunological analysis at admission for acute renal injury. PTA, Prothrombin Activity; ADAMTS 13 , A disintegrin and metalloprotease with thrombospondin Type 1 motifs, 13 member; LDH , Lactate dehydrogenase. Given that antiphospholipid syndrome (APS) and catastrophic antiphospholipid syndrome (CAPS) are important differential diagnoses in patients with SLE-associated thrombotic microangiopathy, antiphospholipid antibody testing was performed. Lupus anticoagulant, anticardiolipin antibodies (IgG/IgM), and anti-β2 glycoprotein I antibodies (IgG/IgM) were negative. No clinical evidence of thrombosis or pregnancy morbidity fulfilling APS classification criteria was identified. Hematological pathology analysis: Blood smear classification: Increased proportion of segmented granulocytes, accounting for 84%; one erythroblast was observed per 100 nucleated cells; mature red blood cells varied in size; spherocytes accounted for 2%; fragmented red blood cells accounted for 3% (uneven distribution); platelets were scattered; a small cluster of platelets was visible at the end of the smear. She underwent whole-exome sequencing (including the mitochondrial genome, totaling 22,223 genes). The interpretation of the test results is divided into three levels ( Table 2 ): The risk variants explicitly associated with SLE are summarized in Table 2 . Table 2 Gene Chromosomal location Variant information SNP ID Homozygous/heterozygous Pathogenic classification Clinical significance IRF5 chr7:128578301 c.-12 + 198G>T(Intron region) rs2004640 het Risk variation Susceptibility to SLE: OR = 1.47 (heterozygous), OR = 2.01 (homozygous) IRF5 chr7:128582314 c.179A>G(p.Asp60Gly) rs201487893 het Uncertain (REVEL=0.906) Bioinformatics predicts toxicity; pathogenicity to be determined Risk variants explicitly associated with SLE. The IRF5 c.-12 + 198G>T (rs2004640) variant is the most significant genetic finding in this case. This variant is located within intron 1 of the IRF5 , creating a novel splice donor site that leads to the production of multiple IRF5 transcripts and increased IRF5 protein expression, which has been associated with increased type I interferon pathway activity in SLE ( 5 ). Analysis results for classic aHUS complement pathway genes To elucidate the genetic background of aHUS, we performed whole-exome sequencing on the patient and focused our analysis on known aHUS-associated genes, including CFH , CD46 (MCP) , CFI , C3 , CFB , THBD and DGKE . The results showed that no pathogenic or likely pathogenic variants were identified in these classic complement pathway-related genes. This negative result strongly suggests that the patient’s aHUS is not caused by a traditional hereditary complement gene defect, but is more likely secondary to an immunodysregulatory state triggered by their active SLE. Among the ‘other reportable variants’ identified in whole-exome sequencing, two heterozygous variants of uncertain significance (c.3575G>A and c.1930G>T) were detected in the NPHP4 , and heterozygous variants of uncertain significance were also found in ATP6V0A4 , DZIP1L and GFRA1. These genes are associated with renal tubular development or ciliopathies, and none have been linked to complement-mediated TMA or aHUS. The two IRF5 variants (rs2004640 and rs201487893) were the only variants identified in immune-regulatory genes. rs2004640 is a well-established SLE risk variant, whereas rs201487893 is a variant of uncertain significance with predicted toxicity but no functional data. Thus, no pathogenic variant in a known aHUS-causing gene was identified. The IRF5 risk variant remains the most plausible susceptibility factor for the autoimmune background, although it is not a direct aHUS-causing gene. We hypothesize the following two-hit sequence, although it remains unproven: Initial onset (genetic susceptibility phase): The patient carries the IRF5 rs2004640 risk variant, which may create a genetic context of increased type I interferon pathway responsiveness, potentially increasing susceptibility to autoimmune diseases. The thrombocytopenia that emerged ‘without any apparent cause’ two years ago may represent an initial manifestation of preclinical SLE. Second trigger (environmental trigger phase): In the two weeks prior to admission, the patient experienced diarrhea and an active EBV infection … Viral infection, as a classic environmental trigger, activates the Toll-like receptor (TLR) signaling pathway. In the context of the IRF5 risk variant, this may further amplify the type I interferon response, potentially contributing to the progression of SLE from a ‘subclinical state’ to a ‘phase of fulminant activity’. Treatment response and outcome: Following the initial intravenous methylprednisolone pulse therapy, the patient was transitioned to oral prednisone at an initial dose of 50 mg/day, which was tapered by 5 mg every two weeks based on clinical response. Hydroxychloroquine 0.2 g daily was continued for long-term SLE control. Eculizumab was administered weekly ( Figure 1 ). The clinical course and treatment response are shown in Figure 1 . After the first dose, platelet counts rose rapidly and LDH levels returned to normal within one week, plasma sC5b-9, which was >1580 ng/mL (normal range 75–219 ng/mL) at admission, normalized after two weeks of eculizumab therapy. These finding confirmed terminal complement blockade. However, renal function did not recover, and the patient progressed to end-stage renal disease (ESRD). Regular maintenance hemodialysis was initiated. No severe infectious complications occurred during concomitant immunosuppressive and eculizumab therapy. Routine long-term monitoring of sC5b-9 after discharge was not performed, which represents a limitation of this case. Figure 1 Treatment outcomes in the patient. Platelet count and LDH trends are shown from admission to follow-up. Key clinical events are annotated below the x-axis: diarrhea onset (Day -14), first hospital visit (Day -5), admission (Day 0), SLE diagnosis and pulse steroids (Day +3), eculizumab initiation (Day +7), hematologic remission (Day +14), ESRD (Week +6), and hemodialysis initiation (Week +8). Plasma sC5b-9 normalized after two weeks of eculizumab”. Discussion Patients with SLE are prone to concurrent TMA due to immune abnormalities, complement activation, and organ damage ( 6 ). A Chinese study showed that among 148 patients with SLE, 36 were confirmed to have TMA by renal biopsy, most presenting with isolated renal TMA (29 cases), while only 2 cases developed TTP-HUS ( 4 ). The principal novelty of this case is the identification of IRF5 susceptibility variants in a patient with SLE-associated complement-mediated thrombotic microangiopathy (C-TMA) presenting with an aHUS phenotype, in the absence of complement gene mutations. Common IRF5 risk haplotypes are well-established susceptibility factors for SLE and may alter IRF5 splicing and expression, with some risk haplotypes being associated with increased circulating interferon-α activity ( 7 – 9 ). However, IRF5 is not currently recognized as an aHUS-associated gene. Observations from a single patient cannot establish a genetic predisposition specific to the coexistence of SLE and aHUS. Therefore, we propose a hypothesis-not a proven mechanism-that IRF5 susceptibility variants may have contributed to an interferon-high inflammatory background that increased vulnerability to complement-mediated endothelial injury, rather than directly causing aHUS. We propose a hypothetical model in which the IRF5 risk variant may lead to increased IRF5 expression and type I interferon signaling, potentially creating an immune-inflammatory milieu in SLE and priming the alternative complement pathway ( Figure 2 ). This proposed sequence is speculative and has not been functionally validated in this patient. Figure 2 Hypothesized mechanistic model: IRF5 risk variant may contribute to atypical hemolytic uremic syndrome (aHUS) in systemic lupus erythematosus (SLE) via type I interferon-mediated priming of the alternative complement pathway. This model is speculative and has not been functionally validated in this patient. We fully acknowledge that there is currently no evidence supporting the use of type I interferon-targeted therapies (e.g., anifrolumab) in aHUS. In our patient, the acute TMA was driven by terminal complement activation, as evidenced by markedly elevated sC5b-9, which provided the rationale for eculizumab. The IRF5/IFN pathway, if involved, likely acts upstream as a disease modifier in SLE rather than as a direct therapeutic target for acute aHUS. Therefore, complement inhibition remains the appropriate treatment for the acute TMA episode, while SLE-directed immunosuppression addresses the underlying autoimmune background. Given the absence of complement gene mutations, the patient’s aHUS is likely acquired and secondary to active SLE. In the absence of genetic ‘positive evidence’ of aHUS, plasma sC5b9 measurement serves as a critical bridge in diagnosis. In this case, significantly elevated sC5b9 levels (more than 6.5 times the upper limit of normal) directly confirmed terminal complement activation, thereby providing strong biological justification for the use of eculizumab. The patient’s rapid response to eculizumab (platelet count recovery on the day following treatment and normalization of LDH levels within one week) further confirms that, even in the absence of complement gene mutations, C5 inhibitors remain effective provided that activation of the terminal complement pathway is confirmed. This is consistent with a systematic review of 30 patients with SLE-associated TMA, in which 93% experienced a favorable outcome, although the available evidence is derived predominantly from case reports and small uncontrolled series and is susceptible to selection and publication bias ( 10 , 11 ). From a therapeutic perspective, adequate SLE control may reduce the risk of aHUS recurrence, potentially allowing earlier tapering or discontinuation of eculizumab ( 12 – 14 ). In our patient, SLE-directed maintenance therapy with oral prednisone, hydroxychloroquine, and regular hemodialysis was continued alongside weekly eculizumab. This combined approach was well tolerated, with no severe infectious complications, and may have contributed to the sustained hematologic remission. Conclusions This case raises the hypothesis that IRF5 risk variants, through type I interferon pathway activation, may provide a molecular susceptibility background for the coexistence of SLE and aHUS. This hypothesis requires functional validation in future studies. The
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