Abstract
Background
Autoantibodies against IFN-α (anti–IFN-α) have been reported in recombinase activating gene (RAG) deficiency, attributed to impaired central and peripheral T-cell/B-cell tolerance. However, the clinical features, especially viral infections, associated with these autoantibodies at baseline, their kinetics over time, and their response to hematopoietic cell transplantation are not well defined.
Objective
We described the clinical and immunologic findings linked to anti–IFN-α IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation.
Methods
We measured anti–IFN-α IgG by enzyme-linked immunosorbent assay in 80 RAG-deficient patients with curated clinical and immunologic data from a multinational collaboration.
Results
Forty-eight patients (60.0%) had positive anti–IFN-α at baseline; these patients were typically older at time of testing, fulfilled the phenotype of delayed-onset combined immunodeficiency with granuloma and/or autoimmunity (70.8% vs 31.3%, P = .001), and had a history of more frequent viral infections, mainly from the Herpesviridae family (62.5% vs 21.9%, P < .001). These patients also showed higher levels of serum immunoglobulins and expanded populations of peripheral blood autoreactive-prone (CD19hiCD21lo) (14.3 vs 5.2%, P = .016) and double-negative (IgD−CD27−) B cells (12.8 vs 5.8%, P = .001). In cases with longitudinal evaluation, anti–IFN-α titers were largely stable, although an increase was observed with concurrent active cytomegalovirus infections. Despite some decline after transplantation, these autoantibodies persisted during follow-up.
Conclusions
Anti–IFN-α autoantibodies reflect immune dysregulation in partial RAG deficiency. Their production is likely aggravated by environmental factors, especially frequent viral infections. Further studies are needed to define their pathogenic role in RAG deficiency.
Key words: RAG deficiency, anti–IFN-α autoantibodies, viral infection
Introduction
The recombination-activating genes (RAG1/2) encode lymphoid lineage-specific proteins that are critical for T and B cells to acquire their diverse antigen recognition repertoire through the V(D)J recombination process.1 Biallelic RAG1/2 deficiency in humans has been linked to a broad spectrum of clinical and immunologic phenotypes, influenced by varying residual enzymatic activity of RAG mutants and different environmental factors.1, 2, 3 Autoantibodies against IFN-α (anti–IFN-α) have been reported in patients with partial RAG deficiency due to the disruption of central and peripheral T-/B-cell tolerance,4, 5, 6, 7 as well as in certain genetic defects (eg, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy [APECED],8 inborn errors of the alternative nuclear factor kappa B [NF-κB] pathway9) and thymoma.10 Anti–IFN-α autoantibodies represent a pathognomonic feature of immune dysregulation in these disorders and are linked to increased susceptibility to severe viral illness.9,11,12 However, the clinical and immunologic features in RAG-deficient patients associated with anti–IFN-α at baseline, their kinetics throughout the disease course, and their response to hematopoietic cell transplantation (HCT) remain elusive.
Results and discussion
We measured plasma anti–IFN-α IgG autoantibodies by an enzyme-linked immunosorbent assay in 80 patients with a broad phenotypic spectrum of RAG1/2 deficiency, including severe combined immunodeficiency (n = 6), Omenn syndrome (n = 5), leaky severe combined immunodeficiency (n = 24), idiopathic CD4+ lymphocytopenia (n = 1), and delayed-onset combined immunodeficiency with granulomas and/or autoimmunity (CID-G/AI, n = 44), collected through a multinational collaboration (Fig 1, A). All baseline samples were obtained before HCT. Details on patient enrollment, phenotype definition, and evaluation of plasma anti–IFN-α autoantibodies are provided in the Online Repository available at www.jaci-global.org.
Fig 1.
Cohort characteristics. (A) Distribution of different clinical and immunologic phenotypes. (B) Frequency of positive anti–IFN-α IgG based on age of testing. (C) Comparison of clinical features in RAG-deficient patients with and without anti–IFN-α IgG. (D) Correlation matrix between key clinical/laboratory findings and positive anti–IFN-α IgG. Pearson r values are shown in each box, with cell borders indicating statistically significant correlations (P < .05).
Patient characteristics are listed in Table I. Those who tested positive for anti–IFN-α IgG (n = 48, 60.0%) were older at the time of testing (median, 8.5 vs 2.0 years, P = .008) and more often fulfilled the CID-G/AI phenotype (70.8% vs 31.3%, P = .001) (Fig 1, B-D). They were less likely to be clinically asymptomatic at the time of testing (6.3% vs 31.3%, P = .005) and experienced more frequent viral infections requiring medical evaluation and/or intervention (70.8% vs 34.4%, P = .001), mainly caused by Herpesviridae viruses (62.5% vs 21.9%, P < .001), with a notable difference in varicella-zoster virus infections (25.0% vs 0.0%, P = .001). Additionally, they had more bacterial infections (83.3% vs 43.8%, P < .001) and clinical autoimmunity (72.9% vs 40.6%, P = .004), especially autoimmune cytopenia (41.7% vs 18.8%, P = .032) (Fig 1, C). In terms of laboratory findings, their median levels of serum immunoglobulins were higher (IgG before replacement, 790 vs 482 mg/dL, P = .014; IgA, 50 vs 9 mg/dL, P = .010; IgM, 89 vs 13 mg/dL, P = .002) (Fig 2, A-C). They also had higher peripheral blood absolute B-cell counts (median, 106 vs 16 cells/μL, P = .013), with fewer cases classified as B lymphopenic based on corresponding age-appropriate ranges (69.8% vs 92.0%, P = .038). An expansion of both peripheral blood autoreactive-prone B cells (CD19hiCD21lo; median, 14.3 vs 5.2%, P = .016) and double-negative B cells (IgD−CD27−; 12.8% vs 5.8%, P = .001) was seen in these patients (Fig 2, D and E). In a multivariate logistic regression analysis, age at anti–IFN-α IgG testing, prereplacement serum IgG levels, and history of Herpesviridae virus–related infections were identified as independent factors associated with the presence of anti–IFN-α IgG autoantibodies (Table II).
Table I.
Characteristics of RAG-deficient patients with and without anti–IFN-α IgG
| Characteristic | All (N = 80) | Anti–IFN-α IgG |
||
|---|---|---|---|---|
| Positive (n = 48) | Negative (n = 32) | P value | ||
| Age (years) | ||||
| Age at clinical diagnosis | 3.0 (0.6-9.0) (n = 58) | 4.0 (1.5-10.0) (n = 35) | 1.3 (0.1-9.0) (n = 23) | .108 |
| Age at molecular diagnosis | 7.5 (2.0-19.0) (n = 63) | 7.9 (2.5-20.0) (n = 41) | 5.5 (0.3-18.0) (n = 22) | .293 |
| Age at anti–IFN-α testing | 7.0 (1.5-18.8) | 8.5 (3.6-21.5) | 2.0 (0.3-15.0) | .008 |
| Age at anti–IFN-α testing <1 year old | 16 (20.0) | 2 (4.2) | 14 (43.8) | < .001 |
| Time between clinical diagnosis and anti–IFN-α testing (years) | 2.0 (0.2-7.6) (n = 58) | 2.0 (1.1-8.0) (n = 35) | 1.0 (0.1-7.0) (n = 23) | .283 |
| Male sex | 32 (40.0) | 22 (45.8) | 10 (31.3) | .192 |
| Clinical phenotype of CID-G/AI | 44 (55.0) | 34 (70.8) | 10 (31.3) | .001 |
| RAG1 genotype | 59 (73.8) | 39 (81.3) | 20 (62.5) | .062 |
| RAG1 recombinant activity (% WT) (per allele) | 25.8 (2.7-41.6) (n = 101) | 25.8 (2.7-41.6) (n = 63) | 24.9 (1.8-41.6) (n = 38) | .709 |
| RAG2 genotype | 21 (26.3) | 9 (18.8) | 12 (37.5) | .062 |
| RAG2 recombinant activity (% WT) (per allele) | 30.8 (11.6-66.3) (n = 29) | 55.2 (19.6-66.3) (n = 15) | 26.5 (6.9-66.3) (n = 14) | .492 |
| CD3+ T cells (cells/μL) | 526 (303-926) (n = 67) | 529 (341-1133) (n = 42) | 453 (158-878) (n = 25) | .400 |
| CD4+ T cells (cells/μL) | 212 (118-364) (n = 65) | 221 (133-374) (n = 41) | 208 (88-361) (n = 24) | .568 |
| CD4+ naive T cells (%) | 8.6 (3.2-16.2) (n = 50) | 9.4 (3.6-16.0) (n = 32) | 5.5 (2.6-21.5) (n = 18) | .693 |
| CD8+ T cells (cells/μL) | 171 (60-394) (n = 65) | 187 (91-399) (n = 41) | 139 (50-373) (n = 24) | .578 |
| CD19+ B cells (cells/μL) | 86 (12-271) (n = 68) | 106 (30-300) (n = 43) | 16 (1-222) (n = 25) | .013 |
| B lymphopenia using age-appropriate range | 53 (77.9) (n = 68) | 30 (69.8) (n = 43) | 23 (92.0) (n = 25) | .038 |
| NK (cells/μL) | 279 (130-521) (n = 62) | 283 (152-516) (n = 38) | 244 (104-522) (n = 24) | .664 |
| Serum IgG (mg/dL) (before IgRT) | 720 (400-1039) (n = 50) | 790 (466-1203) (n = 33) | 482 (196-862) (n = 17) | .014 |
| Serum IgA (mg/dL) | 26 (6-98) (n = 55) | 50 (7-106) (n = 35) | 9 (5-22) (n = 20) | .010 |
| Serum IgM (mg/dL) | 65 (16-114) (n = 55) | 89 (31-128) (n = 35) | 13 (5-64) (n = 20) | .002 |
| Clinically asymptomatic when tested | 13 (16.3) | 3 (6.3) | 10 (31.3) | .005 |
| History of viral infections requiring medical evaluation/intervention | 45 (56.3) | 34 (70.8) | 11 (34.4) | .001 |
| History of infections caused by Herpesviridae viruses∗ | 37 (46.3) | 30 (62.5) | 7 (21.9) | < .001 |
| History of infections caused by CMV | 16 (20.0) | 13 (27.1) | 3 (9.4) | .085 |
| History of infections caused by EBV | 8 (10.0) | 5 (10.4) | 3 (9.4) | 1.000 |
| History of infections caused by HSV-1/2 and HHV-6 | 7 (8.8) | 5 (10.4) | 2 (6.3) | .696 |
| History of infections caused by VZV | 12 (15.0) | 12 (25.0) | 0 (0.0) | .001 |
| History of vaccine-related varicella infection | 5 (6.3) | 5 (10.4) | 0 (0.0) | .080 |
| History of bacterial infections | 54 (67.5) | 40 (83.3) | 14 (43.8) | < .001 |
| History of fungal infections | 18 (22.5) | 9 (18.8) | 9 (28.1) | .325 |
| History of clinical autoimmunity | 48 (60.0) | 35 (72.9) | 13 (40.6) | .004 |
| History of autoimmune cytopenia | 26 (32.5) | 20 (41.7) | 6 (18.8) | .032 |
| History of organ autoimmunity: skin | 21 (26.3) | 13 (27.1) | 8 (25.0) | .836 |
| History of organ autoimmunity: GI/liver | 10 (12.5) | 7 (14.6) | 3 (9.4) | .732 |
| History of biopsy-proven granuloma | 16 (20.0) | 10 (20.8) | 6 (18.8) | .820 |
| IgRT | 53 (66.3) | 30 (62.5) | 23 (71.9) | .385 |
| Prior corticosteroids and/or immunomodulatory therapies | 27 (33.8) | 20 (41.7) | 7 (21.9) | .067 |
| Prior rituximab | 11 (13.8) | 7 (14.6) | 4 (12.5) | 1.000 |
| HCT | 42 (52.5) | 23 (47.9) | 19 (59.4) | .315 |
| Mortality | 18 (22.5) | 9 (18.8) | 9 (28.1) | .325 |
Data are presented as medians (IQRs) or nos. (%) unless otherwise indicated. EBV, Epstein-Barr virus; GI, gastrointestinal; HHV, human herpesvirus; HSV, herpes simplex virus; IgRT, immunoglobulin replacement therapy; NK, natural killer; VZV, varicella-zoster virus; WT, wild type.
Some patients had history of infections caused by more than one Herpesviridae virus, as detailed in breakdown list.
Fig 2.
Immunologic findings in RAG-deficient patients with and without anti–IFN-α IgG. (A) Serum IgG levels before IgRT. (B) Serum IgA levels. (C) Serum IgM levels. (D) Percentages of autoreactive-prone B cells (CD19hiCD21lo). (E) Percentages of double-negative B cells (IgD−CD27−). IgRT, Immunoglobulin replacement therapy.
Table II.
Logistic regression analysis of factors associated with positive baseline anti–IFN-α IgG
| Characteristic | Univariate analysis |
Multivariate analysis |
||
|---|---|---|---|---|
| OR (95% CI) | P | OR (95% CI) | P | |
| Age of anti–IFN-α testing <1 year old | 0.056 (0.012-0.271) | <.001 | 0.042 (0.006-0.292) | .001 |
| Clinical phenotype of CID-G/AI | 5.343 (2.020-14.132) | .001 | ||
| Serum IgG < 400 mg/dL (before IgRT) | 0.155 (0.038-0.638) | .010 | 0.065 (0.011-0.376) | .002 |
| History of infections caused by Herpesviridae viruses | 5.952 (2.143-16.535) | .001 | 4.731 (1.258-17.787) | .021 |
| History of bacterial infections | 6.429 (2.292-18.034) | <.001 | ||
| History of clinical autoimmunity | 3.935 (1.521-10.177) | .005 | ||
CI, Confidence interval; IgRT, immunoglobulin replacement therapy; OR, odds ratio.
A similar prevalence of patients with and without anti–IFN-α IgG received immunoglobulin replacement therapy at the time of testing (62.5% vs 71.9%, P = .385). Our prior study also demonstrated that immunoglobulin products did not contain elevated levels of autoantibodies.5 Otherwise, there was no significant difference in prior treatment with systemic corticosteroids and/or immunomodulatory agents (41.7% vs 21.9%, P = .067), including rituximab (14.6% vs 12.5%, P = 1.000). During follow-up, a comparable percentage of patients from both groups underwent HCT (47.9% vs 59.4%, P = .315), with no significant difference in long-term outcomes (mortality, 18.8% vs 28.1%, P = .325).
Ten patients with positive anti–IFN-α IgG at baseline had serial measurements (median [interquartile range (IQR)], 4 [4-11]) over their disease course (median [IQR] time of follow-up, 24.2 [10.1-48.6] months), including 4 who subsequently underwent HCT. Among the 6 patients who did not undergo HCT, anti–IFN-α IgG titers remained relatively stable (Fig 3, A). Of the 4 patients who underwent HCT (see the Online Repository), 3 showed some decline in anti–IFN-α IgG titers after HCT, but autoantibodies in all 4 remained highly positive at their last visits (median [IQR] time of follow-up after HCT, 9.4 [8.6-10.2] months) (Fig 3, B). Notably, one RAG1-deficient patient was breast-fed by her cytomegalovirus (CMV)-seropositive mother shortly after birth and had anti–IFN-α IgG first detected at 3 months of age, although both CMV IgG and IgM were negative at that time. At 10 months old, she showed an increase in anti–IFN-α IgG titers during an episode of acute CMV infection, as evidenced by viremia and subsequent CMV seroconversion. Of note, her brother, with whom she lived, also had an acute CMV infection at the same time. After the clearance of acute CMV viremia, her anti–IFN-α IgG titers declined, with an additional decrease after HCT. However, these autoantibodies remained positive after HCT; she was found to have low-grade CMV viremia during her post-HCT follow-up (Fig 3, C).
Fig 3.
Longitudinal titers of anti–IFN-α IgG in RAG-deficient patients. (A) No HCT during follow-up (n = 6). (B) HCT during follow-up (n = 4). Age when HCT was performed for each patient is indicated in parentheses (years old [yo]). (C) Correlation between anti–IFN-α IgG titers and acute CMV infection in RAG1-deficient patient. Age when indicated event happened is shown in parentheses. Ranges of anti–IFN-α IgG titers considered normal are shaded in gray.
Anti–IFN-α autoantibodies have emerged as an important factor linked to virus susceptibility and may also modify disease activity in autoimmune diseases.11,13 The critical role of disrupted thymic selection in the development of these autoantibodies is highlighted by their increased prevalence in certain genetic disorders (eg, RAG deficiency,5 APECED,8 and inborn errors of the alternative NF-κB pathway9) and thymoma.10 Environmental triggers likely act as a second hit, as suggested by the observation in both APECED14 and RAG deficiency (Fig 1, B), where these autoantibodies are typically absent at birth but develop later in life. A similar observation was also made in individuals without inborn errors of immunity that anti–IFN-α autoantibodies were acquired as they aged and persisted thereafter.15 Acute viral infection, which triggers a large amount of endogenous type I interferons, can potentially stimulate or amplify this process.5,15,16 Moreover, the inflammatory milieu in viral infection and autoimmunity leads to an expansion of atypical autoantibody-secreting B cells.4,17,18 Whether these autoantibodies can develop transiently in response to acute viral infections and modulate the immune response in otherwise healthy young adults requires further investigation.
Our observation of more frequent viral infections, primarily comprising viruses from the Herpesviridae family, along with the increase of anti–IFN-α IgG titers during acute viremia in a patient, suggest that viral infection could serve as the potential second hit, triggering autoantibody production. This is supported by the significant rise in endogenous IFN-α during such infections and the fact that human interferons can be immunogenic,15,19 which our RAG-positive patients may be particularly vulnerable to, given the disrupted T-cell/B-cell tolerance. We acknowledge that the retrospective nature of our study cannot confirm a causal link between viral infection and autoantibody production; these autoantibodies may have existed before our first measurement, predisposing these patients to more viral infections. However, the detection of anti–IFN-α IgG at 3 months of age in one patient is the earliest reported example in RAG deficiency, which may be related to her exposure to CMV through breast milk. We did observe subsequent changes in anti–IFN-α IgG titers in response to acute CMV infection and treatment. Further studies with longitudinal sampling in more cases starting from early infancy are needed to track the development of anti–IFN-α IgG in RAG deficiency, as we did not identify any cases with anti–IFN-α seroconversion in our cohort. Notably, such events have been demonstrated in individuals without inborn errors of immunity, albeit at a much older age.15 Importantly, our findings of expanded populations of autoreactive-prone and double-negative B cells in patients with anti–IFN-α IgG imply that these B cells could be a potential source of autoantibody production.6,20 Our longitudinal results also showed the relative stability of such autoantibodies without HCT. It is noteworthy that the titers of these autoantibodies remained high after HCT, implying an underlying long-lived autoantibody-secreting cell population,21 although the number of transplanted cases and duration of follow-up are both limited in the current study. Regarding other circulating tissue–related IgG autoantibodies, although their levels declined significantly after HCT in Rag-deficient mice,22 the picture in humans remains less clear. While most clinical autoimmunity tends to improve after HCT, certain autoantibodies may persist.23 Additional studies are required to expand these observations by evaluating more patients after HCT with longer follow-up durations to better understand the kinetics of these autoantibodies, as well as their potential relationship with post-HCT disease risks. Last, the presence of biopsy-proven granuloma in our patients is not linked to anti–IFN-α IgG, which may suggest different pathogenic processes in these two findings.3
In conclusion, anti–IFN-α autoantibodies are surrogates of immune dysregulation in partial RAG deficiency, with their production likely aggravated by environmental triggers, particularly recurrent or chronic viral infections, in the setting of diminished self-tolerance. Further studies are required to better evaluate the mechanisms underlying their production and to solve the pathogenic conundrum of these pathognomonic autoantibodies in RAG deficiency.
Clinical implication.
Anti–IFN-α autoantibodies, which are present in two thirds of patients with partial RAG deficiency, are associated with more frequent viral infections, particularly those caused by members of the Herpesviridae family, and serve as a marker of immune dysregulation.
Disclosure statement
L.D.N. is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH, grant ZIA AI001222). J.E.W. is supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health 5K08AI103035, sub-R01AI100887-05 and R01AI153830-05, Robert A. Good Endowment at University of South Florida, and Jeffrey Modell Foundation. L.I.G.-G. is supported by the Instituto de Salud Carlos III (ISCIII) through project FIS-PI21/01642, cofunded by the European Union. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Research laboratory studies were performed on deidentified samples under institutional review board–approved protocols at the University of South Florida (USF-Pro00035468, USF-Pro00025693), and Johns Hopkins Medical Institute/Johns Hopkins All Children’s Hospital (JHMI-IRB00175372).
Disclosure of potential conflict of interest: J. E. Walter reports receiving grant, research, and/or clinical trial support from Takeda, Janssen, Chiesi, MustangBio, ADMA Biologicals, and Octapharma; serving on consultant and/or advisory boards for Takeda, X4-Pharmaceuticals, CSL-Behring, Grifols, ADMA Biologicals, Enzyvant, and Regeneron; and serving on the speakers’ bureau for Takeda. The rest of the authors declare that they have no relevant conflicts of interest.
Footnotes
The first 2 authors contributed equally to this article, and both should be considered first author. The last 2 authors contributed equally to this article, and both should be considered senior author.
Preliminary data from this study were presented in abstract form at the 21st biennial meeting of the European Society for Immunodeficiencies, Marseille, France, October 17, 2024.
Contributor Information
Luigi D. Notarangelo, Email: luigi.notarangelo2@nih.gov.
Jolan E. Walter, Email: jolanwalter@usf.edu.
Supplementary data
References
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