Clinical spectrum and therapeutic options in monogenic CTLA-4, LRBA, or SOCS1-related primary immune regulatory disorders

Abstract

Primary immune regulatory disorders (PIRDs) are defined by a loss of immune homeostasis and are clinically characterized by autoimmunity, autoinflammation, lymphoproliferation, infection susceptibility, and cancer predisposition. An increasing number of genetic defects have been described that result in impaired regulation of immune responses. Evolving clinical manifestations and variable disease spectrum lead to significant diagnostic challenges and treatment conundrum. In this review, we present three clinical vignettes of PIRDs, including CTLA-4 haploinsufficiency, LRBA deficiency, and SOCS1 deficiency, to illustrate step-by-step approaches to diagnostic evaluation, disease assessment, and therapeutic management. We describe tailored treatment strategies, including immunomodulatory agents and hematopoietic stem cell transplantation, that address each patient’s clinical manifestations, treatment response, and adverse effects. We also explain the clinical decision-making process, incorporating immunologic insights from the specific underlying genetic defects, relevant literature, and pearls from our clinical experience. Through these cases, we aim to offer a practical framework for clinicians managing patients with PIRDs.

Introduction

Primary immune regulatory disorders (PIRD) represent an expanding but heterogeneous subset of inborn errors of immunity (IEI)(1). Clinical presentations include recurrent infections, early-onset autoimmunity, lymphoproliferation, and autoinflammation with end organ disease. Disease penetrance and expressivity are often variable, presumably depending on the underlying genetic factors and environmental exposures. The increased availability of genetic testing and specialized functional assays have facilitated diagnosis and patient care, leading to recognition of broader phenotypes and offering new insights into the critical pathways that govern human immune tolerance. In addition, the growing armamentarium of therapeutic options, including small molecule inhibitors and biologics, provide targeted treatment options and personalized interventions for PIRD patients. However, the optimal integration of underlying immune defects, individual patient comorbidities, and the risk of potential adverse effects continues to challenge clinicians in all practice settings.

In this review, we present three clinical vignettes of PIRD with distinct underlying genetic etiologies. All patients were enrolled in an Institutional Review Board-approved natural history study protocol (NCT00001355) at the National Institutes of Health Clinical Research Center and provided informed consent. Each case demonstrates a dynamic and progressive disease course, punctuated by a series of carefully considered therapeutic interventions, illustrating the diagnosis, management, and longitudinal care in this patient population. We focus on PIRDs characterized by lymphoproliferation and autoimmunity, with particular emphasis on disorders involving prominent T regulatory (Treg) cell dysfunction. Other PIRDs and management explicitly with Jakinibs will be discussed more extensively in other review articles within this themed issue.

CTLA-4 haploinsufficiency

P1 is a 30-year-old white male with a childhood history of recurrent pneumonia and cutaneous viral infections, including molluscum contagiosum and herpes zoster. Family history was noncontributory. He was initially diagnosed with common variable immunodeficiency (CVID) at 18 years of age based on a limited evaluation showing pan-hypogammaglobulinemia and started immunoglobulin (Ig) replacement therapy. One year later, he developed symptomatic anemia requiring transfusion. Bone marrow biopsy showed significant hypocellularity with T cell aggregates, consistent with aplastic anemia (Figure 1A–D). He did not respond to monotherapy with either eltrombopag or cyclosporine. Following treatment with a combination of eltrombopag, horse antithymocyte globulin, and cyclosporine, he achieved a complete hematologic response. While tapering cyclosporine, he developed abdominal pain with diarrhea; stool gastrointestinal pathogen panel was positive for norovirus. Endoscopy revealed unremarkable upper tract (esophagus, stomach, and duodenum) but patchy atrophic mucosa in the colon and ulcerated mucosa in the rectum. Histologic evaluation showed chronic active duodenitis and colitis with increased intraepithelial CD8⁺ T lymphocytes (Figure 1E–G).

Figure 1. Histopathologic findings and biomarker trends of P1 with CTLA-4 haploinsufficiency.

(A-D) Bone marrow core biopsy (100×) showed markedly hypocellular marrow with trilineage hypoplasia (A). CD79a demonstrated the paucity of B-lineage cells (B). Multiple atypical T-cell aggregates with increased interstitial T-lymphocytes were highlighted by CD4 and CD8 staining. (E-G) Duodenal biopsy revealed significantly increased intraepithelial lymphocytes, predominantly CD8⁺ T cells (scale bar 100 μm). (H) Trends of soluble CD25 and CXCL9 in response to treatment.

This patient presented with a constellation of hypogammaglobulinemia and autoimmunity characterized by prominent end organ lymphocytic infiltration. Although his diagnosis could fall under the umbrella of CVID, the relatively early disease onset and severe multi-organ immune dysregulation warrant further investigation for PIRD(1). Beyond the standard humoral and cellular immune workup (e.g., serum immunoglobulin levels, vaccine response, and lymphocyte immunophenotyping), genetic testing has revolutionized the evaluation of PIRD, including CVID-like PIRD(2). Clinically available genetic testing for IEI includes targeted gene panels and whole exome/genome sequencing; although the latter may offer certain advantages, such as broader gene coverage, a streamlined diagnostic workflow, and potential for novel disease discovery(3), targeted panels remain more accessible in routine practice with lower cost and shorter turnaround times. Tregopathies, due to defective Treg cell number and/or function, are particularly high on the differential diagnosis for this patient, supporting the decision to pursue genetic testing(4). Identification of relevant genetic variants can guide the selection of appropriate confirmatory functional studies and guide therapeutic decision making(5).

Immunologic workup showed low IgA and IgM levels, with adequate IgG on replacement. Peripheral blood flow cytometry demonstrated lymphopenia affecting both T and B lineages. Serum soluble CD25 level was significantly elevated. Whole exome sequencing identified a heterozygous, pathogenic variant in CTLA4 (c.1A>G, p.Met1?), resulting in loss of the start codon, which was confirmed by Sanger sequencing. Parents were not available for genetic testing.

CTLA-4 is a critical immune checkpoint receptor that is constitutively expressed on Treg cells. It restricts T cell activation by outcompeting the costimulatory receptor CD28 for binding to CD80/86 on the antigen presenting cells. Once captured by CTLA-4, these ligands are eliminated by a process called transendocytosis(6). In 2014, causative heterozygous loss-of-function variants in the CTLA4 gene, including a start loss variant similar to P1 (c.2T>C, p.Met1?)(7), were identified in patients manifesting with hypogammaglobulinemia, lymphoproliferation, and multisystem autoimmunity. Thus, CTLA-4 haploinsufficiency was identified as a novel PIRD and its key role in maintaining immune tolerance was reinforced(7,8). Notably, this disorder has incomplete clinical penetrance(9); therefore, it would not be unexpected if one parent carries the same pathogenic variant yet remains clinically asymptomatic.

Gold-standard functional studies using an in vitro transendocytosis assay demonstrated impaired CD80 uptake of the start loss variant(6,9), consistent with a loss-of-function effect. At this time, the transendocytosis assay is only available on a research basis. Other assays include Treg cell enumeration, which is frequently, but not uniformly low, as well as assessment of Treg CD25, FOXP3 and CTLA-4 expression, which is typically diminished in affected patients with CTLA-4 haploinsufficiency. Soluble CD25 (i.e., interleukin-2 receptor alpha chain) measurement, is a commercially available assay that is used as a marker of T cell activation. In patients with diminished CTLA-4 expression and function with significant immune activation, it emerges as a useful tool in longitudinal follow-up.

In the setting of persistent, uncontrolled diarrhea, computed tomography revealed colonic wall thickening, and gastrointestinal pathogen panel testing was persistently positive for norovirus. He was started on oral sirolimus, targeting a trough level of 10–15 ng/mL, to manage his active colitis with some improvement in diarrhea. Monitoring of his lipid panels showed onset of mild hypertriglyceridemia which was managed with dietary modifications. However, he subsequently developed painful cystic acne-like skin eruptions despite topical therapies, as well as persistent hypertension, which ultimately led to sirolimus discontinuation. He was transitioned to enteral budesonide for his enteropathy.

Sirolimus inhibits the mechanistic target of rapamycin kinase (mTOR), preferentially suppressing the proliferation of effector T cells while allowing the expansion of Treg cells(10). Beyond its approved indications (e.g., kidney transplantation rejection prophylaxis), clinical improvement from off-label sirolimus therapy has been reported in patients with CTLA-4 haploinsufficiency and related Tregopathies, such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome and LRBA deficiency(9,11). Routine therapeutic drug monitoring is recommended for all patients to guide dose adjustment, typically targeting a trough level between 5–15 ng/mL for autoimmune indications(12). Higher troughs are targeted in cases of more active disease, as in P1. Notably, sirolimus is associated with a number of potential adverse effects that require close monitoring(13). In addition to well recognized hematologic (e.g., cytopenias), metabolic (e.g., hyperlipidemia and impaired glucose metabolism), and renal toxicities (e.g., acute kidney injury, proteinuria, and thrombotic microangiopathy), it is also linked to mucocutaneous adverse events(14), such as acneiform lesions observed in P1. In addition, painful mouth ulcers (i.e., stomatitis) happen frequently and may be managed with topical corticosteroids and/or anesthetics, but severe cases may necessitate dose reduction or discontinuation(15,16). Notably, a history of chronic or recurrent viral infections, including norovirus, molluscum contagiosum, and herpes zoster, is not a contraindication to initiating sirolimus therapy. In this case, viral infections did not worsen or reactivate while on therapeutic doses of sirolimus. Furthermore, sirolimus-associated stomatitis is not virally mediated; however, herpes simplex should be ruled out in patients presenting with severe oral ulcerations.

Autoantibody screening at 22 years of age found elevated anti-glutamic acid decarboxylase 65 (GAD65) antibodies without clinical diabetes mellitus. Two years later, routine laboratory monitoring identified hyperglycemia and glucosuria, prompting budesonide discontinuation due to concerns for systemic absorption. Further studies, including fasting glucose, glycated hemoglobin, and an oral glucose tolerance test, confirmed the diagnosis of diabetes mellitus; reduced C-peptide levels and positive anti-GAD65 autoantibodies supported an autoimmune etiology (i.e., type 1 diabetes [T1D]). He was started on insulin therapy for glycemic control. In addition, his colitis remained active with persistent norovirus infection; therefore, abatacept was initiated (intravenous, 500 mg, monthly).

T1D is among the most common autoimmune endocrinopathies in CTLA-4 haploinsufficiency and may present either as the initial manifestation or develop later in the disease course(9). In retrospect, budesonide is unlikely to have contributed to his diabetes, given its minimal systemic bioavailability due to high first-pass hepatic metabolism(17). Abatacept, a soluble fusion protein composed of the extracellular domain of CTLA-4 and the Fc region of human IgG1(18), has been shown to preserve some pancreatic β-cell function in individuals with non-monogenic T1D(19,20). Furthermore, abatacept is considered a targeted immunomodulatory therapy in CTLA-4 haploinsufficiency, although it may not fully replace the function of endogenous, membrane-bound CTLA-4(21). Whether abatacept can prevent or delay the onset of T1D in CTLA-4 deficient patients remains unknown.

Baseline safety laboratories prior to initiating immunomodulatory or immunosuppressive therapy, including abatacept, in patients with IEI, should include testing for active or latent infections, such as tuberculosis by interferon-γ release assay, and hepatitis B and C viruses, Epstein-Barr virus (EBV), cytomegalovirus, JC virus, and BK virus by polymerase chain reaction-based assays. Most patients with CTLA-4 haploinsufficiency, who were started on standard abatacept dosing extrapolated from rheumatoid arthritis studies (i.e., intravenous ~ 10 mg/kg/month, or subcutaneous 125 mg/week)(22) had some clinical response. However, these physician-assessed responses vary depending on the affected organs and there is currently no established organ-specific response criteria for CTLA-4 haploinsufficiency(23). As of 2025, abatacept remains FDA-approved for the treatment of rheumatoid arthritis, psoriatic arthritis, severe COVID-19, and prophylaxis of acute graft-versus-host disease (GVHD). Thus, abatacept’s use for most manifestations of Tregopathies remains off-label. Abatacept also failed to show clinical benefits in patients with moderate-to-severe inflammatory bowel disease in several placebo-controlled studies(24). However, a clinical trial investigating abatacept for granulomatous-lymphocytic interstitial lung disease (GLILD) under the umbrella of CVID is currently ongoing (NCT04925375).

Because the patient’s enteropathy was not adequately controlled on standard dose abatacept, supplemental subcutaneous abatacept (125 mg/week) was added to intravenous therapy, with modest clinical improvement. Laboratory investigation revealed persistently elevated levels of soluble CD25 as well as CXC motif chemokine ligand 9 (CXCL9). Oral ruxolitinib was added (10 mg twice daily), and up titrated (15 mg twice daily). Acyclovir prophylaxis was also started given his history of herpes zoster infection. His diarrhea resolved, and both soluble CD25 and CXCL9 levels showed improvement despite persistent norovirus positivity in stool (Figure 1H).

In selected patients with CTLA-4 haploinsufficiency, a higher-than-standard dose of abatacept may be necessary to adequately control immune dysregulation(25–28). Increased dosing requirement in these patients may reflect faster medication consumption driven by heightened immune activation. In our experience, patients with active enteropathy often require higher doses, suggesting possible medication loss through an inflamed gastrointestinal barrier, as has been implied in inflammatory bowel diseases(29); this warrants further study. In clinical practice, abatacept dosing can be guided by serial measurement of soluble CD25 levels(30) and organ-specific symptoms, such as diarrhea in this patient. In this case, despite abatacept dose-escalation, disease remained not well uncontrolled, and addition of a second immunomodulatory agent was clinically indicated.

Treatment-refractory enteropathy is a common and often multifactorial complication of CTLA-4 haploinsufficiency, likely driven by a combination of dysbiosis at the mucosal barrier interface, dysregulated immune responses, and superimposed chronic infection, such as norovirus in this case(31,32). Increased infiltration of intraepithelial CD8⁺ T cell is a well-recognized histopathologic feature of CVID enteropathy, including cases with underlying monogenic defects, such as CTLA-4 haploinsufficiency(33). Emerging evidence has implicated excessive interferon-γ signaling in CTLA-4 checkpoint inhibitor-induced colitis(31,34) and CVID enteropathy(33,35). Importantly, CXCL9, an interferon-γ-inducible chemokine is commercially available as a clinical biomarker for T cell activation and interferon-γ signaling(36). Given the elevation of blood CXCL9 levels in this patient, a potent oral Janus kinase (JAK) 1/2 inhibitor was chosen as an add-on therapy. Unfortunately, the lack of standardized organ-specific response criteria in CTLA-4 haploinsufficiency hampers direct comparisons of different treatment regimens (Table 1). Therefore, serial monitoring of selected biomarkers, such as soluble CD25 and CXCL9 in this patient may provide practical, objective therapeutic guidance(35,37). Furthermore, class-wide and drug-specific adverse reactions of JAK inhibitors, including infections, cytopenia, and thrombosis, warrant close surveillance(38).

Table 1.

Off-label targeted biologics and small molecules in CTLA-4, LRBA, or SOCS1 defect-related PIRDs

Treatments	Off-label indications in PIRDs related to CTLA-4, LRBA, or SOCS1 defects					Potentially useful biomarkers (frequency3)	Notable adverse effects4	Important safety labs (frequency)5
	GLILD	CNS	LP	Cytopenia	Enteropathy
Soluble CTLA-4-Ig: abatacept	√	√	√	√	√	Soluble CD25 (every 1–3 months)	Minimal infectious risk, except for potential worsening of viremia and related complications in patients with preexisting uncontrolled EBV infection*	EBV and possibly CMV viral load
mTOR inhibitor: sirolimus, everolimus	√	√	√	√	√	Trough (5–7 days after starting therapy or change in dose; every 3 months once stable), VEGFD (?)	Oral ulcers, acneiform skin eruptions, hypertension, dyslipidemia, kidney injury, hypokalemia, proteinuria	CBC, lipid panel, kidney function, electrolytes, urinalysis
Anti-CD20 MAb: rituximab	√1	×2	√	√	×	B cell counts (every 6–12 months)	Hypogammaglob ulinemia*, infusion reaction, HBV reactivation, PML	Ig, HBV viral load and LFT in those with prior infections* (up to monthly depending on risk category and whether on antiviral prophylaxis), JC viral load
JAK inhibitors: e.g., ruxolitinib, upadacitinib	√	?	?	?	√	CXCL9 (every 1–3 months)	Infections (especially herpes virus*), cytopenia, thrombosis, malignancy	CMV/EBV/JC/B K viral load, CBC, LFT, CPK
Anti-IL-12 and/or IL-23 MAb: e.g., ustekinumab, risankizumab	×	×	×	×	√	Fecal calprotectin (?)	Localized candidal or other fungal infections	NA

Abbreviations: PIRD, primary immune regulatory disorder; GLILD, granulomatous-lymphocytic interstitial lung disease; CNS, central nerve system; LP, lymphoproliferation, such as lymphadenopathy; NA, not applicable; VEGF, vascular endothelial growth factor; CBC, complete blood count; MAb, monoclonal antibody; HBV, hepatitis B virus; PML, progressive multifocal leukoencephalopathy; Ig, immunoglobulins; LFT, liver function test; CXCL9, CXC motif chemokine ligand 9; CMV, cytomegalovirus; EBV, Epstein-Barr virus; JC, John Cunningham; CPK, creatine phosphokinase; IL, interleukin.

Explanation of symbols: √, known clinical benefits; ?, unclear/uncertain clinical benefits due to limited data; ×, not recommended, due to either a low likelihood to be effective based on mechanism of action or negative prior experience.

^1.For GLILD therapy, rituximab is typically used in combination with antimetabolites (e.g., mycophenolate mofetil).

^2.Acutely symptomatic patients with CTLA-4 haploinsufficiency typically respond to high-dose intravenous corticosteroids. Rituximab alone may lead to accumulation of plasma cells in the CNS lesions despite depletion of peripheral blood B cells.

^3.Monitoring frequencies are recommended for biomarkers with established clinical utility. In certain cases with rapidly changing clinical conditions, more frequent monitoring may be warranted.

^4.The frequencies of treatment-related adverse events may not be markedly different from those observed in other common indications (e.g., abatacept use in rheumatoid arthritis), except for those labeled with an asterisk (*), for which the underlying disease may confer intrinsic susceptibility to these complications.

^5.In addition to the full set of baseline safety labs described in the main text, these labs should be monitored regularly while on treatment. They can be obtained at the same intervals as the biomarkers, except for those labeled with an asterisk (*), for which additional information is provided.

Chronic norovirus infection persisted throughout the course of enteropathy management. Although histopathologic findings such as villous atrophy and intraepithelial lymphocytosis are non-specific, and may result from either IEI-related enteropathy or chronic norovirus infection, colitis is not typically seen with chronic norovirus infection alone and is attributable to the underlying PIRD(39,40). Nonetheless, chronic norovirus infection may exacerbate the interferon response within the intestinal tissue(33). Currently, no therapy has demonstrated consistent efficacy in the treatment of chronic norovirus infection(41). Optimization of the underlying immune dysregulation remains the cornerstone of enteropathy complicated by chronic norovirus infection, although adoptive transfer of virus-specific T cells or definitive therapy with hematopoietic stem cell transplantation (HSCT) may have a role in selected patients(42).

LRBA deficiency

P2 is a 24-year-old white female who was first diagnosed with polyarticular juvenile idiopathic arthritis at the age of 2 years and was treated with etanercept. She subsequently developed fever and splenomegaly concerning for macrophage activation syndrome, requiring a prolonged course of systemic corticosteroids. Between the ages of 4 and 8 years, she experienced refractory autoimmune cytopenias (anemia and thrombocytopenia), unresponsive to multiple therapies, including high-dose corticosteroids, intravenous Ig, and rituximab, ultimately leading to splenectomy. Her cytopenias resolved only after initiation of sirolimus therapy.

At 14 years of age, she developed abdominal pain and diarrhea; infectious workup was negative, and colonoscopy showed active colitis. Concurrently, extensive lymphadenopathy was noted, and an excisional inguinal lymph node biopsy showed atypical follicular hyperplasia with no evidence of malignancy. She later developed persistent headaches, and MRI revealed multiple contrast-enhancing lesions involving the brain and thoracic spine (Figure 2A–C). Lumbar puncture showed a lymphocytic pleocytosis with negative infectious workup, and brain biopsy revealed lymphoplasmacytic infiltration (Figure 2D). She was started on systemic corticosteroids with partial improvement. Trio whole exome sequencing identified compound heterozygous variants in LRBA (c.2352T>A, pTyr784*; c.4004+166A>G). High dose abatacept was initiated (intravenous ~ 10 mg/kg/month plus subcutaneous 125 mg/week), which facilitated corticosteroid tapering.

Given the severity of her disease, she was referred for hematopoietic stem cell transplantation (HSCT) evaluation. She subsequently underwent a matched-related donor HSCT using a reduced-intensity conditioning regimen (NCT03663933). She is now 5 years post-HSCT with full donor chimerism, no GVHD, and no evidence of active disease or ongoing immunomodulatory therapy.

Figure 2. Histopathologic, radiologic, and immunologic findings of P2 with LRBA deficiency.

(A-C) MRI showed multiple white matter signal abnormalities (white arrows) involving the left parietal lobe (A), right cerebellar hemisphere (B), and cervical-thoracic spinal cord (C) on T2-weighted imaging. (D) Brain biopsy of the left parietal lobe lesion revealed lymphoplasmacytic infiltrates and numerous histiocytes with intracytoplasmic crystals (20× with 40× inset). (E) Flow cytometry demonstrated reduced peripheral blood Treg (%) and diminished intracellular CTLA-4 level compared to healthy controls (HC, n = 10). MFI, mean fluorescence intensity.

This patient has a complex history of early-onset, multi-organ immune dysregulation very similar to P1, but with earlier presentation to medical care. Her course was later complicated by a severe neuroinflammatory disorder with focal, enhancing radiographic lesions and lymphocytic infiltration on biopsy. These findings are highly suggestive of CTLA-4 haploinsufficiency as in P1(43) or defects impacting CTLA-4 function, such as LRBA or DEF6(44,45). In each case, lack of effective CTLA-4 function leads to unrestricted T cell activation and proliferation in multiple organs. Genetic testing results were highly suspicious for LRBA deficiency, a recessively inherited PIRD as opposed to autosomal dominant CTLA-4 haploinsufficiency. Her clinical phenotype was compatible with this diagnosis, and trio analysis confirmed that the two LRBA variants were in trans: the nonsense variant was inherited from the father, and the intronic variant from the mother, thereby affecting both alleles and resulting in an autosomal recessive disorder. Although this specific nonsense variant (p.Tyr784*) has not been previously reported in LRBA deficiency, multiple nonsense variants located even more proximally to the C-terminus of the protein have resulted in complete loss of LRBA protein expression(46). Accordingly, together with additional supportive evidence (e.g., extreme rarity in population database gnomAD v4.1.0 and deleterious predictions from computational tools), p.Tyr784* is classified as pathogenic. In contrast, c.4004+166A>G, which has not been previously reported, is classified as a variant of uncertain significance (VUS). Although it is predicted to impact splicing (i.e., SpliceAI score 0.95)(47), readily accessible clinical tools to functionally validate deep intronic variants are currently lacking. Support for pathogenicity of the compound heterozygous variants in this patient was provided by reduced peripheral blood Treg percentage with diminished intracellular CTLA-4 levels in Treg cells (Figure 2E), an indirect functional finding consistent with LRBA deficiency(48). For the Treg analysis, gating on CD45RA⁻ cells enables evaluation of activated Treg in the peripheral blood, the subset with high and consistent intracellular CTLA-4 expression in healthy individuals(49,50). Given the severity of her presentation, diagnostic uncertainty should not delay appropriate clinical management, and the patient was started on therapy prior to further functional studies.

LRBA acts as a posttranslational regulator of CTLA-4 preventing its degradation in the lysosome(44). Therefore, supplementation of soluble CTLA-Ig (abatacept), as was done in P1 with CTLA-4 haploinsufficiency, represents a targeted and effective therapeutic approach(51). However, LRBA deficiency is often associated with a more severe disease course compared to CTLA-4 haploinsufficiency and patients who fail to achieve a complete response to abatacept tend to have poorer clinical outcomes(51). Thus, a diagnosis of LRBA deficiency with severe manifestations supports early consideration of curative HSCT(52). The decision of whether, when, and how to proceed with HSCT in individuals with LRBA deficiency but milder disease is more nuanced and requires a careful, case-by-case evaluation with an experienced clinical immunologist in collaboration with an HSCT team. Worse outcomes in LRBA deficiency following HSCT have been associated with higher disease burden, prolonged disease duration, and lung involvement before HSCT(53). In addition, analysis of a large cohort of patients with T cell defects, including LRBA deficiency and CTLA-4 haploinsufficiency, suggests that severe and invasive viral infections and autoimmunity are associated with decreased survival(54). Among HSCT survivors, long-term disease control has been superior to that achieved in non-transplanted patients using abatacept or conventional immunosuppressants, with most patients no longer requiring long-term immunomodulation beyond the peri-HSCT period(53).

SOCS1 deficiency

P3 initially presented in infancy with panniculitis followed by lipodystrophy after a natural varicella infection at 2 years of age. At 20 years old, he was diagnosed with inflammatory arthropathy, later complicated by uveitis. He failed multiple biologics and targeted therapies, including etanercept, adalimumab, infliximab, tofacitinib, and abatacept. At 26 years of age, he developed EBV-positive Burkitt lymphoma and was treated with methotrexate, leucovorin, cytarabine, and rituximab.

At 34 years of age, computed tomography of the chest revealed traction bronchiectasis, numerous nodular ground-glass opacities (GGO), as well as mediastinal, hilar, and retroperitoneal lymphadenopathy. He underwent bronchoscopy for further evaluation. Bronchial culture grew Moraxella catarrhalis and Streptococcus pneumoniae, for which he completed a 3-week course of antibiotics without resolution of the GGO. A respiratory viral pathogen panel was negative. Cultures for Mycobacterium, Nocardia, Legionella, Pneumocystis jirovecii, and fungi were negative from both bronchoalveolar lavage and mediastinal lymph node needle aspiration. Urine histoplasma antigen was also negative. Biopsy of a retroperitoneal lymph node showed non-caseating granulomas. At this time, he was found to have hypogammaglobulinemia (IgG 223 mg/dL) with low IgA (27 mg/dL) and normal IgM (28 mg/dL). Whole genome sequencing identified a previously reported heterozygous pathogenic variant in SOCS1 (c.476_480dup; p.Met161AlafsTer46)(55). He was started on Ig replacement therapy.

The intracellular, inducible suppressors of cytokine signaling (SOCS) family of proteins is an essential endogenous, negative regulator of the JAK-STAT pathway. SOCS1 is the most potent inhibitor of signaling through the γc chain (IL-2 family) and interferons; and SOCS1 deficiency was first described in 2020 as a PIRD characterized by early onset autoimmunity and lymphoproliferation. Functional assays in SOCS1 deficiency point to elevations in phospho-STAT1, phospho-STAT5, CXCL9 and CXCL10 as well as a decrease in Tregs(55). Later case series have expanded the phenotype to include hypogammaglobulinemia and infectious susceptibility similar to LRBA deficiency and CTLA-4 haploinsufficiency(56,57).

Optimal pharmacologic management for SOCS1 deficiency has not yet been established. Current strategies are guided by our understanding of the underlying immunologic pathways, parallels with clinically similar disorders (e.g., CTLA-4 haploinsufficiency and LRBA deficiency), and the specific indications for immunomodulation (e.g., lymphoproliferation and autoimmunity). Because SOCS1 is an endogenous negative regulator of the JAK-STAT pathway, and Jakinibs have shown efficacy in other PIRDS, such as STAT1 and STAT3 gain-of-function diseases, they represent a rational therapeutic option(58–60). Treatment selection may also be informed by experience with other Treg-deficient PIRDs, including the use of abatacept and sirolimus. Additional therapies reported in SOCS1 deficiency include traditional DMARDs (e.g., azathioprine, mycophenolate mofetil, methotrexate) and monoclonal antibodies (TNF-α inhibitors, rituximab, tocilizumab, and ustekinumab). For atopic manifestations, omalizumab, mepolizumab, and dupilumab have also been used in selected cases(57).

Given the critical role of immune surveillance in preventing malignancy, and the lymphoproliferative phenotype associated with CTLA-4 haploinsufficiency, LRBA deficiency, and SOCS1 deficiency, multiple malignancies have been reported in these patients. SOCS1 deficiency is a recently described PIRD, and the full spectrum of associated malignancies have yet to be defined. Reported cases include Hodgkin and non-Hodgkin lymphomas, including Burkitt, diffuse large B-cell, angioimmunoblastic T-cell subtypes, with variable EBV positivity(55,57). In a cohort of 133 CTLA-4 haploinsufficiency patients, 11 (8%) developed malignancies. Lymphoma was the most common, occurring in 8 patients, including 5 EBV-associated, and resulting in 3 deaths. In addition, three patients had gastric cancer associated with enteropathy, one of which was also EBV-associated(9). Other malignancies observed in CTLA-4 haploinsufficiency include multiple myeloma and metastatic melanoma(61). Similarly, patients with LRBA deficiency have been reported with lymphomas and gastric cancer(44,62,63). In a literature review, the risk of malignancy was significantly higher in patients with CTLA-4 haploinsufficiency compared to those with LRBA deficiency (17.1 vs 7.1% respectively). This difference may be due to earlier disease onset in LRBA deficiency shorter time to diagnosis, and/or a higher likelihood of receiving definitive therapy in LRBA deficiency, such as HSCT(64).

As previously discussed, mTOR inhibition has been used in the treatment of CTLA-4 haploinsufficiency and LRBA deficiency, and more recently in SOCS1 deficiency(57) (Table 1). The antiproliferative and antiangiogenic properties of mTOR inhibitors may be advantageous for PIRD patients with high lymphoproliferative potential. Importantly, other immunomodulatory agents commonly utilized off-label in the setting of PIRDs, such as Jakinibs and abatacept, have been linked to an increased risk of malignancy, including lymphoma and dermatologic cancers(38,65–68), although this has not been studied PIRDs. In contrast, sirolimus, an mTOR inhibitor, has been efficacious in the setting of post-solid organ transplant lymphoproliferative disease and lymphomas(69–72). Furthermore, mTOR inhibitors have been used to treat Kaposi sarcoma in renal transplant recipients and in a single patient with CTLA-4 haploinsufficiency(73,74).

In retrospect, P3 had chronic hepatosplenomegaly noted at 30 years of age. A liver biopsy at that time showed steatohepatitis. He had persistent low-grade transaminitis (e.g., aspartate aminotransferase 70 U/L (normal 5–34 U/L), alanine aminotransferase 77 (normal 0–55)) with elevated gamma-glutamyl transferase at 134 U/L (normal 12–64 U/L) while alkaline phosphatase and direct bilirubin levels remained normal. He also had thrombocytopenia (e.g., 81 K/mcL; normal 161–347 K/mcL). A repeat liver biopsy at 41 years of age showed nodular regenerative hyperplasia (NRH) (Figure 3A–C). Contemporaneous transient elastography revealed a normal controlled attenuation parameter at 218 dB/m, indicating no hepatic steatosis, but a markedly elevated stiffness of 15.6 kPa (normal 2–7 kPa), consistent with an F3 fibrosis score (severe scarring or cirrhosis). Hepatic venous pressure gradient measured 12 mmHg (normal < 5 mmHg), consistent with clinically significant portal hypertension. Small esophageal varices were seen during endoscopy, and he was started on carvedilol for variceal bleeding prophylaxis.

Positron emission tomography scan revealed fluorodeoxyglucose-avid lymphadenopathy in the bilateral axilla, mediastinum, hilum, and inguinal region (max standardized uptake value of 14.4) (Figure 3D). Because of his prior history of lymphoma and the risk of recurrent lymphoma on JAK inhibition, excisional lymph node biopsy was performed, which showed nodular polyclonal hyperplasia, rare non-necrotizing epithelioid granulomas, and no evidence of lymphoma. A bone marrow biopsy showed a markedly hypercellular marrow without lymphoma (Figure 3E–G). Initiation of ruxolitinib therapy has resulted in marked improvement in inflammatory arthropathy and inflammatory markers. Liver stiffness improved from 15.6 to 9 kPa.

Figure 3. Histopathologic and radiologic findings of P3 with SOCS1 deficiency.

(A-C) Liver biopsy (10×) showed nodular regeneration with abnormal CD34 positivity in approximately one-third of sinusoidal endothelial cells. (D) Positron emission tomography demonstrated multiple foci of abnormally increased fluorodeoxyglucose uptake (black circle). (E-G) Bone marrow core biopsy (100×) revealed markedly hypercellular marrow with trilineage hematopoiesis. CD3 staining demonstrated frequent interstitial T-cells, and CD20 staining highlighted fewer scattered B-cells.

NRH is the most common form of chronic liver disease in patients with CVID(75). A high index of suspicion is necessary, as standard hepatic panels are often normal or only minimally abnormal until late in the disease course, as observed in P3. Alkaline phosphatase was found to be elevated in most NRH cases within CVID cohorts(75,76), and persistently unexplained elevation of gamma-glutamyl transferase also supports the diagnosis(75,77). Liver stiffness measured by transient elastography is frequently abnormal and may help to identify affected patients alongside laboratory evaluations(78,79). Additional features include splenomegaly, thrombocytopenia, esophageal varices, portal hypertensive gastropathy, ascites, and increase in the size of the portal vein(80). Liver biopsy typically shows nodular areas of enlarged hepatocytes alternating with compressed liver cell plates, often accompanied by sinusoidal fibrosis and focal portal inflammatory infiltrates (i.e., interface hepatitis)(76). Importantly, liver disease in CVID is associated with increased mortality from severe complications, including late synthetic failure and hepatopulmonary shunt(81,82). Furthermore, progression of liver disease and significant portal hypertension may limit eligibility for HSCT.

The true prevalence of NRH in PIRDs is unknown. In CVID, risk factors include enteropathy and prominent immune dysregulation(76), both common in lymphoproliferative PIRDs. In a recent SOCS1 deficiency cohort, liver disease was present in 19%, including autoimmune hepatitis in 13% and one individual who required liver transplantation(57). Patients with SOCS1 deficiency may be at particularly increased risk due to the proposed role of SOCS1 in controlling hepatic fibrogenesis(83). In a CTLA-4 haploinsufficiency cohort, 20% had hepatomegaly and liver disease account for 1 of 15 deaths(9). Similar rates have been reported in LRBA deficiency(64). However, because patients were not uniformly assessed in these studies, the true prevalence is likely underestimated. The pathogenesis of NRH remains poorly understood, but involves vascular changes in the liver, potentially driven by immune dysregulation (especially of intra-sinusoidal T cells), infections, and/or microthrombotic events(84).

Management of NRH centers on prevention of complications, such as endoscopic banding of esophageal varices and β-blockade for variceal bleeding prophylaxis. As observed in P3, in whom liver stiffness improved during ruxolitinib therapy, immunomodulatory therapy targeting the underlying immune dysregulation may also prove important in changing the natural history of NRH in PIRDs(76). However, to date, no immunomodulatory therapy has been shown to consistently improve clinical outcomes in PIRDs-associated NRH, and treatment decisions therefore relies on comorbidities and concurrent treatment indications (e.g., GLILD and enteropathy).

Liver transplantation has rarely been pursued in patients with CVID and PIRD phenotypes, but disease often recurs in the allograft without definitive therapy for the underlying immunologic defect, and risk of infections is higher than in non-IEI hosts, resulting in high mortality(81,85). Combined liver and HSCT has been attempted in rare cases, but remains experimental and carries substantial risk(86).

Summary

The term PIRD has been introduced to encompass a broad group of monogenic disorders defined by prominent immune dysregulation that extends beyond the classic immunodeficiency. As illustrated in the cases presented, the genes associated with PIRD often encode key players of immune homeostasis. CTLA-4 and its intracellular regulator LRBA are critical for Treg function, while SOCS1 serves as a prototypical negative feedback modulator of cytokine signaling. Precise identification of the underlying molecular defects through genetic testing, complemented by appropriate functional assays, can inform personalized, pathway-based therapeutic options for these patients. The natural history of PIRD is often dynamic and evolving. While some patients can be successfully managed with immunomodulatory therapies, others require HSCT as a definitive curative approach.

Table 2.

Key messages of each clinical vignette

CTLA-4 haploinsufficiency

• Organ involvement is typically characterized by prominent lymphocytic infiltration.

• Enteropathy is a multifactorial complication and may be compounded by chronic norovirus infection.

• Abatacept is a targeted therapy; selected patients may require higher-than-standard dosing, which can be guided by serial assessment of clinical response and biomarker trends (e.g., soluble CD25).

• Sirolimus represents another reasonable upfront treatment option but requires therapeutic drug monitoring and vigilance for potential side effects.

• JAK inhibitors may benefit patients with organ involvement associated with an excessive interferon-γ response.

LRBA deficiency

• Its clinical manifestations resemble those of CTLA-4 haploinsufficiency but are often associated with a more severe disease course.

• Reduced intracellular CTLA-4 expression in Treg supports the diagnosis.

• Early consideration of hematopoietic stem cell transplantation is indicated for symptomatic cases.

SOCS1 deficiency

• Lymphoma, often EBV-positive, is a recognized complication of lymphoproliferative PIRDs, including SOCS1 deficiency.

• Elevations in alkaline phosphatase and/or gamma-glutamyl transferase may be the only initial laboratory abnormalities in patients with nodular regenerative hyperplasia; therefore, a high index of suspicion is required to prompt more comprehensive workups (e.g., transient elastography, liver biopsy).

• JAK inhibitors represent targeted therapeutic options for SOCS1 deficiency.

Abbreviations: EBV, Epstein-Barr virus; PIRD, primary immune regulatory disorder.

Abbreviations used

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4

CVID

Common variable immunodeficiency

CXCL9

CXC motif chemokine ligand 9

DMARDs

Disease-modifying antirheumatic drugs

DEF6

DEF6 guanine nucleotide exchange factor

EBV

Epstein-Barr virus

GAD65

Glutamic acid decarboxylase 65

GLILD

Granulomatous-lymphocytic interstitial lung disease

GVHD

Graft-versus-host disease

HSCT

Hematopoietic stem cell transplantation

IEI

Inborn errors of immunity

Ig

Immunoglobulin

IPEX

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked

JAK

Janus kinase

LRBA

Lipopolysaccharide-responsive beige-like anchor protein

MRI

Magnetic resonance imaging

mTOR

Mechanistic target of rapamycin kinase

NRH

Nodular regenerative hyperplasia

PIRD

Primary immune regulatory disorders

SOCS1

Suppressor of cytokine signaling 1

T1D

Type 1 diabetes

Treg

Regulatory T

VUS

Variant of uncertain significance