1 INTRODUCTION

Primary immunodeficiency diseases (PIDs), also known as inborn errors of immunity, are genetically heterogeneous monogenic diseases, affecting development, maturation, or function of cells essential for immune system. Due to the monogenic nature, PIDs serving as natural gene knock-out/in models have been received increasing attention. To date, 485 known genetic defects are listed in the latest update of the International Union of Immunological Societies Expert.¹ In the clinical setting, PIDs present with diverse clinical manifestations, particularly recurrent and refractory infections. Of note, autoimmunity as the second most prevalent phenotype shouldn't be underestimated.

Systemic lupus erythematosus (SLE) is a multisystem autoimmunity disease with variable clinical and laboratory features. The intricate interactions among gene, environment, and immune system contribute to the immunopathogenesis of SLE, resulting in the tissue inflammation and various organs damage.² More recently, genome-wide association studies (GWASs) provide an opportunity to identify the genetic risk factors of SLE, and more than 100 risk loci have been demonstrated.³ Interestingly, there is overlap between genes that confer susceptibility to SLE and those responsible for PIDs. In some PIDs cases, SLE is the initial phenotype and/or the prominent phenotype. Compared with the classic SLE, SLE in PIDs is more severe and is refractory to classical treatment, which is a particular concern for the management of PIDs.

In the present review, we discuss the mechanisms behind the development of SLE-like phenotype in primary immunodeficiency diseases from the sight of gene background. Further, we summarize the treatment strategy relieving lupus symptoms, exploring the potential treatment based on the mechanism.

2 COMPLEMENT DEFICIENCIES

As one of the first lines of host defense, activated complement components mark the pathological materials or transformed/damaged biological materials and then provide the removal signals to phagocytes of the innate immune system.⁴ In parallel, it enhances antibody response and regulates both B-lymphocyte and T-lymphocyte activity. Thus, complement system is a functional bridge between innate and adaptive immunity. The relationship between complement system and SLE appears paradoxical. On the one hand, low level complement proteins in activate SLE suggests that consumption and/or deposition of complement components contributes to inflammation reaction, leading to tissue and organ damage. On the other hand, inherited complement deficiencies predisposed to lupus raise the hypothesis that deficiency of complement system is a risk factor for SLE.⁵

The prevalence of SLE phenotype shows significant variations in the order of complement activation cascade. 93% of patients with C1q deficiency develope SLE, more than 70% of whom present with mucocutaneous manifestations and positive ANA.⁶ And followed, SLE can be seen in 57% with C1r/C1s deficiency, 75% with C4 deficiency, and 10% with C2 deficiency.^{7, 8} In addition, defects in the lectin pathway such as mannan-binding lectin–associated serine protease 2 can also contribute to the pathogenesis of SLE.⁹ The pathogenetic mechanisms of early component complement deficiencies with SLE-like phenotype might be implicated in impaired scavenging of autoantigens, compromised immune tolerance to self-antigens, defective autoantibodies and immune complex removal, and dysregulated cytokine production.^{8, 10}

SLE associated with complement deficiency is often treated by the standard therapeutic regimens used in patients with sufficient complements, but only high dosage prednisolone is effective and the symptoms flare up once the dosage reduces.¹¹ Of note, manipulation of the complement system by supplementation is proposed as a potential treatment. Complement-repletion using fresh frozen plasma (FFP) has been used. Regular FFP infusions release the condition of these patients, which means that temporarily restoring complement activity is sufficient to prevent the production of intracellular self-antigen and maintain homeostasis in immune system. FFP has been reported in SLE with C1q deficiency for 10-year, demonstrating the safety and effectiveness of this reagent.¹² Furthermore, C1q is predominantly synthesized in bone marrow, hence bone marrow transplantation would be used as a cure for C1q deficiency.¹³

3 TYPE I INTERFERONOPATHIES

Recognition of pathogen-derived nucleic acids by pattern-recognition receptors (PRRs) is the first step against microbial threats for immune defense, which induces the generation of inflammatory signaling molecules, such as Type I IFNs.^{14, 15} Subsequently, type I IFNs receptor (IFNAR) interacts with the type I IFNs and activates the receptor-associated protein tyrosine kinases Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which ultimately initiates the transcription of interferon-stimulated genes (ISGs) through the phosphorylation of latent cytoplasmic transcription factors signal transducer and activator of transcription (STAT). Nucleic acid sensors are not limited in pathogen-derived nucleic acids. The recognition of self-DNA or RNA in the cytosol also initiates a Type I IFNs response, leading to the development of autoimmunity.¹⁶ In 1979, increased IFNs had been reported in patients of SLE.¹⁷ Henceforth, studies have repeatedly measured the up-regulated type I IFN signaling in SLE, which suggests the close association between them.^18-21

Type I interferonopathies are a genetically and phenotypically heterogeneous group of monogenic diseases caused by aberrant upregulation of type I IFNs. Based on the gene background, four putative cellular mechanisms at least have been proposed, which add to our understanding of SLE. First, nuclease deficiency leads to endogenous nucleic acid accumulation, enhancing sustained IFN response inappropriately. Second, gene variants that result in enhanced sensitivity or constitutive activation of nucleic acid sensors activate the IFN signal pathway below the threshold or bypass the need for ligand. Third, mutations in extracellular nucleases increase TLR-dependent IFN responses. Finally, defects in molecules or pathways that negatively regulate type I IFN signaling lead to upregulation of IFN signaling or overproduction of IFNs.²² Below, the key points about them are discussed specifically.

4 JAK-STAT SIGNAL PATHWAY

JAK-STAT signal pathway activated by a wide range of cytokines and growth factors. It plays a vital role in various physiological processes including innate and adaptive immune responses, hematopoiesis, growth, and development.⁶⁷ At present, SLE have been reported in patients with STAT1 gain of function and STAT3 loss of function, which is considered to a consequence of increased amplified transcription of IFN responsive genes.^{32, 68}

Patients with autosomal dominant gain of function STAT1 mutations impair the dephosphorylation of activated STAT1 protein, causing the accumulation of phosphorylated STAT1 and followed by higher levels of STAT1 responsiveness to IFN.⁶⁹ In addition, hypotheses about IL-27 through STAT1 have been reported to explain the molecular mechanism of developing SLE manifestations.⁷⁰ As a result, a wide spectrum of clinical manifestations of SLE, including arthritis, serositis, hemolytic anemia, autoimmune thrombocytopenia, proteinuria and neurological disorders, were showed.^{32, 71}

Based on the treatments in classical SLE, systemic corticosteroids was used among these patients, and lupus symptoms were partially improved.⁷¹ But clinical disease frequently worse progressively due to the gene variant context. As reported, the oral JAK inhibitor was used in patients with GOF mutation, and normalized both STAT1 protein and pSTAT1 levels.⁷² However, JAK inhibitor in patients with STAT1 gain of function mutation developing SLE phenotype has not been reported. More investigations are needed to demonstrate the safety and availability of the drugs. HSCT seems to be an alternative and curative therapeutic option. But complications including secondary graft failure, infections and bleeding limit its usage and the overall survival was reported as 40%.^{73, 74} The secondary graft failure might be related to the enhanced interferon signaling of resident cells in hematological system and tissues, which results in the uncontrolled inflammation.⁷⁴ Recently, ruxolitinib (a JAK inhibitor) acted as a conditioning regimen provides a better outcome after transplantation, which offered better disease management for STAT1 gain of mutation.⁷⁵

Interestingly, several early studies demonstrated that the level of STAT3 links to SLE disease activity closely.^{76, 77} STAT3 gain of function often accompanies autoimmunity and autoinflammation.⁷⁸ Thus, STAT3 inhibition is considered to be a target therapy in SLE. However, SLE have also been observed in patients with STAT3 loss of function mutation, suggesting the multiple and distinct biological roles of STAT3 in autoimmunity.⁷⁹ It is reported that STAT3 loss-of-function mutations have the clinical features observed in SLE, such as nephritis, autoimmune cytopenia, discoid rash, and alopecia. The probable pathogenesis of SLE in these variants is associated with the impaired induction of suppressor of cytokine signaling 3 (SOCS3), resulting in the upregulation of the STAT1 pathway and followed the increased expression of ISGs.⁸⁰

SLE phenotype in STAT3 loss of function is treated with a combination of immunosuppressants. Surprisingly, these drugs can lead to disease remission. Given the increased expression of ISGs and NET formation, target treatment such as JAK inhibition can be used for SLE symptoms of these mutations.⁷⁹

5 TREG DYSFUNCTION

To avoid the autoreactive response, T cells are selected in the thymus. But the recognition of various pathogens provide a random repertoire of antigen receptors for T cells, resulting the presence of autoreactive T cells. In normal immune system, Tregs maintain the immunotolerance state by a key receptor named Cytotoxic T-lymphocyte protein 4 (CTLA-4), which can regulate the activity of antigen presenting cells (APC) and naïve T cells through the competence with CD28.⁸¹ Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) controls intracellular trafficking of Cytotoxic T-lymphocyte protein 4 (CTLA-4), and a loss of LRBA causes the insufficient CTLA-4 expression on the surface of Tregs, resulting the development of autoimmune diseases. LRBA deficiency is identified in a SLE patient with polyarthritis, pericarditis, autoimmune hemolytic anemia, alopecia, persistent malar rash and aberrant immunological testing.⁸² According to the function of CTLA-4, CTLA4-Ig (abatacept) therapy may be considered in patient with LRBA mutation.

DOCK8 protein is involved in cells signaling about the arrangement of the cytoskeleton, which maintains cells structure and the right location. Therefore, it is critical for the survival and function of immune system cell.⁸³ SLE manifestations have been reported in several patients with DOCK8 deficiency.^83-85 The potential pathogenic mechanism is connected with the decreased number and suppressive activity of Tregs binding to the break of peripheral B cell tolerance checkpoint, which was strongly proved by the identification of enriched autoreactive B cells in the mature naïve B cell compartment among DOCK8-deficient patients.⁸⁶ DOCK8 gene mutation patients with SLE respond to immunosuppressive therapy, but 10-year follow-up of a DOCK8-deficient child with SLE feature reveals more effective therapies are needed.⁸⁵ Base on the availability in various autoimmune diseases (including SLE) and DOCK8 deficiency, HSCT is regarded as a fundamental treatment for these patients.⁸⁷ Normal complement fractions at 1 month post-HSCT and disappeared autoimmune features at 12 months post-HSCT highlight the usefulness and curability of HSCT.⁸³

6 ABERRANT T-CELL RECEPTOR (TCR) SIGNALING

Phosphoinositide 3-kinase delta (PI3Kδ) composed of catalytic subunit p110δ and regulatory subunit p85α (encoded by genes PIK3CD and PIK3R1 respectively) is a member of the class IA family of PI3Ks. It transduces signal from cell-surface receptors by the conversion of phosphatidylinositol 3,4,5-trisphosphate (PIP₃), promoting phosphorylation of RACα serine/threonine-protein kinase (AKT) and activation of downstream proteins involving mammalian target of rapamycin (mTOR).^{88, 89} P110δ protein is predominantly expressed in leukocyte, which plays a critical role in B lymphocyte and T lymphocyte development and responses.⁹⁰ Dominant gain-of-function mutations in the PIK3CD gene or dominant loss-of-function mutations in the PIK3R1 gene cause activated PI3Kδ syndrome, a novel PID also named APDS.⁹¹ The hyperactivation of PI3Kδ exhibits enhanced AKT-mTOR signaling, resulting in the expansion and survival of follicular helper T (Tfh) cell and incompetent B cells.⁸⁸ Wide range of autoimmunity manifestations can be seen in patients with APDS, and SLE is a newly phenotype descripted in 2019.^92-95 Cytopenias have a benefit in the treatment of steroids.⁹⁶ And given the genetic etiology of this disease, PI3K pathway inhibitors functioning as putative immunosuppressive drugs, may be the effective therapy. Rapamycin, a mTOR inhibitor, has been found to improve symptoms including pericardial effusion, abdominal effusion and proteinuria. But there was no change in positive ANA and low level of C3.⁹⁷ Leniolisib (CDZ173) as a selective oral inhibitor of p110δ can diminish the increased T-cell senescence in APDS, which indicates that it might be a new treatment option for these patients.⁹⁸ Although these targeted therapies appears attractive, serious side effects reported can't be ignored. Therefore, more clinical trials should be carried out to titrate the best dose and weight the long-term risks and benefits.

Purine nucleoside phosphorylase (PNP) is a critical enzyme in the purine salvage pathway. PNP deficiency leads to the generation of deoxyguanosine triphosphate (dGTP). As a lymph-toxic metabolite, dGTP inhibits ribonucleotide reductase and impairs T-cell maturation and differentiation consequently. Due to the protective effect of high nucleotidase activity, B cell number and function can be normal.⁹⁹ PNP deficiency has variable clinical presentations including infection, neurological impairment and autoimmunity. It is reported that autoimmune complications exist in one-third of patients with this disease. And SLE phenotype is found to have relation with PNP deficiency from 1991. At present, there are three patients with this disease who also have SLE, which may be attributed to the immune dysregulation and disturbed of the cellular homeostasis in T cells.^{32, 100, 101} In consideration of severe infection, HSCT is curative treatment for PNP deficiency.¹⁰²

7 B-CELL-INTRINSIC DEFECTS

As an essential component of a signaling pathway, PKCδ induces the homeostasis and tolerance in B cells. PKCδ protein is encoded by gene PRKCD. Biallelic loss-of-function mutations in PRKCD reduce expression and activity of PKCδ, resulting in B-cell hyperproliferation and defective apoptosis.¹⁰³ Since SLE is predominantly caused by loss of immune tolerance to autoantigens, the impairment of the B cell tolerance checkpoint in PKCδ deficiency contributes to the development of lupus phenotype. To date, at least six patients with PKCδ deficiency from four unrelated families have been reported to present with SLE phenotype.^104-107 All of these patients developed SLE before the age of 10 years, and manifestations such as lupus rash, lupus nephritis and arthritis are involved. Based on the nature of this disease, B cell depletion is likely to have a logical targeted therapeutic role for these patients. Rituximab as a chimeric monoclonal antibody that targets CD20 positive B cells improves clinical outcomes.¹⁰⁸ But severe infusion reactions is its main limitation.¹⁰⁴ Ofatumumab is a fully humanized monoclonal antibody that targets B cells from a different epitope of CD20. Patients intolerant of rituximab showed a good response to ofatumumab.¹⁰⁴ Interestingly, hydroxychloroquine as a classical SLE treatment improved skin feature and lymphoproliferation in patient with PKCδ deficiency, which revealed that autoreactive B cells could be modulated by hydroxychloroquine.¹⁰⁹

8 APOPTOSIS DEFECTS

As prototypical members of the small GTPases, Ras proteins induce a wide range of cellular processes, such as cell proliferation, differentiation, survival, apoptosis and gene expression.¹¹⁰ In addition, NRAS mutation and KRAS mutation are responsible for the non-malignant lymphoproliferation disease called Ras-associated autoimmune leukoproliferative disorder (RALD). Since its first identification, RALD was designated as the type IV of autoimmune lymphoproliferative syndrome (ALPS).¹¹¹ Previous study indicated that patients with this disease may have elevated or normal TCRαβ+ CD4- CD8- lymphocyte.^{112, 113} Given that the increased TCRαβ+ CD4- CD8- lymphocyte is one of the most specific findings for APLS, a new nomenclature of RALD was used in 2019.¹¹⁴ Manifestations including severe hematologic changes, arthritis, low level of complements were observed in RALD patients, which were often identified as SLE at first.^{115, 116} NRAS and KRAS proteins have found to suppress the proapoptotic protein BCL-2 interacting mediator of cell death (BIM), leading to impaired intrinsic T-cell apoptosis.¹¹³ Therefore, the SLE phenotype in RALD can be attributed to defects in lymphocyte apoptosis. In view of precise medicine, small molecule inhibitors of kinase effectors of Ras-GTP are the optimal treatment for RALD. But it is disappointing that these drugs are mainly used as anticancer agents.¹¹⁷ Fortunately, most of SLE symptoms is released by corticosteroid and/or immunosuppressive drugs.

9 CONGENITAL DEFECTS OF PHAGOCYTE FUNCTION

Reactive oxygen species (ROS) generated mainly by the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) complex during respiratory burst are essential for antimicrobial and immunoregulatory function of Phagocytic cell.¹¹⁸ Mutations in genes (such as CYBB, NCF1, NCF2 and NCF4) encoding the subunits of NADPH oxidase complex lead to chronic granulomatous disease (CGD), which is charactered by severe infection (particularly catalase-positive bacteria and fungi) and tissue granuloma formation due to the low production of ROS.¹¹⁹ Besides, CGD has an increased risk of developing autoimmune diseases like SLE. Discoid lupus was noted both in carriers and in patients with CGD at first.^120-124 Subsequently, several studies reported that CGD could manifest with SLE symptoms including photosensitivity, malar rash, glomerulonephritis, leukopenia, hypocomplementemia, ANA and dsDNA.^125-127 The possible mechanisms proposed by the researchers are listed as follows: Impaired phagocytosis leads to the overburden of biological waste and the exposure of autoantigens.¹²⁸ And decreased information of neutrophil extracellular traps (NETs) prevents the proinflammatory material from degradation, resulting in unlimited inflammation.¹²⁹ Type I IFN response is contributed to oxidized mitochondrial DNA generated by increased mitochondrial ROS and enhanced JAK/STAT pathway.^{130, 131} In addition, low ROS production enhances the presentation of autoantigens in macrophage.¹³² Therefore, SLE features in CGD appears to have self-amplifying nature because of a pathogenic interplay among ineffective immune tolerance, hyperactive autoantigens presentation, upregulate JAK/STAT signal and tissue damage. Typical SLE treatment was used in the management of SLE symptoms in CGD. HCQ is effective for discoid lupus, and transplantation is chosen in some patients.¹²³ Activator of the NOX2 complex might be the potential treatment in the future.¹²⁹

10 CONCLUSION

PIDs composed of 465 known genetic defects are heterogeneous diseases that mainly impair the development and function of immune system, which present a diverse spectrum of presentations. As it has been explored in this review, more than 30 genes responsible for PIDs confer susceptibility to SLE, which leads to critical insights into SLE pathogenesis. Mechanisms involved include complement deficiency, abnormal upregulation of type I IFNs, JAK-STAT pathway dysfunction, ineffective central and peripheral tolerance, apoptosis defects and low production of ROS. To date, there are only a few patients reported. But as natural pathogenesis models, these patients attract broad attention. And based on these genes background, more effective treatments (see table 1) such as JAK1/2 and mTOR inhibitor are explored. However, due to the limited number of patients, more trials and long-term follow-up are needed to evaluate the risks and benefits of the targeted drugs. New drugs such as reverse transcriptase inhibitor, nucleic acid degradation agonists, or even gene therapy need exploring.

AUTHOR CONTRIBUTION

Shan Liu is responsible for writing the manuscript. Zhiyong Zhang is responsible for translating and revising. Xuemei Tang and Xiaodong Zhao are responsible for revising. Yunfei An is responsible for reviewing and revising.

CONFLICT OF INTEREST STATEMENT

Xiaodong Zhao is the Deputy Editor-in-Chief of Pediatric Discovery. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication. The remaining authors declare no conflict of interest.

ETHICS STATEMENT

Not applicable.