Primary immune deficiencies (PID) are characterized by increased susceptibility to infections, due to genetic defects involving development and/or function of the immune system. After the first description of a boy suffering from recurrent pneumococcal infections, who lacked serum gamma globulines by Bruton (1952) , the first classification of PID including several distinct disorders was proposed in 1968 . Manifestations of PID can range from life-threatening infections in infancy, to susceptibility to common infections, persistent inflam-mation, and autoimmunity in adulthood. As much as 1% of population may have a PID, which is more than previously predicted . Over the several decades, it has been realized that autoimmunity, autoinflammation, allergy, and malignancy can be common, and predominant in some, clinical manifestations associated with monogenic defects of immunity. To encompass this broad range of phenotypes associated with these disorders, the term “inborn errors of immunity” (IEI) has been proposed . Now many cases with autoimmune cytopenias, inflam-matory bowel diseases, or primary immune regulation disorders are designated as a form of IEIs.
Advances in molecular genetics and cellular immunology, especially the introduction of next generation sequencing (NGS), have permitted a precise definition of various IEIs and identification of sky-rocketing number of IEIs in recent years . The expert committee of the International Union of Immunological Society (IUIS) on IEI has proposed genotypic classification of all IEIs every other year since 2013 to facilitate research on as well as diagnosis of IEIs worldwide. For 2019 phenotypic classification the key clinical and laboratory features of 430 IEIs were reported within 10 broad categories of IEIs [6,7]. The IUIS Expert Committee undated the classification in 2022 which includes a total of 484 IEIs. Since the previous update features of 55 novel monogenic gene defects and 1 phenocopy due to autoantibodies were added . IEIs are currently categorized into 10 groups: 1) combined immunodeficiencies; 2) combined immuno-deficiencies with syndromic features; 3) predominantly antibody deficiencies; 4) diseases of immune dysregulation; 5) congenital defects of phagocytes; 6) defects in intrinsic and innate immunity; 7) autoinflammatory diseases; 8) complement deficiencies; 9) bone marrow failure; and 10) phenocopies of inborn errors of immunity [7,8].
In Korea, only a few studies have been conducted to evaluate the prevalence of PID. A retrospective analysis of PID from 2001 to 2005 identified 152 cases of various diseases . More recently, a total of 398 cases were collected through the literature review (2001-2018) and big data analysis of National Health Insurance System, Korea on year 2017 . The small number of PID cases in Korea reported reflects underestimation of cases due to difficult genetic diagnosis of diverse phenotypes in earlier days. Newborn screening for severe combined immunodeficiency (SCID), which has just been introduced in the United States, and several European countries would be a hope for early diagnosis and treatment for PID [11,12].
In parallel with the advances in cellular and molecular studies on IEIs, treatment paradigm has been shifted from supportive care, mostly focusing on prevention and treatment of infection and inflammation to precision medicine. The first allogeneic hematopoietic stem cell transplantation (HSCT), successfully performed in a baby with X-lined SCID has paved the way for the application of HSCT to a large number of otherwise fatal immunodeficiency diseases as well as a variety of hematologic and malignant diseases [5,13,14]. Moreover, targeted therapeutic approaches based on replacement of the missing product were attempted for the first time in patients with adenosine deaminase (ADA)-SCID, and approved later by FDA . Other examples of pharmacological approaches among others are: use of IL1 antagonist in autoinflammatory diseases, use of CTLA4-Ig in the treatment of CTLA4- and LRBA- deficiencies, PI3Kd inhibitors in APDS, complement inhibitor in CD55 deficiency, and JAK inhibitors in gain of function mutations in STAT-1/3 . However, details are beyond the scope of this review article.
The correction of the gene defects could provide definitive cure to patients with IEIs . First gene therapy was attempted for ADA-SCID patients, initially using gene modified autologous T cells in 1992 and later combined with hematopoietic stem cell precursors (HSPCs) . Initial clinical success in patients with ADA-SCID, X-linked recessive (XR)-SCID and Wiskott-Aldrich syndrome (WAS) based on first generation g-retroviral vectors encountered a significant obstacle of development of T-cell acute lymphoblastic leukemia due to insertional mutagenesis [18,19]. This led investigators to develop safer vector delivery systems. Now, self-inactivating lentivirus (SIN-LV) vectors are considered the most efficient and safest gene delivery vectors for both T cells and HSPCs [5,16]. Most recently, gene editing using CRISPER/ Cas9 nuclease system might be fascinating because it preserves spatiotemporal regulated gene expression . Preclinical trials are underway for several IEIs, including XR-SCID, hyper-IgM syndrome, and IPEX.
Regarding to the treatment modalities for patients with PID, a survey of physician-reported data was performed through the Jeffrey Modell Foundation global network. For the year 2021 the number of patients with severe PID to receive specific therapies other than immunoglobulins was 7,406 worldwide. Most of the patients were treated by HSCT (n=7,032, 94.9%), followed by gene therapy (n=248, 3.3%), and pegylated-ADA (n=126, 1.7%) . Thus, although gene therapy seems to be very promising in growing numbers of IEIs, HSCT remains the most important treatment modality in current practice worldwide, as the affordability of gene therapy remains a major financial and ethical challenge .
The survival following allogeneic HSCT for PID is now generally >80% with gradual improvement over half century in transplantation technology, including high- resolution HLA typing, increased use of alternative donors, adoption of less toxic conditioning regimens and pharmacokinetic monitoring, development of more effective T-cell depletion methods, and better supportive care. In addition, early identification of infants with SCIDs by genetic diagnosis with NGS prior to infectious complications contributed to a better survival [22-24]. However, the diverse spectrum of PID with clinical and immunologic phenotypes caused by more than 450 monogenic gene defects makes it difficult to define a universal transplant regimen. As such, integration of immunologic and genetic knowledge into transplantation field is necessary for the development of innovative and improving transplant protocols.
This article will discuss current status and recommendations from specialists in HSCT for PID. Although PID stemming from defects in the hematopoietic compartment are largely cured by HSCT, immunologic diseases due to thymic stromal or other extra-hematopoietic defects are not likely to be corrected by HSCT. Table 1 summarizes classical indications for HSCT in PID [24,25]. However, the list of indications needs to be updated in accordance to the improvement of transplant technology and addition of new types of PID. Moreover, the indication and timing of transplant must be individualized not only on the basis of the specific PID but also on the characteristics of the individual patient.
The use of alternative donors and new graft manipulation techniques has also dramatically improved access to allogeneic HSCT. The gold standard for HSCT has been using matched related donors, but they should be evaluated for the possibility of recurrence of the disease in the family. Although the outcome of HSCT from matched unrelated donors are equivalent to those from matched siblings, only a minor proportion of the patients in need may benefit from those donors. Recently, haploidentical transplants with
Pre-transplant conditioning is essential component of successful allogeneic HSCT for both malignant and benign hematologic diseases. However, HSCT for PID differs from that for other hematological malignancies in that the goal is not to eradicate certain immune cells but to achieve immune reconstitution in general. Although a small portion of SCID cases may not need conditioning before stem cell infusion, most of PID or IEI patients need a conditioning regimen to achieve a high donor chimerism, which is known to be associated with better outcomes and improved quality of life (QOL) . Myeloablative conditioning using busulfan and cyclophosphamide was the norm in earlier days, but modified conditioning regimens significantly contributed to improved HSCT outcome by reducing short- and long-term transplant-related mortality and morbidity [14,24]. The substitution of cyclophosphamide with fludarabine, and the development of pharmacokinetics-based busulfan dosing as well as treosulfan-based conditioning have resulted in decreased toxicity and stable engraftment [30-32]. The Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) and the European Society for Immune Deficiencies (ESID) recently published guidelines for HSCT for IEI. They recommend six protocols (A-F) as conditioning regimens based on reported data, center experiences and expert opinions rather than prospective studies (Fig. 1) . Protocol A and protocol B are myeloablatvie conditioning regimens recommended for patients without severe preexisting organ damage and non-SCID diseases where a complete donor chimerism is desired for optimal disease correction. Protocols C and D are reduced intensity conditioning (RIC) regimens for patients with preexisting organ damage. Mixed donor chimerism is more likely to occur compared to Protocols A and B. The details of dosing schedules are provided in the article . The choice of myeloablative versus reduced intensity conditioning, and the implication of mixed donor chimerism with acceptable level of mixed chimerism after HSCT will be discussed under specific representative disease categories.
Therapeutic drug monitoring for busulfan to optimize exposure is mandatory for Protocols A and C. Because of its favorable toxicity profile, treosulfan was used instead of busulfan, showing similar survival and outcome, but the predictability to reach full donor chimerism is less in the case of treosulfan [25,31]. Fludarabine is a primarily lymphodepleting agent, commonly used in combination with either busulfan or treosulfan instead of cy-clophosphamide. Fludarabine is incorporated in every pro-tocol from A to F. Thiotepa is often used to add myeloablative activity, and has the potential to cross the blood- brain barrier which may be beneficial in diseases with central nervous system (CNS) involvement, such as hemo-phagocytic lymphohistiocytosis (HLH) . Serotherapy consisting of antithymocyte globuline (ATG)/antilymphocyte globulin (ALG) and alemtuzumab is an essential component in most conditioning regimens. Serotherapy is used to facilitate engraftment and to prevent GvHD, especially in unrelated or mismatched family donor settings. Thus, the choice of the optimal conditioning regimen should be considered for each patient based on the phenotype or genotype of IEI, donor type and co-morbidity of the patient.
Now we review current status of HSCT outcomes for several representative PID, along with our personal experience of PID treatment in Korea.
SCID is a group of most severe form of immuno-deficiency affecting both cellular and humoral immunity. Affected patients suffer from severe, recurrent, and opportunistic infections from early after birth, and usually die within a year, without definitive treatment. Nineteen different genetic defects are known to be responsible for SCID according to current classification . They are cate-gorized by the molecular pathways affected and immu-nologic phenotypes: SCID T-B+NK+/-, SCID T-B-NK+/- . For SCID T-B+NK-, X-linked SCID with impaired gC signaling and autosomal recessive (AR)-SCID with JAK3 deficiency are indistinguishable in clinical and immuno-phenotypic findings, as JAK3 is coupled with the common g chain of interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors and mediates their downstream signaling.
HSCT has been used as a curative therapy, resulting in 10-yr overall survival after HSCT of 70-80% [24,34]. The later age of HSCT (after 3.5-4 months) or active infection at HSCT is recognized as a risk factor for poor survival after HSCT [29,34]. Choice of conditioning regimen will be mainly based on donor type and SCID phenotype/genotype. In some cases, such as X-SCID or ADA deficiency, conditioning is not required to attain T cell reconstitution, but better functional B and NK cell recovery is achieved with the use of conditioning [14,29,35]. Thus, EBMT/ESID recommended RIC of either Protocol C or Protocol D for all SCID patients irrespective of donor type, but they allowed no conditioning for select cases with T-B+NK-, such as JAK3 or IL2R deficiency or cases of ADA deficiency when matched donor is used . The authors reported the first case of molecularly diagnosed X-SCID in Korea, successfully rescued by CD34+ selected peripheral blood HSCT from haploiden-tical father .
X-linked hyper-IgM syndrome (XHIGM) is a rare combined immunodeficiency disease (CID), generally less profound than SCID, having recurrent infections associated with low or absent levels of IgG and increased levels of IgM. Binding of CD40 ligand (CD40L, CD154) to its receptor CD40 on B cells is critical for immunoglobulin isotype switching and an effective secondary antibody response. Also its binding to CD40 in dendritic cells and macrophages is engaged in their maturation, activation, and cytokine secretion leading to an effective T-cell response . Patients with defective CD40 signaling, either by CD40L deficiency (XHIGM) or by CD40 deficiency (autosomal recessive in inheritance) are characterized by opportunistic infections, especially
WAS, one of the examples of CID with associated or syndromic features, is an X-linked recessive disease cause by
Familial hemophagocytic lymphohistiocytisis (FHL) syndromes are one of the subgroups of diseases of immune dysregulation. Seven diseases are included in the category: Perforin deficiency (FHL2); UNC13D/Munc13-4 deficiency (FHL3); Syntaxin 11 deficiency (FHL4); STXBP2/ Munc18-2 deficiency (FHL5); FAAP24 deficiency; SLC7A7 deficiency; and RHOG deficiency . HLH is a syndrome of life-threatening systemic hyperinflammation, characterized by unremitting fever, cytopenia, hepatospleno-megaly, coagulopathy, and organ failure, including the liver, CNS and/or others . HSCT is considered to be the only curative therapy for genetic HLH disorders after achieving disease remission following immuno- and myelosuppressive drugs, with the 5-year OS of 60-80% after HSCT . Earlier studies using myeloablative conditioning showed poor outcome after HSCT because of pre-existing multiorgan toxicity and infections before HSCT, and incidence of hepatic venoocclusive disease. The use of RIC containing fludarabine, melphalan, and alemtuzumab or thiotepa, and better HLH control prior to conditioning were associated with better outcome [29,44]. The use of RIC is further supported by the fact that a donor chimerism >20-30% was protective against late reactivation. Thus, complete chimerism was not necessary to suppress HLH .
Two forms of X-linked proliferative (XLP) disease are known, showing susceptibility to EBV and lymphoproliferative conditions under the category of disease of immune dysregulation . SAP deficiency, also known as XLP1, is due to mutation of the
XLP type 2 (XLP2) is due to mutations of the X-linked inhibitor of apoptosis (
CGDs are disorders of phagocytic function due to defects of respiratory burst. X-linked and autosomal recessive forms are caused by mutations of the genes for respective subunits of NADPH complex. The main clinical features of CGD include recurrent bacterial and fungal infections from catalase-positive organisms, and high rate of inflammatory complications, such as inflamma-tory bowel disease, and granuloma formation in the liver, lungs and skin . A recent study from EBMT/IEWP reported excellent overall and event-free survival on 712 children and adult patients with CGD . Older age at transplantation, transplant from other than matched siblings, and cord blood transplantation have been associated with poor survival [29,51]. The use of alkylator- based RIC and treosulfan-based RIC have resulted in comparable survival, but graft failure is of concern in some patients . Thus, protocol C and D are the preferred regimens by EBMT/ESID, as reduced toxicity conditioning leads to sustained neutrophil production of donor origin in most of the cases. Moreover, stable mixed chimerism (>20% myeloid) is known to be sufficient to protect against serious infections. Some centers may prefer protocol A or B to favor myeloid engraftment, but direct comparison is not available so far. Every effort should be paid before HSCT to best possible control of autoinflammation, such as colitis, or lung disease. Also, serotherapy consisting of either ATG or alemtuzumab is recommended for all CGD patients to control extensive inflammation . Female carrier donors of X-linked CGD may not be ideal as HSCT donors as many female carriers may have inflammatory and autoimmune symptoms, not related to the degree of lyonization .
With advances in molecular genetics and cellular immunology, the definition and identification of specific PID or IEI, now almost reaching to 500 defects, became possible. HSCT has been used as a mainstay of specific treatment for many otherwise lethal PIDs. Recent progresses in HLA typing, expansion of donor availability, choice of optimal conditioning regimen, better supportive care and early diagnosis through newborn screening all have contributed to long-term outcome >80% in recent years. The transplant procedure should be indivi-dualized, and the resultant transplant outcomes including engraftment, chimerism status, transplant-related mortality, GvHD, infection, survival and long-term toxicity should be varied based on the specific PID, timing of HSCT, comorbidities, donor selection, conditioning regimen, and center experiences. Refinement in gene therapy and incorporation of pharmacological approaches will further pave the road to cure for all PID in the future.
The authors have no conflict of interest to declare.