Selective IgM Deficiency: Evidence, Controversies, and Gaps

Selective Immunoglobulin M deficiency (SIgMD) has been recently included in the inborn errors of immunity (IEI) classification by the International Union of Immunological Societies Expert Committee. The understanding of SIgMD is still extremely limited, especially so in cases of SIgMD in the pediatric population. The epidemiology of SIgMD in the pediatric population is still unknown. The pathogenesis of SIgMD remains elusive, and thus far no genetic nor molecular basis has been clearly established as a definitive cause of this primary immunodeficiency. Recurrent respiratory infections represent the main clinical manifestations in children, followed by allergic and autoimmune diseases. No conclusive data on the correct therapeutic management of SIgMD are available. Although, for most SIgMD patients, Ig replacement therapy is not required, it may be recommended for patients with significantly associated antibody deficiency and recurrent or severe infections. Prophylactic antibiotics and the prompt treatment of febrile illness are crucial. There is insufficient evidence on the prognosis of this condition. Therefore, further studies are required to define the disease trajectories and to increase our understanding of the molecular mechanisms underlying SIgMD in order to facilitate a better clinical, immunological, and prognostic characterization of the condition and develop tailored therapeutic management strategies.


Introduction
Selective Immunoglobulin M deficiency (SIgMD) is a predominantly antibody-affecting deficiency that has been included in the International Union of Immunological Societies (IUIS) classification of inborn errors of immunity (IEI) since 2017 [1][2][3].According to the European Society for Immunodeficiencies (ESID) criteria, SIgMD is defined by absent or reduced serum immunoglobulin M (IgM) levels in the absence of immunoglobulin deficiencies of the other classes [4].The significant comorbidities for SIgMD are recurrent infections (even including those with life-threatening severe infections) and an increased frequency of allergic and autoimmune diseases [5].However, only a few studies have assessed the clinical and immunological features of SIgMD.The pathogenesis of SIgMD remains unclear, and no definitive genetic alterations have been established.SIgMD remains a diagnostic and therapeutic dilemma, especially in the pediatric population, because no conclusive data are available on the correct therapeutic management and the prognosis of SIgMD.
This review aims to summarize the evidence about this apparently rare primary immunodeficiency (PID), focusing on clinical and immunological features, particularly in pediatric patients, to allow for a better understanding of this condition.

Materials and Methods
A literature search was performed via the online database PubMed by combining the terms "Primary selective IgM deficiency", "Primary selective immunoglobulin M immunodeficiency", "Selective IgM deficiency AND children", "Selective IgM deficiency AND pediatric population", "Pediatric selective IgM immunodeficiency", and "gamma-M deficiency AND children".
The literature review on SIgMD was performed in May 2023, including all publication years.All studies that met the following criteria were included: (i) articles published in English in peer-reviewed journals and (ii) studies wherein the participants were children and adult patients diagnosed with SIgMD.Potentially eligible publications were manually screened and reviewed, and non-relevant publications were excluded.

Results
The database search found 850 articles.Based on their titles and abstracts, 166 articles met the inclusion criteria.After removing duplicates, 80 articles were analyzed for this review (Figure 1).

Definition (Clinical and Laboratory)
According to the European Society for Immunodeficiencies (ESID) registry criteria, SIgMD is defined as repeatedly absent or reduced serum immunoglobulin M (IgM) levels (less than 2 SD or <10% of the values obtained from healthy controls of the same age or an absolute value <20 mg/dL in pediatric age) with normal levels of serum immunoglobulin A (IgA) and immunoglobulin G (IgG) and IgG subclasses, normal vaccine responses, and the absence of T cell defects (numbers and function) after the exclusion of secondary hypogammaglobulinemia (infections, genetic syndromes, chromosomal abnormalities, drugs, lymphomas, protein-losing enteropathy, nephrotic syndrome, thymoma) [6-8] and any other specific IEI.Despite this definition, some authors propose that SIgMD should be defined without the exclusion of the IgG subclass deficiency, alterations in T cell subset numbers and functions, and impaired responses to vaccines in order to better understand the different clinical and immunological phenotypes that lie behind the diagnostic term "IgM deficiency" [9].In this context, in their 2022 Update of the Classification, the International Union of Immunological Societies (IUIS) Expert Committee defines the only main criteria as the absence/reduction in serum IgM without limiting the definition with additional features (Table 1) [2].[10], and it was considered to be a rare condition [11][12][13][14][15].It is still mostly ignored as an IEI [16], and no large-scale studies have reported its epidemiology.An unselected community health screening survey reported a prevalence of 0.03% of patients with a complete absence of IgM [17].More recently, in a screening of more than 3000 healthy adult blood bank donors in Iran, the prevalence of SIgMD was 0.37% [18].A 0.07-2.1% prevalence in Immunology Clinics has been reported [19].However, the prevalence of SIgMD in the pediatric population (<18 years of age) is unknown.In children, the reported median age at the onset of symptoms is 3 years, with a median age of diagnosis of 8 years [20] and an average age at the time of diagnosis of 6.0 ± 4.7 years [21].Male predominance has been reported, along with a variable ratio of male to female patients (7:5 [21], 3:1 [20]).

Evidence from Genetic Studies (Table 2)
No genetic or molecular basis has been established as a definitive cause of SIgMD, and no definitive inheritance pattern has been demonstrated [22].However, SIgMD has been reported in several chromosomal abnormalities (chromosome 13, 18,19, and 22) [23][24][25][26][27].The most common association of SIgMD has been with 22q11.2deletion syndrome [26].Moreover, SIgMD has been commonly associated with Bloom Syndrome, and it has been reported that preferential damage to IgM production via UV irradiation may be due to the abnormal repair of DNA damage in the lymphoblastoid cell line [28].
Regarding the role of specific genes, no mutations nor deletions have been observed in the IGHM gene, including the region encoding the secretory domain of IgM.However, mutations in the BTK gene and BCR molecular signaling pathway have been reported in patients with SIgMD [29,30].Also, BAFFR deficiency has been associated with very low IgM and IgG serum concentrations, as well as very few circulating B cells [31].↓ = reduced levels.

Evidence from Immunological Studies (Table 3)
To date, the pathogenesis of SIgMD remains unclear.The selective absence of IgM is hard to explain because most studies reveal normal numbers of circulating surface IgM-positive B cells and normal serum levels of IgG and IgA.Therefore, considering the ontogeny of B cell maturation may indicate normal B cell responses.Conflicting results have frequently been reported by several in vivo and in vitro immunologic, phenotypic, and functional studies conducted over the past 20 years [5].For these reasons, several studies have focused on T helper cells, regulatory suppressor cells, and the intrinsic defects of B cells [32].Some in vitro studies have revealed the inability of B lymphocytes to differentiate into IgM-secreting cells due to the insufficient synthesis of secreted Igµ messenger RNA [32][33][34][35].
Moreover, in other studies, IgM-positive B cells produced normal amounts of IgM in vitro when cultured with normal T cells, while T cells showed decreased helper activity for IgM and both for IgG and IgA production.These findings suggest a defect in T helper cell function [36].A reduction in germinal center (GC) cells and defective specific antibody response were also seen in some patients with SIgMD and mice with defective IgM secretion [37].Kasahara et al. stated that alterations in follicular helper T (T FH ) and/or follicular regulatory T (T FR ) cells might play a role in the pathogenesis of SIgMD, but their role is not clear despite the lower percentage of circulating T FR (CT F ) cells [38]. Louis et al. demonstrated the potentially pathogenetic role of increased CD8+ Treg in SIgMD [37], and Inoue et al. [39] found increased IgM isotype-specific suppressor T cell activity in patients with SIgMD, as previously reported by Matsushita et al. [40].Moreover, decreased FcµR expression on marginal zone B-cells may play a role in the pathogenesis of SIgMD [41].Despite these studies, the specific causative mechanism of IgM deficiency is still unclear.Of note, most data available has been derived from adult patients with SIgMD, and only a few studies include pediatric SIgMD patients [21].T FR cells: follicular regulatory T cells; cT FH cells: circulating follicular helper T cells; FcµR: IgM Fc receptor.
Mycobacteria infections have also been described in association with SIgMD [46].Hassanein et al. identified a case of miliar tuberculosis in a 31-year-old man [53].Of note, as reported by Consonni et al., SIgMD may be associated with a severe clinical course of Mycobacterium infection compared to other healthy children [54].Other infectious manifestations, such as skin infections [20,21,55-57], multiple recurrent hordeola [58], chronic gastritis, cholecystitis, and epididymitis [15], have been reported in these patients.
Several patients (up to almost 40% of patients with SIgMD) display allergic manifestations [20,21], and the frequency of asthma and allergic rhinitis in SIgMD ranges from 30 to 45% [5].Likewise, autoimmunity and autoimmune diseases are more frequent in patients with SIgMD than in the general population [59].
Various investigators have also reported a failure to thrive in a few pediatric patients [21,36].

Idiopathic angioedema and anaphylaxis (reported in adulthood)
Atopic dermatitis

Immunological Characterization (Table 5)
As previously mentioned, several authors have reported additional immunological abnormalities in patients initially identified with SIgMD.
B cells are normal in most SIgMD patients.However, low B cells have been reported in a few patients with SIgMD [43,68,74].Non-switched memory B cell values were significantly lower in a subgroup of SIgMD patients than in healthy controls [75,76].Mensen et al. found reduced class-switched memory B cells, but naïve B cells were normal in their cohort [77].
The lymphocytic proliferation response to mitogens and antigens is maintained in most patients with SIgMD [78].Raziuddin et al. reported CD4+ T cell deficiency and defective interleukin 2 receptor expression and production by the patient's peripheral blood lymphocytes in response to mitogenic stimulation.Thus, impaired T cell function may be responsible for IgM-deficient antibody production [79].Yamasaki et al. previously described a reduction in the proliferative response of patient B cells to Staphylococcus aureus Cowan strain I (SAC).Considering in vitro immunoglobulin production, IgM production could be normal [74] or reduced.At the same time, IgG and IgA have been reported to be normal (using a T cell-independent culture system) [35], as reported by Karsh et al. [32].Considering the response to polysaccharides and proteic antigens, Lucuab et al. reported an unprotected/impaired anti-Streptococcus pneumoniae antibody in 47% of patients and an inadequate response to tetanus toxoid in up to 12% of patients in their cohort [36,68].

Therapeutic Interventions (Table 6)
No conclusive data on the correct therapeutic management of SIgMD are available.Although, for most SIgMD patients, Ig replacement therapy (IgGRT) is not required [71], it may be recommended for patients with significantly associated antibody deficiency or recurrent or severe infections [5,80].It is also interesting to observe that Goldstein et al. reported that IgGRT in patients with SIgMID and bronchiectasis might lead to a reduced risk of pulmonary infection with consequently better infection control and a preventive role in further progressive bronchiectasis [81].Notably, it is conceivable that IgM-enriched immunoglobulin replacement therapy with biologically active IgM can potentially prevent bacterial respiratory infections.However, further studies must be conducted to determine the potential role of IgM-enriched IgRT [82].Prophylactic antibiotics and the prompt treatment of febrile illness are crucial.Adult patients receive more frequent antibiotics and/or IgGRT [20,68] compared to the pediatric population [21].Vaccines, including pneumococcal and meningococcal vaccines, should be given as scheduled for healthy populations.However, antibody response may be decreased, and conjugate vaccines may require repeated doses to provide protection (if any).However, considering the immunological abnormalities associated with SIgMD, the impairment of T cell function should be excluded before the administration of attenuated vaccines.

Intervention Notes
Vaccination Before the administration of attenuated vaccines, an evaluation of T cell function is advised.Prompt treatment of febrile illness

Immunoglobulin replacement therapy
Patients with significant antibody deficiency, particularly in the presence of impaired pneumococcal antibody responses, recurrent or severe infections and/or bronchiectasis.

Prophylactic antibiotics
Particularly in patients with other associated immunological defects.

Management of atopic diseases
May be helpful in reducing the incidence of complicating sinopulmonary infections.

Prognosis
Although, in some infants, SIgMD may be transient [43], insufficient evidence is available on the prognosis of this condition.In particular, no conclusive data have been collected regarding the course of the disease and the possible evolution of SIgMD to common variable immunodeficiency (CVID) [83].

Discussion
SIgMD has been recently included in the IEI classification by the IUIS Expert Committee [1][2][3].However, as recently reported by the US National Institutes of Health (https://rarediseases.info.nih.gov/diseases/12547/selective-igm-deficiency(accessed on 29 May 2023)), our understanding of this condition requires improvement.
The definition of SIgMD is still controversial.Although specific ESID criteria are available, some authors propose that SIgMD should be defined without the exclusion of the IgG subclass deficiency, alterations in T cell subset numbers and functions, and impaired response to the vaccine in order to better understand the different clinical and immunological phenotypes that lie behind the diagnostic term "IgM deficiency."Indeed, as demonstrated by Janssen et al., only a limited number of SIgMD-diagnosed patients reported in the literature adhere to the ESID criteria [7].From a clinical perspective, according to the Jeffrey Modell Foundation's "Four stages of testing" [84], patients usually undergo quantitative IgG-, IgM-, and IgA-level dosage as the first step in the immunological workup.From the available evidence, it is clear that patients exhibiting absent/reduced serum IgM levels after this first stage of testing should undergo a complete immunological workup to identify other possibly associated immunological abnormalities.
According to our literature review, the main clinical manifestations are represented by infections, especially respiratory infections, followed by allergic manifestations [85,86] and autoimmune diseases [20,21,68,87].Neoplastic diseases have been described with a non-conclusive association with SIgMD.
Considering the probably pathogenetic defects associated with SIgMD reported in the literature, some of them are of particular interest, namely BTK gene mutation [29,30], BLNK gene mutation [30], BAFFR deficiency due to TNFRSF13C gene mutation [31], and Igµ deficiency [33].Some of these are also causes of agammaglobulinemia.In this category of IEI, we have the BTK deficiency X-linked agammaglobulinemia (XLA), the autosomal recessive µ heavy chain deficiency, and BLNK deficiency [2].These conditions are characterized by severe bacterial infections, a severe reduction in all serum immunoglobulin isotypes, and profoundly decreased or absent B cells (CD19+ less than 2%) [88].These features are partially shared with SIgMD, reinforcing the etiopathogenetic hypothesis that it could be determined by a B-cell intrinsic defect.BAFF receptor deficiency due to TNFRSF13C gene mutation is one the IEI showing a CVID phenotype (defined as an age-specific reduction in the serum concentrations of IgG in combination with low levels of IgA and/or IgM and a poor or absent response to immunizations and/or absent isohemagglutinins and/or low switched B cells (<70 percent of age-related normal value) and the absence of profound T cell immunodeficiency and absence of any other defined immunodeficient state [89,90]) characterized by low IgG and IgM serum levels with a variable clinical expression [3].This consideration strengthens the possible evolution of SIgMD to CVID [83] and the need for a close follow-up for all patients with SIgMD.
Regarding the immunological characterization, according to ESID criteria [4] and Janssen et al.'s definition [7,46], "truly" selective SIgMD has been defined as repeatedly decreased serum IgM levels, normal levels of serum IgG, IgA, IgG subclasses, and normal vaccination responses and the exclusion of T cell defects through the absence of clinical signs suggesting a T cell defect.However, as previously mentioned, several additional immunological abnormalities have been reported in the literature.These findings strengthen the above recommendation for a complete immunological workup in patients with absent/reduced serum IgM levels.
No conclusive data regarding the course of the disease, its potential therapeutic management, and the possible evolution of SIgMD to CVID are available.The most important forms of therapeutic intervention are represented by measures to prevent infections.Both inactivated vaccines (e.g., vaccines against Tetanus, Diphtheria, Pertussis), and live attenuated vaccines (e.g., vaccines against measles, rubeola, mumps, chickenpox, and Rotavirus) are safe in minor antibody deficiencies; thus, they are also safe in SIgMD.On the other hand, in antibody deficiency disorder, the response to active immunization can be highly variable in patients with antibody defects, from cases with an adequate response, as in healthy subjects, to cases in which it is reduced or even absent [91], as reported above.As reported by Ko et al., it is plausible that it could depend on B-memory cell values for polysaccharide antigens in CVID [92].Because there are several reports of patients with SIgMD with associated T cell defects before administering live attenuated vaccines, it is recommended to check the lymphocyte subsets to inoculate these vaccines safely.In particular, the following immunological parameters are requested: CD4+ T cells ≥500 cells/µL, CD8+ T cells ≥200 cells/µL, and normal T cell response to mitogen (The Center for Disease Control and Prevention recommends even higher CD4+ levels in children below the 6 years of age, namely, CD4+ ≥1000 cells/µL for those between 1 and 6 years of age and ≥1500 cells/µL for those under one year of age) [93].
An accurate extended follow-up (clinical and immunological) in Immunology Clinics, even in asymptomatic patients, is crucial in order to evaluate the evolution of SIgMD in children and adults (persistent or transitory) and identify the possible progression to CVID or other well-defined immunodeficiencies, with a specific focus on patients who showed immune abnormalities in addition to low IgM [20,94].

Conclusions
Our overall understanding of SIgMD is still extremely limited, especially with respect to the pediatric population.This review evaluated the evidence regarding SIgMD to clarify the condition's etiopathogenetic and pathophysiologic mechanisms, its main clinical manifestations and immunological features, and its potential treatment options in order to define present and future needs.Further studies, including prospective longitudinal studies with regular immunological evaluation and, if possible, genetic testing, are required to understand the disease trajectories and increase our understanding of the molecular mechanisms underlying SIgMD to facilitate a better clinical, immunological, and prognostic characterization of the condition and therefore develop tailored therapeutic management strategies.

Table 1 .
SIgMD definition criteria modified from "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee" Tangye et al. (2022) [2].

Table 2 .
Summary of the actual genetic evidence for SIgMD.

Table 3 .
Summary of the immunological pathogenetic evidence for SIgMD.

Table 6 .
Summary of therapeutic interventions that may be beneficial for SIgMD deficiency.