eMedicine Specialties > Allergy and Immunology > Immunodeficiencies
Immunoglobulin M Deficiency
Updated: Jun 8, 2006
Introduction
Background
Selective immunoglobulin M deficiency (SIgMD) is a rare form of dysgammaglobulinemia characterized by an isolated low level of serum immunoglobulin M (IgM). Reported IgM concentrations in SIgMD vary from 40 mg/dL (though some sources say 20 mg/dL) to undetectable levels (reference range 45-150 mg/dL in adults) (Sorenson, 2000). Values in children must be compared with reference range values for age (Ballow, 2002). The levels of other immunoglobulin classes are within reference ranges.
SIgMD may occur as a primary or secondary condition. Secondary SIgMD is much more common than primary SIgMD and may be seen in association with malignancy, autoimmune disease, gastrointestinal disease, and in patients treated with immunosuppressive agents.
Some patients are asymptomatic, whereas others (often infants and small children) develop serious infections. Patients may develop prolonged or life-threatening infections caused by both encapsulated bacteria and viruses, especially in infancy. In older children and adults, SIgMD is usually discovered during the investigation of other conditions, such as autoimmune disease or malignancy.
Serum immunoglobulin levels are controlled by intricate immunological regulatory mechanisms, and heterogeneity is believed to exist in the pathogenesis of SIgMD. Little is known about the pathological features of SIgMD at a cellular level, given that the condition is so uncommon.
Pathophysiology
The cause of SIgMD is unknown. Increased regulatory T-cell activity specific for IgM has been described (Ohno, 1987). The absence of IgM in the presence of immunoglobulin G (IgG) and immunoglobulin A (IgA) has yet to be explained, as this appears to contradict the theory of sequential immunoglobulin gene rearrangement. Normal mature B cells are expected to have IgM and immunoglobulin D (IgD) on their surfaces, and, with proper stimulation, rearrange their immunoglobulin genes to switch from expressing IgM to IgG, IgA, or immunoglobulin E (IgE).
Having normal levels of IgG and IgA in the face of a low IgM is thus counterintuitive. However, few studies are available to determine whether only the serum IgM level is low or whether the number of B cells with surface IgM is also decreased in most patients. Most of the studies in the literature on this subject were performed before current understanding of the rules governing B-cell switching was elucidated. Gradually, current state-of-the-art laboratory technology is being applied in studying patients with SIgMD, though much remains to be learned at this point.
The currently available literature suggests a heterogeneous population of patients of SIgMD. Some patients are capable of normal antibody responses of other immunoglobulin classes following specific immunization, whereas others respond poorly. Certain patients have been described who have decreased helper T-cell activity (De la Concha, 1982). Cell-mediated immunity appears to be intact, but an insufficient number of detailed studies are available to confirm this. Suggested etiologies include rapid isotype switching of B cells from production of IgM to production of other isotypes and hypercatabolism of IgM.
Frequency
International
SIgMD is rare, with an incidence of less than 0.03% in the general population and 1% in hospitalized patients (Inoue, 1986).
Mortality/Morbidity
Infants can succumb to overwhelming infections such as meningitis, pneumonia, and gram-negative sepsis.
Patients with SIgMD are susceptible to overwhelming infection with encapsulated bacteria (eg, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae). They may also have autoimmune disease, malignancies, chronic dermatitis, diarrhea, and upper respiratory infections.
Race
The incidence of SIgMD in various races has not been reported, given the low overall incidence.
Sex
The disorder occurs in both males and females, with no known discrepancies between the sexes.
Age
Infants can present with severe and overwhelming infections. Older children may present with recurrent sinopulmonary infections secondary to encapsulated organisms and an increased incidence of gram-negative septicemia.
Clinical
History
- Patients may be asymptomatic, with a decreased IgM level noted during the investigation of other diseases, such as malignancies or autoimmune diseases.
- Prolonged or life-threatening infections also occur, especially in infancy. Recurrent infections (eg, sinusitis and pneumonia) are caused by encapsulated bacteria. Infections with gram negative bacteria are also more common, especially with Pseudomonas aeruginosa.
- Associated disorders or symptoms may include atopic or chronic dermatitis, allergic rhinitis, wheezing, and diarrhea. Patients may have a history of splenectomy.
Physical
Failure to thrive may be present, due at least in part to frequent infections. Other associated signs may include features of dermatitis, allergic rhinitis, wheezing, and splenomegaly, as well as those of other primary conditions associated with secondary SIgMD, such as malignant or autoimmune disorders.
Causes
The cause of SIgMD is unknown, and any pattern of inheritance appears to be variable.
- Patients with malignant neoplasms (eg, clear cell sarcoma, Bloom syndrome, promyelocytic leukemia), autoimmune diseases (eg, rheumatoid arthritis, Hashimoto's thyroiditis, systemic lupus erythematosus, autoimmune hemolytic anemia), infections (eg, Brucella), or those given immunosuppressive agents may develop secondary SIgMD (Yamasaki, 1992; Herrod, 2001).
- As cited by Zaka-ur-Rab (2005), associations exist between SIgMD and gastrointestinal conditions, including Crohn disease, chronic diarrhea, lymphoid nodular hyperplasia, Whipple disease, and splenomegaly.
- Infants with permanent congenital hypothyroidism were shown to have undetectable or lower concentrations of IgA and lower concentrations of IgM than normal controls (Stagi, 2005).
- A report of 13 multiple myeloma patients in a phase 2 study showed that the 7 patients who received rituximab following autologous stem cell transplantation developed severely depressed levels of IgM that were persistent with continued rituximab therapy. When compared to the 6 myeloma patients who had received autologous stem cell transplantation without rituximab, not only were IgM levels significantly decreased, but those in the rituximab group experienced far more infections, including 21 cases of pneumonia, 2 cases of sepsis, and one death during the first 12 months (Lim, 2004).
- One case report describes a 15-year-old female with 22q11.2 deletion syndrome (in her case, partial DiGeorge Syndrome) who presented with recurrent and chronic otitis media who was found to have SIgMD, associated with no other immunologic defects (Al-Herz, 2004).
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References
Al-Herz W, McGeady SJ, Gripp KW. 22q11.2 deletion syndrome and selective IgM deficiency: an association of a common chromosomal abnormality with a rare immunodeficiency. Am J Med Genet. 2004;127A:99-100.
Ballow M. Primary immunodeficiency disorders: antibody deficiency. J Allergy Clin Immunol. 2002;109:581-91.
De la Concha EG, Garcia-Rodriguez MC, Zabay JM. Functional assessment of T and B lymphocytes in patients with selective IgM deficiency. Clin Exp Immunol. Sep 1982;49(3):670-6. [Medline].
Fallon KE. Inability to train, recurrent infection, and selective IgM deficiency. Clin J Sport Med. 2004;14:357-9.
Faulk WP, Kiyasu WS, Cooper MD. Deficiency of IgM. Pediatrics. Feb 1971;47(2):399-404. [Medline].
Guill MF, Brown DA, Ochs HD. IgM deficiency: clinical spectrum and immunologic assessment. Ann Allergy. Jun 1989;62(6):547-52. [Medline].
Herrod, HG. Common variable hypogammaglobulinemia and other humoral immune deficiencies. [Full Text].
Inoue T, Okumara Y, Shirahama M, et al. Selective partial IgM deficiency: Functional assessment of T and B lymphocytes in vitro. J Clin Immunol. 1986;6(2):130-5. [Medline].
Lim SH, Zhang Y, Wang Z, et al. Rituximab administration following autologous stem cell transplantation for multiple myeloma is associated with severe IgM deficiency. Blood. 2004;103:1971-2.
Nies KM, Stevens RH, Louie JS. Impaired immunoglobulin M synthesis by peripheral blood lymphocytes in systemic lupus erythematosus: a primary B-cell defect. Clin Immunol Immunopathol. Apr 1981;19(1):118-30. [Medline].
Ohno T, Inaba M, Kuribayashi K. Selective IgM deficiency in adults: phenotypically and functionally altered profiles of peripheral blood lymphocytes. Clin Exp Immunol. Jun 1987;68(3):630-7. [Medline].
Sorensen RU, Moore C. Primary immune deficiencies: presentation, diagnosis, and management. Pediatr Clin North Am. 2000;47:1240.
Stagi S, Azzari C, Bindi G, et al. Undetectable serum IgA and low IgM concentration in children with congenital hypothyroidism. Clin Immunol. 2005;116:94-8.
Yamasaki T. Selective IgM deficiency: functional assessment of peripheral blood lymphocytes in vitro. Intern Med. Jul 1992;31(7):866-70. [Medline].
Zaka-ur-Rab Z, Gupta P. Pseudomonas septicemia in selective IgM deficiency. Indian Pediatrics. 2005;42:961-2.
Further Reading
Keywords
selective IgM deficiency, SIgMD, hypogammaglobulinemia, IgM, IgM deficiency
