SelectiveIgM Deficiency

M. Julia B. Felippe

■ Definition and Etiology Selective IgM deficiency is a very rare, poorly characterized immunologic disorder described based on absent or markedly decreased serum IgM concentra­tions with normal or elevated levels of other Ig isotypes.¹ Three presentations of the disorder have been described in horses.^2-6 The most common involves foals that have severe infectious pneumonia, arthritis, or enteritis, resulting in death before 10 months of age.

1 to 2 years. The third involves older horses that are usually

2 to 5 years of age at initial diagnosis. These horses do not necessarily have problems with recurrent infections, but about half ultimately have lymphosarcoma.⁶ Selective IgM deficiency has been most frequently reported in Arabians and American Quarter Horses, although it affects other breeds.

It is unclear whether the selective IgM deficiencies reported in foals are primary or secondary or are a feature of other immunodeficiencies. The levels of endogenous IgM present before the onset of infections have not been measured. The occurrence of multiple cases within groups of related horses suggests a genetic basis. However, to date, breeding trials have been inconclusive regarding the heritability of this condition. In humans, there is no described genetic or molecular mecha­nism as the cause of selective IgM deficiency, and this condition has been shown to manifest with infections, atopy, autoim­munity, and cancer, although it can also be asymptomatic.^7-9 Recent literature points out the importance of ruling out other humoral deficiencies and performing clinical case follow-up to confirm persistence of selective IgM deficiency.

■ Clinical Signs and Differential Diagnoses Foals with selective IgM deficiency tend to have frequent respiratory infections, and Klebsiella spp. are commonly isolated. Other infections, such as enteritis and septic arthritis, have also been reported. The age of onset of clinical signs may be slightly later than in foals with SCID, and the condition may be difficult to diagnose when colostrum-derived antibodies are still circulat­ing. The most important differential diagnosis is delayed hypogammaglobulinemia of the young, which may take several months (i.e., 6 to 24 months) to resolve.

Although low serum IgM concentration has been shown to have a low specificity, sensitivity, and positive predictive value for the diagnosis of lymphoma, older horses with IgM deficiency should be carefully evaluated for neoplasia using definitive diagnostic tests (e.g., lymph node biopsy, cytology, and histology), since the clinical signs and hematologic features of lymphoma in horses are often nonspecific¹⁰ (see Chapter 37).

■ Clinical Pathology Selective IgM deficiency is defined by a persistently low or absent serum IgM concentration, whereas levels for other classes of Ig are normal or elevated for age. Serum IgM concentrations are more than two standard deviations below the age-specific mean (see Table 53.6). In one study, serum IgM concentrations in adult healthy horses during a period of 5 months ranged from 50 to 242 mg/dL, and 20% of these horses had values below 60 mg/dL; based on these data, IgM deficiency was suggested at values lower than 23 mg/dL.¹⁰ Serum IgM concentration of 10 to 22 mg/ dL may be measured beyond 185 days of gestation in the equine fetus, and levels of 25 mg/dL may be measured in presuckle foals; however, there is marked individual variation in how serum IgM concentration increases with age.^11-13 Because IgM levels may transiently decrease, especially in critically ill foals, it is essential to document that IgM levels are persistently low rather than to base a diagnosis on a single sample. Lymphocyte counts and other in vitro immunologic tests, such as lymphocyte proliferation to mitogens (including PHA, ConA, PWM, and LPS), are generally normal.^2,4 However, in one horse with selective IgM deficiency, lymphocytes failed to respond to the B-cell mitogen LPS, whereas responses to the T-cell mitogens ConA and PHA were normal.⁵ The hemogram and biochemical profile may reflect infection or inflammation, depending on the underlying infectious process (e.g., neutrophilia, hyperfibrinogenemia, anemia) and the organ system involved, but no diagnostically specific changes occur.

■ Pathophysiology The pathophysiology of selective IgM deficiency is difficult to explain when B-cell development in the bone marrow depends on IgM expression on the cell surface, as part of the B-cell receptor, and patients have normal numbers of IgM-expressing B cells.^1,7,8 Exclusive impaired secretion of IgM could be caused by intrinsic B-cell dysfunction or dysfunction of T cells during B cell-T cell interaction in lymphoid tissues, but it is curious why such deficiencies do not affect more elaborated B-cell differentiation into other isotype (e.g., IgG, IgA)-secreting plasma cells. Whether IgM is low because of decreased production, hypercatabolism, or loss is not known. In one case with lymphosarcoma, suppressor activity was identified in the neoplastic cells, suggesting that the low IgM may be a result of suppression of B-cell function by neoplastic cells.^5,14 IgM plays a role in complement activation and neutralization of antigens, but such functions can also be accomplished by IgG or IgA, which are generally within normal levels.

■ Necropsy Findings Lymphoid tissue in affected foals is grossly and histologically normal. Other findings reflect secondary infections. Pneumonia is frequently present and is often caused by infections with encapsulated bacteria (e.g., S. aureus, S. zooepidemicus, A. equuli, Klebsiella spp., and E. colt).¹*

■ Treatment and Prognosis For the clinical cases diagnosed in the literature, selective IgM deficiency has an unfavorable long-term prognosis. Most horses eventually succumbed to infection despite appropriate antimicrobial therapy. However, some of the reported foals recovered IgM and IgG productions when yearlings.^2,4 Plasma therapy may provide transient benefit not for IgM replacement (because only small amounts of IgM are present in plasma and the half-life of transfused IgM is short) but for expansion of IgG concentration and potentially coverage (neutralization, opsoniza­tion, complement activation) against pathogens.⁷ No concen­trated IgM preparations are commercially available for parenteral use. If persistently low IgM levels can be documented, a poor to grave prognosis can be expected.

■ Prevention and Control Some cases of selective IgM deficiency may be hereditary, and therefore it may be advisable to avoid repeating matings that produced an affected offspring. However, no firm recommendations can be made.