IgM levels are found markedly elevated in a series of autoimmune diseases. Whether increased IgM levels participate in the induction of autoimmunity or represent epiphenomena is unclear. IgM autoantibodies against specific antigens are frequently found in autoimmune conditions.
Fig. 1. Scheme of IgM immune response. (Duarte-Rey, 2012)
Common IgM-related Autoimmune Disorders
- Autoimmune hemolytic anemia (AIHA)
AIHA is characterized by red cell lysis with specific IgM and IgG autoantibodies directed against erythrocytes. The annual incidence of AIHA is 1 to 3 per 100,000, it is found in people of all ages, but more common in adults. There are 4 distinctive clinical types of AIHA: warm AIHA, cold agglutinin syndrome, mixed-type AIHA, and paroxysmal cold hemoglobinuria, principally determined by the temperature in which anti-globulins bind with RBC. IgM antibodies related to AIHA behave as cold-reacting antibodies (reacting at 4℃) in vitro, however, in vivo, they are able to fix complement to polysaccharides at temperatures below 37℃. Because of the high molecular weight of IgM, agglutination in the intravascular compartment is common. Patients with IgM-mediated AIHA typically have what are coined cold agglutinins. Warm AIHA is usually caused by IgG antibodies, which are reactive at 37℃ and cold AIHA is typically caused by IgM autoantibodies that are reactive at 4℃.
- Cryoglobulinemia
There are three types of cryoglobulin groups. Type I makes up 10 to 15% of the total cryoglobulins found and is made up of single monoclonal immunoglobulin, an IgM paraprotein. Other less common forms are IgG and light chains proteins found in urine. The presence of IgM paraproteins, suggests the concurrence of an active lymphoproliferative disorder. Type II are the most common cryoglobulins found in more than half of the reported cases. Occasionally, they belong to an IgG isotype. Nonetheless, the IgM fraction demonstrates rheumatoid factor (RF) activity toward polyclonal IgG, the F(ab)2 fragment, and also with the Fc fragment of autologous IgG, creating stable immune complexes that subsequently deposit on healthy tissue, activating inflammatory pathways. Type III cryoglobulinemia accounts for approximately 25 to 30% of the cryoglobulins and is characterized by belonging to polyclonal IgG and IgM isotypes. Other types of oligoclonal IgM are said to belong to types II and III variants referred to as mixed cryoglobulinemia (MC).
- Multiple sclerosis (MS)
There is a subset of patients with multiple sclerosis that have more aggressive disease and an increase of CD5+ B lymphocytes in cerebrospinal fluid (CSF). Oligoclonal IgM band detection of intrathecal antibody synthesis, along with C3 complement in CSF has also been described. The concentration of IgM in CSF correlates with the concentration of myelin basic protein, which was established as a demyelination index. The presence of this marker is associated with a poor prognosis in adults, but not pediatric patients. IgM reacts to lipid-specific IgM and activates complement-dependent demyelination. Thus, it augments pathology, including myelin phagocytosis by macrophages.
- Primary biliary cirrhosis (PBC)
PBC is a liver-specific autoimmune disease where destruction of small and medium-size intrahepatic bile ducts takes place, with accompanying portal inflammation and progressive fibrosis. The serologic hallmark of PBC is antimitochondrial autoantibodies directed in particular to the E2 component of pyruvate dehydrogenase complex (PDC-E2). The vast majority of patients with PBC have elevated serum IgM but normal levels of IgG and IgA. Such IgM is pentameric, with only 5% of sera IgM belonging to the monomeric form. Using immunohistochemistry, plasma cell infiltrates expressing IgM are frequent compared to other autoimmune liver diseases. Interestingly, the presence of high levels of IgM in sera is directly related to the presence of interlobular bile duct lesions.
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Reference
- Duarte-Rey, C.; et al. IgM predominance in autoimmune disease: genetics and gender. Autoimmun Rev. 2012, 11(6-7): A404-12.
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