Researchers highlighted the importance of autoreactive immunoglobulin M (IgM) in establishing autoimmune diseases such as cold agglutinin disease (CAD) in a literature review published in Antibodies. 

The immune system seeks to preserve physiological homeostasis by avoiding self-destruction features, which is sometimes known as autoimmune reactions. In autoimmune diseases such as CAD, autoreactive B cells may be subject to peripheral tolerance mechanisms, ultimately rendering B cells unable to respond to monovalent antigens. 

To date, a number of diagnostic criteria focus on immunoglobulin G (IgG) autoantibodies and ignore autoreactive IgM. Studies indicate that patients who are unable to class-switch to IgG and hence only able to produce IgM autoantibodies are candidates for severe autoimmunity. Numerous studies indicate that autoreactive IgM plays a significant role in autoimmune pathogenesis. 

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“Here, autoreactive IgM targeting red blood cells (autoimmune hemolytic anemia) or thrombocytes (idiopathic thrombocytopenic purpura) lead to a drastic autoimmune phenotype,” the authors of the review wrote.

During the COVID-19 pandemic, the issue of whether SARS-Cov-2 triggered autoimmunity became the subject of much discussion. Studies conducted during this period suggest that IgM autoantibodies are primarily associated with the SARS-Cov-2 antibody response. 

“In summary, the production of autoreactive IgM upon infection that does almost certainly not belong to the class of [natural IgM] indicates the presence of an autoreactive canonical B cell population capable of differentiating into IgM+ plasma cells,” the authors of the study wrote. 

Read more about CAD etiology 

With regard to autoimmune diseases, clinicians have largely switched from using certain autoreactive IgGs as a diagnostic aid, preferring to measure IgM autoantibody involvement instead. For example, in rheumatoid arthritis, research indicates that anti-modified protein antibodies (AMPA) IgM can readily bind to modified self-proteins and thus drive disease progression. 

“The mechanisms by which IgM autoantibodies induce pathology might differ from effects that IgG autoantibodies with identical specificities exert on targets,” the authors of the study wrote. “Further, autoreactive B cells that differentiate into IgM autoantibody-secreting plasma cells might cause a vast variety of autoimmune diseases via pathogenic IgM autoantibodies.” 


Amendt T, Yu P. TLR7 and IgM: dangerous partners in autoimmunityAntibodies (Basel). 2023;12(1):4. doi:10.3390/antib12010004