Antibodies: The New Kids on the Intracellular Block

On the first day of class, we learned that antibodies patrol the extracellular fluids for pathogens and T-cells survey what is going on inside the cells. Once a virus finds a new intracellular home, antibodies are not effective. As it turns out, immunologists were underestimating the antibody. In a study published yesterday, researchers showed that antibodies have an intracellular role in pathogen neutralization. Tripartite motif-containing 21 (TRIM21) is a cytosolic protien with an extremely high-affinity Fc binding domain. When IgM or IgG binds adenovirus, the antibody enters the host cell with the virus. TRIM21 is recruited to the complex, and binds the Fc domain. Proteases are recruited, and the virus is degraded inside the cell, before it has a chance to replicate. The authors report that without antibody, adenovirus infected about 50% of the cells. With 400ng/mL antibody, infection was reduced about 60 fold. With TRIM21 siRNA (TRIM21 knockdown) and 400ng/mL antibody, infection was only reduced by about 3 fold, indicating TRIM21’s neutralizing effect.

This method of virus neutralization has several advantages. First, this is a noncytotic process because it targets the virus rather than an infected cell. Additionally, the virus is neutralized before transcription, inhibiting the spread if infection. TRIM21 is also expressed on most tissues, not just the professional cells of the immune system. Its ability bind to IgM and IgG isotypes also make it a useful mechanism in the early immune response, and later when the T-cells are involved. The authors suggest that stimulation of TRIM21 may be a new target for vaccines. The mechanism for TRIM21 neutralization of other viruses has not been elucidated, nor whether this process works on enveloped viruses.

Donna L. Mallerya,1, William A. McEwana,1, Susanna R. Bidgooda,1, Greg J. Towersb, Chris M. Johnsona, and Leo C. Jamesa. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proceedings of the National Academy of Sciences of the United States of America. 2010 doi: 10.1073/pnas.1014074107