Saturday, March 7, 2015

Persistence of immune complexes (ICs) impair Fc-receptor effector functions

Chronic viral infections represent incompletely understood immune condition. Previously it has been shown CD8 T cells functions were impaired during chronic viral infections. 

Now, two new back-to-back papers in journal Immunity provided evidence suggesting that chronic viral infection impairs Fc-receptor effector functions through excessive production and persistence of immune complexes (ICs).

First paper came from David Brooks lab at the University of California, Los Angeles (UCLA). 

The authors (First author Douglas H. Yamada) observed that antibody-mediated depletion of target cell population was severely impaired in chronic LCMV-infected mice (LCMV-Clone 13).

Similar impairment was observed with LCMV-Clone 13 infected mice that receive human CD20 expressing tumor cell line (hCD20-EG7) and depleting α-CD20 antibody (Rituximab).

The authors observed that impairment of antibody-depleting function were selectively impaired in mice infected with LCMV virus producing persistent infection (LCMV-Clone 13), but not with LCMV virus producing acute infection (LCMV-Armstrong).

Additionally, the authors found that the presence of endogenous antibodies were necessary to impair depleting function of exogenously administered antibody.

Adoptive transfer showed that target cells in chronically infected hosts remained susceptible to antibody depletion.  

Additionally, presence of endogenous immune complexes (ICs) but not of free antibodies correlated with depletion deficiency.

Mechanistically, the authors showed that deficiency of macrophage population could recapitulate antibody depleting functional impairment.    

Furthermore, the presence of excess ICs in chronically infected hosts impaired priming of antigen-specific CD8 T cells via defective dendritic cell acquired antigen-antibody complexes.

In summary, these results suggest that excessive production of circulatory ICs during persistent viral infections (HBV, HBC, HIV, etc) impairs antibody-dependent Fc-receptor function (clearance of infected target cells, priming of antigen-specific CD8 T cells). It appears that macrophage Fc-receptors are overwhelmed in the presence of excess circulatory ICs (almost identical research results were presented in the 2nd paper by Rafi Ahmed's lab).

This knowledge could help to better understand the limitations of vaccine efficacy in human populations with chronic viral infections.

David Usharauli

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