Oral bacteria induce IgA autoantibodies against a mesangial protein in IgA nephropathy model mice.

IgA nephropathy (IgAN) is caused by deposition of IgA in the glomerular mesangium. The mechanism of selective deposition and production of IgA is unclear; however, we recently identified the involvement of IgA autoantibodies. Here, we show that CBX3 is another self-antigen for IgA in gddY mice, a spontaneous IgAN model, and in IgAN patients. A recombinant antibody derived from gddY mice bound to CBX3 expressed on the mesangial cell surface in vitro and to glomeruli in vivo. An elemental diet and antibiotic treatment decreased the levels of autoantibodies and IgAN symptoms in gddY mice. Serum IgA and the recombinant antibody from gddY mice also bound to oral bacteria of the mice and binding was competed with CBX3. One species of oral bacteria was markedly decreased in elemental diet-fed gddY mice and induced anti-CBX3 antibody in normal mice upon immunization. These data suggest that particular oral bacteria generate immune responses to produce IgA that cross-reacts with mesangial cells to initiate IgAN.

Subcutaneous immunisation with zymosan generates mucosal IgA-eliciting memory and protects mice from heterologous influenza virus infection.

Immunoglobulin A (IgA) is the most abundant isotype of antibodies and provides a first line of defense at the mucosa against pathogens invading the host. It has been widely accepted that the mucosal IgA response provided by vaccination requires mucosal inoculation, and intranasal inoculation has been proposed for vaccines against influenza virus. Considering the difficulty of intranasal vaccination in infants or elderly people, however, parenteral vaccination that provides the mucosal IgA response is desirable. Here, we demonstrate that subcutaneous immunisation with zymosan, a yeast cell wall constituent known to be recognised by Dectin-1 and TLR2, potentiates the production of antigen-specific IgA antibodies in the sera and airway mucosa upon intranasal antigen challenge. We confirmed that the antigen-specific IgA-secreting cells accumulated in the lung and nasal-associated lymphoid tissues after the antigen challenge. Such an adjuvant effect of zymosan in the primary immunisation for the IgA response depended on Dectin-1 signalling, but not on TLR2. The IgA response to the antigen challenge required both antigen-specific memory B and T cells, and the generation of memory T cells, but not memory B cells, depended on zymosan as an adjuvant. Finally, we demonstrated that subcutaneous inoculation of inactivated influenza virus with zymosan, but not with alum, mostly protected the mice from infection with a lethal dose of a heterologous virus strain. These data suggest that zymosan is a possible adjuvant for parenteral immunisation that generates memory IgA responses to respiratory viruses such as influenza virus.

Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including ßII-spectrin. Most patients with IgAN also have serum anti-ßII-spectrin IgA. As in patients with IgAN, IgA+ plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to ßII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous ßII-spectrin exposed on the surface of embryonic kidney-derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.