Antibodies come in a few different flavors. In lupus, antibodies against the body’s own tissues—called autoantibodies—clump up to form large immune complexes that cause organ damage in people with lupus, worsening the progression of disease. Most of the autoantibodies in the complexes are of one particular shape, called IgG. Though most research focus has been on how IgG in immune complexes causes disease in lupus, Dr. Hamerman’s group is studying a different type of autoantibody called IgA. She has also shown that these IgA’s stimulate the immune system in lupus.

In her future work funded with the Lupus Mechanisms and Targets Award, she plans to test if these newly discovered IgA autoantibodies are key in the development of lupus, and if so, if they might be targeted with new drugs.

What this means for people with lupus

Dr. Hamerman showed that a type of autoantibody, IgA, that has not been well studied before, is important in lupus. If IgA proves key in causing the disease, it may offer a good target for drug development.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence of circulating autoantibodies to nucleic acids and proteins with which they associate, termed anti-nuclear antibodies (ANA). Immune complexes (IC) containing ANA and self-antigens from dying cells are pathological in SLE due to immune complex deposition in organs, and they also promote a feed forward loop in SLE by enhancing immune responses in leukocytes that can endocytose these complexes. ANA immune complexes facilitate nucleic acid entry to the endosome via receptors binding the Fc portion of antibodies, where the endosomal-resident Toll-like receptors (TLRs) can promote cytokine production upon binding nucleic acids. Importantly, most studies have focused on IgG isotype ANA immune complex uptake and function despite the fact that SLE patients often have ANAs of multiple isotypes. Plasmacytoid dendritic cells (pDCs) are one leukocyte that internalizes ANA ICs and responds to nucleic acids within ICs by producing high levels of type I IFNs, cytokines important in SLE pathogenesis. pDCs express the IgG binding Fc receptor FcgRIIa (CD32a) through which they internalize IgG-containing ANA IC, and pDCs also express FceRI and internalize IgE-containing ANA IC leading to IFNa production. However, IgE represents only ~0.01% of total serum antibodies. In contrast, IgA makes up ~15% of serum antibodies and IgA ANA have been identified in ~1/2 of SLE patients, yet the function of IgA in ANA IC in SLE has not been studied. Additionally, it is not known if pDCs express the human-specific IgA Fc receptor FcaRI (CD89). We show novel preliminary data that human pDC express the IgA FcR FcaRI/CD89, that IgA in SLE serum is a critical component of IC-mediated pDC IFNa secretion, and that pDC from SLE donors have increased FcaRI/CD89 expression compared to those from healthy control donors. In Aim 1, we will define the synergy between IgA and IgG in smRNP-containing immune IC, generate novel reagents for these studies, and identify the mechanism of synergy between IgA and IgG. In Aim 2, we will determine if pDCs from SLE donors have increased FcaRI/CD89 expression, correlate this expression with specific disease parameters, and determine if this increased expression leads to increased pDC IFNa production in SLE. Experiments in this proposal will use human samples from healthy control donors and lupus donors available through the Benaroya Research Institute Immune Mediated Disease Registry and Repository. Our preliminary data suggest that the role of IgA autoantibodies in immune complex activation of pDC via FcaRI/CD89 is an important unexplored mechanism in SLE. Successful completion of the proposed research will allow us to understand if the IgA-FcaRI/CD89 axis is a therapeutic target for the subset of SLE patients with IgA autoantibodies.