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Autoimmune manifestations in aged mice arise from early-life immune dysregulation

Tamer I. Mahmoud,Jingya Wang,J. Karnell,Qiming Wang,Shu Wang,B. Naiman,P. Gross,P. Brohawn,C. Morehouse,J. Aoyama,C. Wasserfall,L. Carter,M. Atkinson,D. Serreze,H. Braley‐Mullen,T. Mustelin,R. Kolbeck,R. Herbst,R. Ettinger

Published 2016 in Science Translational Medicine

ABSTRACT

Autoimmune manifestations are driven by peripheral immune dysregulation in early life and are prevented by prophylactic targeting of the CD40/CD40L pathway. Costimulatory blockade curbs development of autoimmunity Autoimmunity is often driven by the collaboration of autoreactive B cells and T cells, which communicate with each other through antigen presentation, cytokines, and costimulatory molecules such as CD40 and CD40 ligand. Mahmoud et al. showed how a single dose of antibody blocking CD40 ligand administered early in life can interrupt development of autoimmunity. This was dependent on the disruption of tertiary lymphoid structures and was effective in mouse models of Sjögren’s syndrome, type 1 diabetes, and autoimmune thyroiditis. These striking results suggest that early blockade of this costimulatory pathway could prevent at-risk individuals from developing autoimmunity. Autoantibodies can be present years to decades before the onset of disease manifestations in autoimmunity. This finding suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. We show that Sjögren’s syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren’s pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks of age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed that early anti-CD40L greatly repressed B cell function while having a broader effect on multiple biological pathways, including interleukin-12 and interferon signaling. A single prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and nonobese diabetic mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life, and for diseases predated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.

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