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

Abstract

Autoantibodies can be present years to decades prior to the onset of disease manifestations in autoimmunity. This suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. Here we show 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 early anti-CD40L greatly repressed B cell function, while having a broader effect on multiple biological pathways including IL-12 and interferon signaling. Importantly, a single, prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and NOD mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest early peripheral immune dysregulation gives rise to autoimmune manifestations later in life and for diseases pre-dated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.

Myd88 is required for disease development in a primary Sjögren's syndrome mouse model

“…In contrast, immune cells may become activated in the periphery and enter the salivary tissue stochastically in SS. Support for this scenario is provided by recent work in a related NOD model (NOD.H-2h4), demonstrating that blockade of CD40 ligand before disease onset abrogates splenic germinal center formation and prevents salivary gland inflammation and autoantibody production later in life [55]. Data from human studies provide support for the importance of early peripheral immune dysregulation in disease, as antibody production is reported to occur years before onset of salivary dysfunction in pSS patients [56,57].…”

To reflect human autoimmune thyroiditis, thyroid peroxidase (not thyroglobulin) antibodies should be measured in female (not sex-independent) NOD.H2h4 mice

“…However, on this regimen there is no difference between sexes in the development of thyroid autoimmunity [9,10], for which reason later studies on NOD.H2 h4 mice involved either one sex or groups of mixed sex [11][12][13][14][15][16][17]. For Hashimoto's thyroiditis, NOD.H2 h4 mice are the most practical and commonly studied model.…”

“…Of note, these studies did not assess TPOAb, a more important marker than TgAb for autoimmune thyroiditis in humans. Consequently, although some investigations in NOD.H2 h4 mice focused on males [11] or females [12,13], many studies combined their observations for both sexes (for example [14,15] or reported their findings without providing mouse sex [16], as in one of our own studies [17]. With this experimental protocol, sexual dimorphism for thyroid autoimmunity has not been observed in NOD.H2 h4 mice, a major difference with human disease.…”

The Importance of Dendritic Cells in Maintaining Immune Tolerance

“…DCs from prediabetic NOD mice have increased CD40 expression that is dependent on adaptive immune cells. Increased CD40 expression could be more indicative of inflammation, as blocking CD40 signals blocks NOD autoimmune diabetes pathogenesis (145–148). …”