Shared and unique immune alterations in pre-clinical autoimmunity

Abstract

Progression from health to a classified autoimmune disease is an evolving process that can happen rapidly in some diseases, but usually takes years to develop. Specific immune alterations predate pathogenic autoimmunity and can be used as disease biomarkers to identify high-risk individuals for prevention studies applied in the pre-clinical state. Here we discuss recent findings that illuminate specific immune pathways that are altered in the earliest phases of pre-clinical autoimmunity as well as those mediators more closely associated with later clinically apparent and classified disease onset.

Figure 1.. Cytokines are dysregulated years before RA and SLE development.

Relative levels of dysregulated cytokines in the periphery are shown according to time of appearance for subjects at-risk and/or progressing to autoimmune disease development compared to healthy controls. Cytokines with no significant change compared to healthy controls are shown in white. Cytokine levels that are increased prior to disease development compared to healthy controls are shown in red, while cytokines that are decreased are shown in blue. Darker colors indicate a greater difference between cases and controls. Cytokines with no available information for a particular time point are indicated by NA. Cytokines that appear prior to autoantibody development are marked with an asterisk (*). Those soluble mediators used in predictive models are marked with a numeric symbol (#). Data sets compiled and used to generate relative levels in each row are noted in the far right of each table within the reference column. As plasma/serum cytokines were run in different studies under various conditions, it is important to note that relative levels are not directly comparable between diseases, nor potentially between studies.

Figure 2.. Model of cell frequency differences of lymphocytes at the time of clinical autoimmune diagnosis.

At the time of SLE diagnosis, an increase in activated B cells can be seen in the periphery, while decreases in NK cell and CD4+ T cells are observed in the blood. In RA, an influx of CD8+ and CD4+ T cells (particularly PD-1^hi CXCR5-Tph cells), along with memory B cells is observed in the synovium, with matched decreases in these cell populations in the periphery. Further, increased numbers of activated T cells and B cells are also observed within the lymph node of recently diagnosed RA patients. T1D onset is also associated with infiltration of the pancreas with CD8+ and CD4+ T cells that are localized outside of the islets. Further, decreases in NK cells are also observed in the periphery with T1D onset.

Figure 3.. Summary of early immune differences that arise in RA, SLE, and T1D.

The path to disease progression likely begins with genetic and environmental factors that predispose certain individuals to the disease. Early autoimmunity is recognized by the appearance of autoantibodies and elevated pro-inflammatory cytokine levels. Early autoimmunity can proceed to pathogenic autoimmunity with epitope spreading and expansion of autoantibodies, increasing cytokine levels, and cell activation. Clinical disease development is characterized by the migration of activated cells within the tissues and symptom onset.