How a Nuclear Molecule Alarms the Immune System

A potential influence of HMGB1 on kidney function has also been demonstrated in humans. In patients with chronic kidney disease (CKD), levels of HMGB1 were negatively correlated with glomerular filtration rate (GFR) suggesting that elimination of this protein may be at least partially mediated via the kidney. In this study, serum HMGB1 levels were correlated with inflammatory markers (TNF-α, hs-CRP, IL-6), suggesting that HMGB1 might be used as a predictor of CKD outcome.¹² Furthermore, HMGB1 was shown to be expressed in the sera of patients with vasculitis, IgA nephritis, and glomeruloneprhritis (GN) associated with antineutrophilic cytoplasmic antibody (ANCA).¹³

The significance of HMGB1 in ANCA-associated vasculitic disorders (granulomatosis with polyangiitis [Wegener’s], microscopic polyangiitis [MPA],and Churg-Strauss syndrome [CSS]) has also been investigated.^13,15 ANCA-associated disorders are inflammatory conditions of small–medium -sized vessels known to affect kidneys. These conditions are characterized by focal necrotizing and/or crescentic pauci-immune glomerulonephritis. Since HMGB1 is released from necrotic cells, its role as a potential mediator of inflammation and damage has been investigated in these disorders. As results of these studies showed, serum HMGB1 levels are significantly increased in patients with active granulomatosis with polyangiitis but not in active MPA; these findings suggest that determination of serum HMGB1 levels could be important clinically in differentiating between active forms of ANCA-associated vasculitis.¹⁵

In contrast to this finding, Bruchfeld and colleagues found that serum HMGB1 levels were increased in all patients with active ANCA-associated vasculitis; however, this increase was not specific to certain form of vasculitis and there was no difference in serum HMGB1 levels between subgroups.¹³ This difference of findings of the studies could be explained by the method used for detection of serum HMGB1 (i.e., ELISA vs. Western blot) and differences in disease characteristics.

click for large version

Table 1: Biological Functions of HMGB1

Lupus Nephritis

Systemic lupus erythematosus (SLE) is a classical immune-complex disorder characterized by type III mechanism in association with the production of a wide array of autoantibodies. Patients with SLE present with many different manifestations that vary in intensity and severity. Among these manifestations, nephritis is among the most serious and dangerous clinical problems, often progressing to end-stage disease with associated morbidity and mortality.

While the basis of lupus nephritis has been extensively studied, the underlying pathogenetic mechanisms remain elusive and there is still uncertainty concerning the key events that lead to glomerular inflammation and damage. Importantly, immune complexes have long been considered key effectors in the induction of renal damage in lupus patients. Data for this mechanism derive from several key observations. Thus, studies using immunofluorescence microscopy have revealed immunoglobulin disposition at sites of injury in the lupus kidney. Among these antibodies, antibodies against DNA are the hallmark of the disease and have been shown to correlate with the SLE Disease Activity Index (SLEDAI). These antibodies can participate in the formation of immune complexes that can be deposited in tissues such as the skin and kidney; this deposition, in turn, activates complement to initiate inflammatory responses.^2,16