Progranulin Antibodies a Common Link in Vasculitis, Lupus, and RA

Patients with autoimmune rheumatic diseases (ARD) such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) face a significantly higher risk of cardiovascular disease (CVD), and often develop it earlier than people without underlying autoimmunity. It’s not yet clear whether CVD is a general consequence of RA and SLE, or whether it only affects a subgroup of patients. Researchers believe that controlling autoimmune inflammation with disease-modifying anti-rheumatic drugs (DMARDs) — especially those targeting immune factors also involved in vasculitis, like T and B cells — has a protective effect. One focus of current research is identifying commonalities across multiple ARDs that point to specific mechanisms behind ARD-related CVD, in order to develop diagnostics, preventatives, and treatments for patients at greatest risk.

IgG2 antibody

A recent article in the Journal of Autoimmunity points to anti-progranulin antibodies as one potential mechanism. Thurner and colleagues used a protein macro-array to screen serum from patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides for novel autoantibodies specific to these diseases. Of six candidate autoantigens reactive with pooled vasculitis patient serum, <\/span>progranulin was the only autoantigen appearing in every vasculitis studied. Extended screening showed that a positive progranulin antibody titer wasn’t specific to vasculitides, though: while its prevalence was low in healthy controls (1/97 or 1%) and patients with melanoma (0/98) or sepsis (0/22), progranulin antibodies also turned up in serum from patients with RA (16/44 or 36%) and SLE (39/91 or 43%).

How Progranulin Affects Inflammation

Progranulin — also called proepithelin, granulin-epithelin precursor, or acrogranin — is a glycoprotein secreted by epithelial cells, neurons, and certain leukocytes. Beyond its growth factor-like activity, progranulin has immunomodulatory effects both in vitro and in vivo. Full-length progranulin reduces oxidant production by activated neutrophils, blocks TNFα-induced immune responses by binding to TNFR-1 and -2, and promotes upregulation of IL-4, IL-5, and IL-10. Progranulin deficiency in mice worsens inflammation in collagen-induced arthritis (CIA) and collagen antibody-induced arthritis models of human RA. Treating either progranulin-deficient or wild-type mice with recombinant human progranulin eases CIA inflammation.

Several proteases cleave progranulin into mature granulins. Unlike progranulin, neither recombinant nor proteolytically released granulins block TNFα — instead, granulins increase expression of the pro-inflammatory cytokines IL-1β, IL-8, and TNFα. SLPI and apolipoprotein A-I binding protect progranulin from being cleaved by matrix metalloproteinases and other proteases. But during inflammation, neutrophils and macrophages release serine proteases that increase progranulin’s digestion. In the context of ongoing inflammation in ARD, this may increase the conversion of anti-inflammatory progranulin into pro-inflammatory granulin.

What This Means for Diagnosis and Treatment

Thurner et al. are the first to report neutralizing anti-progranulin antibodies in RA, SLE, and small- and medium-vessel vasculitides — a pattern that may represent a pro-inflammatory mechanism shared across several autoimmune diseases. Their findings add support for exploring the progranulin/granulin pathway as a therapeutic target, and suggest anti-progranulin antibodies could serve as a diagnostic or prognostic tool in ARD. Further studies using sera from patients with known autoimmune disease states are needed to confirm these findings and address the questions they raise: What causes the failure of self-tolerance to progranulin and the resulting anti-progranulin antibodies, seen in roughly 20-40% of the patients in this study? Are these anti-progranulin antibodies common across all autoimmune diseases? Could progranulin-neutralizing antibodies become a biomarker in ARD — for example, as a predictor of DMARD therapy response, or an indicator of future progression to ARD-related CVD? We look forward to the results of these and other studies in this area.

Further Reading:

Progranulin antibodies in autoimmune diseases. Thurner L, Preuss KD, Fadle N, Regitz E, Klemm P, Zaks M, Kemele M, Hasenfus A, Csernok E, Gross WL, Pasquali JL, Martin T, Bohle RM, Pfreundschuh M. J Autoimmun. 2013 May; 42:29-38.

Insights into the role of progranulin in immunity, infection, and inflammation. Jian J, Konopka J, Liu C. J Leukoc Biol. 2013 Feb; 93(2):199-208.

Cardiovascular disease in autoimmune rheumatic diseases. Hollan I, Meroni PL, Ahearn JM, Cohen Tervaert JW, Curran S, Goodyear CS, Hestad KA, Kahaleh B, Riggio M, Shields K, Wasko MC. Autoimmun Rev. 2013 Aug; 12(10):1004–1015.

Sanguine supplies research-grade human serum for studies like this.