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) have a significantly increased risk of developing cardiovascular disease (CVD) and often develop CVD earlier than those without underlying autoimmunity, although it is not clear whether CVD is a general consequence of RA and SLE or only affects a subgroup of patients.  Control of autoimmune inflammation by disease-modifying anti-rheumatic drugs (DMARD), especially those that target immune factors also involved in vasculitis (e.g., T and B cells), is believed to have a protective effect.  One area of current research is focused on identifying commonalities across multiple ARD that suggest specific mechanisms of ARD-related CVD in order to develop diagnostics, preventatives, and treatments for those at greatest risk.

IgG2 antibody
IgG2 antibody

A recent article in the Journal of Autoimmunity suggests 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 the six candidate autoantigens reactive with pooled vasculitis patient serum, progranulin was the only autoantigen appearing in every one of the vasculitides studied.  However, extended screenings showed that a positive progranulin antibody titer was not specific for vasculitides; although the prevalence was low in healthy controls (1/97 or 1%) and patients with melanoma (0/98) or sepsis (0/22), progranulin antibodies were also detectedin serum from patients with RA (16/44 or 36%) and SLE (39/91 or 43%).

Progranulin, also called proepithelin, granulin-epithelin precursor, or acrogranin, is a glycoprotein secreted by epithelial cells, neurons, and certain leukocytes.  In addition to growth factor-like activity, progranulin has immunomodulatory effects in vitro and in vivo.  Full-length progranulin decreases oxidant production by activated neutrophils, blocks TNFα-induced immune responses via binding to TNFR-1 and -2, and promotes up-regulation of IL-4, IL-5, and IL-10.  Progranulin deficiency in mice results in greater inflammation in collagen-induced arthritis (CIA) and collagen antibody-induced arthritis models of human RA; treatment of either progranulin-deficient or wild-type mice with recombinant human progranulin ameliorates CIA inflammation.

Progranulin is cleaved by several proteases into mature granulins.  Neither recombinant nor proteolytically released granulins antagonize TNFα.  Rather, granulins increase expression of pro-inflammatory cytokines IL-1β, IL-8, and TNFα.  SLPI and apolipoprotein A-I binding to progranulin protects it from cleavage by matrix metalloproteinases and other proteases.  However, during inflammation, neutrophils and macrophages release serine proteases that increase progranulin digestion.  In the context of ongoing inflammation in ARD, this may result in increased cleavage of anti-inflammatory progranulin to pro-inflammatory granulin.

Thurner et al. are the first to report the presence of neutralizing anti-progranulin antibodies in RA, SLE, and small- and medium-vessel vasculitides, which may represent a pro-inflammatory mechanism common to several autoimmune diseases.  Their findings provide additional support for exploration of the progranulin/granulin pathway as a therapeutic target and suggest the potential use of anti-progranulin antibodies as a diagnostic and/or prognostic tool in ARD.  Further studies using sera of patients with known autoimmune disease states are needed to confirm these findings and address the additional questions raised, such as –  What causes the failure of self-tolerance to progranulin and the generation of anti-progranulin antibodies, as seen in ~20-40% of the patients in this study?  Are these anti-progranulin antibodies common to all autoimmune diseases?  Could the development of progranulin-neutralizing antibodies even become a biomarker in ARD, for example as a predictor of responsiveness to DMARD therapy, or an indicator of future progression to ARD-related CVD?  We await the results of these and other studies in this area with great interest.

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.

Identification of New Potential Drug Targets for Treatment of Lupus

autoantibodies Systemic lupus erythematosus (SLE) is a complex autoimmune disease that afflicts tens of millions of people worldwide.  The most prominent feature is generation of “autoantibodies” to self-proteins and nucleic acids, resulting in immune complex (IC) formation and organ inflammation.  Affected patients may demonstrate rashes, joint pain, anemia, or kidney damage, and untreated complications can often be fatal.  In addition, most SLE patients demonstrate continuously elevated levels of interferon (IFN) α, which is naturally produced by activated plasmacytoid dendritic cells (pDCs) 1.  pDCs are a rare subset of DCs found in the blood and peripheral lymphoid organs that function in host defense by secreting proinflammatory cytokines to initiate the innate immune response.  pDCs are activated following engagement of Toll-like receptors (TLRs), which recognize molecular signatures of bacteria and viruses.  Studies have shown that the frequency of circulating pDCs is significantly reduced in SLE patients, due to increased migration to inflammatory sites in affected organs 2.  Although pDCs have been implicated in contributing to autoimmunity via continuous type I IFN production, their exact role in lupus pathogenesis has not been clearly elucidated.

Recently, in PNAS, Baccala et al. provided direct evidence that in the absence of pDCs, the disease manifestations of Lupus were significantly decreased 3.  Since IRF8 is a hematopoietic cell-specific transcription factor known to be essential for pDC development 4, the authors knocked out IRF8 in NZB mice, a widely used mouse model for SLE.  Appropriately, pDCs were absent in IRF8-deficientNZB mice, and type I IFNs were undetectable even after injection with CpG DNA, a standard method of inducing the interferon pathway.  Interestingly, autoantibody production was almost completely abrogated and kidney disease was drastically improved compared to wild-type NZB mice.  Taken together, their results suggest that without pDCs, SLE disease manifestations are significantly reduced.

Next, the authors sought to examine specifically how pDCs promote systemic autoimmunity.  They used another mouse model with a mutation in Slc15a4, which is characterized by normal development of pDCs but an absence of type I IFN production by pDCs.  It is still unclear how a mutation in Slc15a4 leads to a disruption in proinflammatory cytokine production in pDCs, but since Slc15a4 is a peptide/histidine transporter, others hypothesize that it transports free histidine from the endosome to the cytosol to enable cathepsin-mediated cleavage of endosomal TLRs required for subsequent signaling 5.  Similar to the IRF8-deficient NZB mice, Slc15a4 mice had significantly reduced autoantibodies, decreased kidney disease, and extended survival.  This finding rules out the possibility that pDCs contribute to disease through other functions outside of type I IFN production.

In summary, Baccala et al. provide direct evidence that pDCs contribute to the abnormal manifestations of SLE via hyperproduction of type I IFNs.  Thus, IRF8 and Slc15a4 serve as new potential drug targets for treatment of SLE.  Current therapies involve broad immunosuppressive drugs, which suppress multiple arms of the immune system, increasing a patient’s risk for various infections and cancer.  Specific pharmacologic inhibition of IRF8 or Slc15a4 could prevent Lupus-specific flare-ups, as well as manifestations of other autoimmune diseases.


1          Gilliet, M., Cao, W. & Liu, Y. J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol 8, 594-606, doi:10.1038/nri2358 (2008).

2          Ronnblom, L. The type I interferon system in the etiopathogenesis of autoimmune diseases. Ups J Med Sci 116, 227-237, doi:10.3109/03009734.2011.624649 (2011).

3          Baccala, R. et al. Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc Natl Acad Sci U S A 110, 2940-2945, doi:10.1073/pnas.1222798110 (2013).

4          Tsujimura, H., Tamura, T. & Ozato, K. Cutting edge: IFN consensus sequence binding protein/IFN regulatory factor 8 drives the development of type I IFN-producing plasmacytoid dendritic cells. J Immunol 170, 1131-1135 (2003).

5          Park, B. et al. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol 9, 1407-1414, doi:10.1038/ni.1669 (2008).