The interferon-signature of Sjögren’s Syndrome: What does it say about the etiopathology of autoimmunity? An Update Dr Ammon B. Peck and Dr Cuong Q. Nguyen

ArunAsif December 21, 2011 848
Brief Report: Based on an article first published in the Journal of Clinical Rheumatology and Musculoskeletal Medicine.

Sjögren’s syndrome (SS) of humans and SS-like (SjS-like) diseases in mouse models are autoimmune-based rheumatic diseases characterized by chronic immune attacks primarily against the salivary and lacrimal glands leading to loss of acini and gland architecture resulting in severe dry mouth and dry eye conditions. One characteristic of SS, quite similar to systemic lupus erythematosus (SLE), is an up-regulated expression of interferon (IFN), both IFN-α/β (type I) and IFN-γ (type II) 1-7, as well as IFN-responsive genes. Both SS and SLE, therefore, have been designated as “interferon-signature” diseases. Although multiple genes are known to be transcribed following activation of the IFN signaling pathways in SS/SjS-like diseases, as pointed out in our recent article, published in the Journal of Clinical Rheumatology and Musculoskeletal Medicine 8, those genes differentially-expressed within the exocrine glands represent highly select subsets. Nevertheless, we still need to ask whether an IFN-signature is merely defined as a subjectively high number of IFN-related genes being up-regulated or does the pattern of IFN-responsive (and non-responsive) genes indicate specific biological processes and molecular mechanisms that are the key to development and onset of autoimmunity? On one hand, type I and type II IFNs are ubiquitous cytokines involved in most immune responses, and therefore may only reflect a consequence of general immunity. On the other hand, the various subsets of differentially-expressed genes belong to distinct multiple functional families, therefore likely to reflect highly specific biological and/or immunological responses. In this short update, we are now able to state that a close examination of the genes defining the IFN-signature of SS/SjS-like disease defines regulatory mechanisms involving immune responses.

As presented in our original paper 8, analyses of global temporal transcriptome data collected during development of SjS-like disease in the C57BL/6.NOD-Aec1Aec2 model of primary SS defined the IFN-signature that could be used to model molecular events and their biological processes underlying SS at time of the innate immune response. Although there is little proof to date that SS is a viral-based disease, multiple lines of evidence clearly point to the possible role of a dsRNA virus: (a) an up-regulated expression of Tlr3 and Tlr4, two genes encoding pathogen recognition receptors (PPRs) that signal through Traf3 via Trif and/or through Traf6 via a Trif-Trim23 complex to activate NF-κβ and Irf3/Irf7 transcription of pro-inflammatory cytokines including IFN, (b) the up-regulation of Ifih1, encoding Mda-5, with a concomitant down-regulation of Ddx58, encoding Rig-1, (c) the up-regulation of the interferon-responsive factors Irf3, Irf7, Irf8 and Irf9, and (d) the down-regulation of Trim27, Trim30 and Trim40 with concomitant up-regulation of Trim8, Trim21 (encoding Ro52), Trim25 and Trim56.

While there are additional genes within each of these gene families that also exhibit differential expressions, as presented in our original paper, these genes point directly to two important concepts. The first raises the question of whether SS/SjS-like disease might be a viral-induced autoimmunity, while the second deals with the possibility that the cytokine storm exhibited in this disease is under the direction of the regulatory Trim molecules. With respect to the first point, the three activated PRRs in our model (Tlr3, Tlr4 and Mda-5) are receptors involved in the recognition of dsRNA viruses. We have not found any other PRR (or class of PRRs) to be activated, including Nod, Nalp, Ipaf, Naip, Rage, Rxfp1, and Dai receptors (unpublished data). Of particular interest, however, is the fact that Mda5 (Ifih1), but not Rig1 (Ddx58), is up-regulated coordinately with Tlr3. Rig-1 tends to recognize viruses of the Paramyxoviridae family (e.g., mumps, measles, respiratory syncytial and parainfluenza viruses), while Mda-5 tends to recognize viruses of the Picornaviridae family (e.g., coxsackie, encephalomyocarditis and rhinoviruses) or Reoviridae family (e.g., rotovirus). It would be intriguing to know if SS patients, especially those with chronic fatigue and anti-SSA/Ro and/or anti-SSB/La autoantibodies, have antibodies to viruses of these latter two virus groups, especially since it has been reported that Mda-5 actually recognizes a dsRNA-antibody complex.

The second point, that the Trim molecules may be directing both the molecular mechanisms underlying the cytokine storm often present in SS patients plus the transition from an enhanced innate response to the adaptive autoimmune response, is strongly supported by the Trim gene expression profile present in the exocrine glands 9. To summarize, the three Trim molecules (Trim27, Trim30 and Trim40), whose genes are down-regulated, function to suppress the signal transductions of the Tlr4, Tlr3 and Mda5 signaling pathways at different signaling points, as presented in Figure 1. In contrast, the genes encoding Trim21, Trim23, Trim25 and Trim56, four molecules whose functions are to up-regulate the Tlr3, Tlr4 and Mda5 pathways at different signaling steps, are each up-regulated (Figure 1). In addition, the gene encoding Trim8, whose function is to suppress the action of the Socs (Suppressor of cytokine synthesis) molecules 10, is strongly up-regulated. Taken as a whole, this profile indicates up-regulation of pathways leading to strong transcription of pro-inflammatory cytokines, interferons and molecules that are known activators of adaptive responses (e.g., IL6, IL12p40, Rantes, CD40, CD80 and CD56). Not surprising, then, that the innate phase of SS transitions to an adaptive immune phase, but these data still raise a question regarding whether or not viruses, known to have strong interactions with Trim molecules, are responsible for this temporal differential gene expression profile.

Peck & Nguyen Figure 1

Peck & Nguyen Figure 1

Figure 1. Regulation of Tlr3, Tlr4 and Mda-5 PRR activation(s) of the Interferon signaling pathway by Trim molecules differentially expressed during the innate immune response of Sjögren’s syndrome-like disease in a mouse model of primary Sjögren’s syndrome. Trim molecules are strong regulators of cellular responses to viruses and viral infections. Genes encoding multiple Trim molecules are either up-regulated (shown in red) or down-regulated (shown in green) during the early disease period of SjS in the C57BL/6.NOD-Aec1Aec2 mouse model of SS. As shown, Trim molecules that are known to down-regulate the TLR/RLH PRR pathways are suppressed, while Trim molecules known to enhance TLR/RLH PRR responses are up-regulated, indicating strong and continuous activation of the innate response via interferon and pro-inflammatory cytokine production. (Figure is an adaptation from Jefferies et al. 9)

References
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About The Authors
Ammon B. Peck 1,2,3 and Cuong Q. Nguyen 3,4
1. Department of Pathology, Immunology & Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610 USA
2. Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610 USA
3. Center for Orphan Autoimmune Diseases, College of Dentistry, University of Florida, Gainesville, FL 32610 USA
4. Department of Infectious Diseases & Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611 USA
peck@pathology.ufl.edu nguyenc@ufl.edu

Dr. Peck received his MS and PhD degrees in Medical Microbiology & Immunology from the University of Wisconsin, Madison followed by post-PhD training with Dr. Fritz Bach and Dr. Hans Wigzell. Dr. Peck is currently a professor in the Department of Pathology, Immunology & Laboratory Medicine at the University of Florida, Gainesville. His overall research focuses on calcium-oxalate kidney stone disease, stem-cell & regenerative medicine, and defining the immunopathology of autoimmunity, especially Sjögren’s Syndrome. He has received international recognition in each of these fields, due mostly to the excellent work carried out by students he has been able to help mentor.

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