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Pathogenesis of Sjogren’s Syndrome: Translating Basic Science from “Bench to Bedside” Sjogren’s Syndrome • Increased mortality risk, particularly due to lympho-proliferative complications • Quality of life- equated with moderate angina • “Disability” predominantly due to fatigue and cognitive • “Limitations”: dry eyes (limits work- especially computer) dry mouth (limits sleep and social interactions around eating) extra-glandular manifestations, particularly neurologic • Expense of artificial tears and dental decay Background-1 Sjogren’s syndrome represents the interface of: a) Immune and exocrine secretory functions (dryness) b) Immune and neural function (neuropathy/cognitive) c) Immune and hypothalamic-adrenal axis (autonomic) d) Autoimmune proliferation and lymphoma e) Lupus-like features of vasculitis and immune complex Background-2 The Danger Signal When we get “flu symptoms” of arthralgia, fatigue, cognitive dysfunction— it is a result of the cytokines/neurotransmitters released by the innate immune system. When these reactions persist due to a vicious cycle perpetuated in genetically predisposed individual by the acquired immune system, the result is autoimmune disease. Pathogenesis: Take Home Lessons-1 1. Innate and Acquired Immune Systems are targets for current therapy—including TNF, BAFF and IL-6 inhibitors, steroids, traditional DMARD’s and new oral agents (Jak and syk inhibitors). 2. Functional circuit that controls immune and neural function comprises the new “frontier” for therapy from fibromyalgia to depression. The functional circuit is the link between cytokines and symptoms. Take Home Lesson - 2 The two arms of the immune system mutually interact in the initiation and perpetuation of Sjogren’s Syndrome Acquired System (HLA-DR)-memory Traditional T-cell and B-cell and their cytokines HLA-DR association with autoantibody production Target of drugs such as DMARDs and certain biologics Innate System (Adaptive, immediate) - HLA independent Dendritic cells Cytokines-particularly Type I interferon Interferon-gamma BAFF, IL-6, IL-17 Complement, CRP Sensors of the innate system Toll receptors (TLR)-pathogen motiffs DAMP (damage recognition patterns)apoptosis RIG-1 (retinoid inducible genes) NOD/Card receptors-more than in colitis Take Home Lesson 3: The Functional Circuit (Cytokines are not enough) Control of tears or saliva flow are complex processes that involve both afferent nerve pathways that go to the midbrain and efferent nerves that modulate glandular function. The midbrain signals are influenced by the cortical outflow and the hypothalamic axis. Normal tearing or salivation secretion requires a functional unit 4. Stimulation of gland water nutrients hormones 3. Stimulation of blood vessel water mucin protein 3. Cortical Outflow Tracts and HPA 1. Ocular or oral surface irritation Nerves on mucosal Afferent nerves 2. Midbrain of central nervous system Lacrimatory or salivatory nuclei The functional circuit involves known neural connections to the brain *Pflugfelder SC, et. al. Dry Eye and Ocular Surface Disorders. NY: Dekker, 2004. In Sjogren’s syndrome, the release of Ach and VIP by efferent nerves to the glands --and the response of the glands to neural transmitters-are impaired by lymphocytes that enter the gland and release inflammatory factors ocular and oral dryness lymphocytes Focal lymphocytic infiltrates in the glands Gland dysfunction •Autoantibodies (anti-muscarinic antibody) Cytokines (type I IFN, g-IFN) •Metalloproteinases (outside-inside signaling molecules) In Sjogren’s, only 50% of the acini and ducts are destroyed. Despite their retention of neural innervation, the residual glands do not function as a result of the inflammatory environment Foci of lymphs Sjogren’s Normal In Sjogren’s syndrome The residual glandular cells are paralyzed by the local immune reaction. Even though the acini/ducts are 50% present, their innervation and their receptors for neurotransmitters are present. Thus, the interesting question is: Why are the residual glandular elements not working? This fundamental question of how immune and neural systems interact will be the “holy grail” of neuroscience for the next decade. Pathogenesis Take Home Lesson- 2 Although many complex interactions take place in the salivary gland, a characteristic type I interferon gene signature is noted repeatedly. The relationship of autoantibody to SS-A/SS-B and type I interferon signature has recently been suggested. This links our blood tests (SS-A) and clinical features. IFN Type I in salivary gland suggests a role in Sjogren’s Syndrome SS SS SG biopsy with type I IFN gene profile SS SG biopsy with type I IFN NML Non-SS sicca Take home lesson-3 Homing receptors determine both glandular and extraglandular features 1. 2. 3. 4. Salivary glands normally lack lymphocytes, so their mere presence in an extraglandular tissues imply a lymphocyte aggressive process. Homing to the gland tissue is due to specific receptors/ligands controlled by chemokines/cytokines. Retention of lymphocytes in the tissue is due to specific ligands. Their apoptosis or expansion is regulated through Fas pathways that are modulated by cytokines and bcl-2 Pathogenesis: Take Home Lessons-4 1. Extraglandular manifestations are determined by lymphocyte homing to tissues-- factors that govern their retention in tissues and their apoptosis. 2. Factors governing their clonal expansion and lympho-proliferation lead to lymphoma-derived from B-cells themselves, T-cells, and dendritic cells. 1. Tissue Homing/Retention of lymphocytes is the key process for accumulation of glandular infiltrates, as virtually no mitotic cells are seen in the gland. 2. Subsequent migration from gland into efferent lymphatic defines re-circulating memory lymphocyte pool. The endothelial cells attract T-cells by ICAM’s and Chemokines Sjogren’s Lip Biopsy B The endothelial cells release B-cell chemo-attractants A B Ref 63 Endothelial cells attract dendritic cells to home to the gland. Take Home Points for Homing Receptors: a)Expressed by salivary glands in NOD.scid mice, so expression is independent of cytokines released from the lymphocytes. b) Thus, the story of Sjogren’s syndrome is not a poor salivary gland that is “beaten up” by the lymphocytes-- but that the glands participate in the homing and pathogenesis of inflammatory cells and subsequent inflammation. c) The problem with blockade of homing receptors (whether Tsabri or Raptiva) has been the emergence of rare but devastating problems due to reactivation of papilloma viruses (such as JC) with clinical PML (progressive multi-focal leukoencephalopathy). Pathogenesis Take Home Lesson 4 SS has lymphoproliferative properties— it lies on the border between autoimmunity and lymphoma. Sjogren’s Syndrome – with parotid enlargement indicates lymphoproliferative tendency Risk factors for lymphoma a) Germinal centers on minor salivary gland biopsy b) Low complement C4 c) MGUS (esp. IgM-K with RF activity) and mixed cryoglobulin The T-cells and dendritic cells drive B-cell clonal expansion, particularly driven by BAFF, until a B-cell clone escapes to become a lymphoma. Germinal Centers in Minor SG Biopsy This provides a rational of understanding for 1. anti-CD20 (rituximab) 2. anti-BAFF and anti-TACI 3. anti-CD22 antibody therapies Overview of the steps in pathogenesis that help explain role of gender (TLR receptors) autoantibodies (anti-SS A) interferon-Type I signature HLA-DR association SS: Hormonal Factors (SS predominantly in women) • X-chromosome location of Toll receptor; • X-linked genes for apoptosis; • X-linked genes for transcription promoter of pro-inflammatory loci including NF-K; • X-linked control of metalloproteinase release under prolactin hormonal regulation. Time course of autoimmune response* 1. Environmental stress is interpreted in context of genetic factors. 2. Antibodies precede disease. 3. Presence of antibody does not mean disease. Environmental Stress (virus-such as EBV) (apoptotic fragment) Innate (Toll receptor) Type I IFN Genetic Genetic Genetic Genetic Factors Factors Factors Factors (including (including (includingsex) sex) sex) (HLA-DR) (HLA-DR) (HLA-DR) (HLA-DR) Autoantibodies Immune system Immune complex Acquired Immune system (HLA-DR) T/B-cells Disease Manifestations Time period of years Ref. 32-33 Genetic Predisposition in SS to Type I Interferon In genome wide screens, association of IRF5 alleles and Stat 4, with predisposition to development of SS* * Refs 36-38 Other Factors in Pathogenesis • Gender - SS is a predominantly a disease of women. • Onset and increase of dryness with menopause. • Increased risk of Klinefelter (XXY) in male SS* —Toll receptor translocation (BXB model). • Aromatase knockout mouse gets SS. • RbAp48--estrogen dependent apoptosis. • DHEA and CRISP-role in glandular processing. * Refs 34-40 At this point … • I want to stop for questions and see if you would like to break or stay for new approaches to therapy • Thanks again for inviting mel. Treatment of Sjogren’s in 2010: Opportunities and Challenges a) Treatment of Dry Eyes and Mouth b) Treatment of Extraglandular Manifestations-• Lupus like symptoms-arthralgia, rash • Neuropathy (central and peripheral) • Cognitive and myalgia (fibromyalgia) • Lymphoproliferative Take Home Points-1 1. Topical therapy of dry eyes and dry mouth: new targets include water transport, mucins, and topical small molecules such as jak 3. 2. Dry mouth symptoms may be “burning” mouth and require treatment as a local neuropathy. Take Home Point-2 1. Poor correlation of symptoms and objective findings of both dryness and neuropathic symptoms. 2. This poor correlation is the greatest challenge since it involves cortical perception of discomfort 3. The neuro-endocrine circuit in Sjogren’s may provide insight into “fibromyalgia” Take home points-3 • Systemic Manifestations for lupus like symptoms DMARDs Hydroxychloroquine Methotrexate Leflunomide Small molecules-Jak3 and Jak ½ Filomodulin (MS approved) Biologic Agents Anti-CD20 rituximab and new variants Anti-BAFF (Benlysta) Anti-CD22 (Eprumazab) Taci-Ig and ICOS Homing receptors New Approaches to Dryness 1. Topical Ocular Dryness “smart artificial tears” Mucin Androgen Micro-iRNA Anti-IL-17* Jak 3 inhibitor* Metalloproteinase inhibitor * Currently cyclosporin is water insoluble and irritating New Approaches to Dryness-2 Oral Agents are better than pilocarpine or cevimeline … since the gland is not destroyed but is paralyzed by cytokines and metalloproteinases • Improved secretagogues (new muscarinic agents in trial) • Anti-cytokine therapy has modest effect only in patients with early disease New Approaches to Dryness-3 Novel methods of water conservation • 1. Transport water across the conjunctiva (diquafasol) p2Y2 purine receptor agonist 2. Decrease evaporative loss (muc 3, muc 5A, lipid) 3.Decrease water reabsorption through membranes of eye by blocking trans-epithelial salt (and water) channels that drain orbit (compound P552-02) p2Y2 receptor directly transport water across conjunctiva Tear film Membranes at the base of the orbit are a major site of ‘water exit” (in addition to the puncta) Electrical Stimulation with intra-oral device Strietzel et al (2011) Arth Rheum pg. 63—Abstract misleading Results: “The active intervention performed better than sham for some secondary outcome measures for dryness frequency. No statistical significance for the parameters oral discomfort, sleeping difficulty, resting salivary flow rate, and stimulated salivary flow rate.” Reminiscent of Electrical Stimulation (Salitron) in 1980’s Stellar (1988); Daniels (1992) a) b) c) d) Approved by FDA as a “device” Denied by insurance due to “efficacy” Price precluded use by patients About the same benefit as use of a vibrator (used intra-oral) or electric toothbrush to stimulate tongue and buccal mucosa Importance of mechanical stimulation, including the use of lozenges The standard joke about therapy • Rheumatologists only have one drug: steroids. • The training of a rheumatologists is how to get the patient to a lower dose of steroids or off them entirely. Systemic Therapies-1 • Traditional DMARDs- alone and combination. • Hydroxychloroquine—works on “antigen processing” by raising pH of antigen loading compartment. • Hydroxychloroquine is a weak diprotic base that diffuses into compartment for loading and raises the pH of the “endosome.” • This effect prevents the “loading” of low affinity (autoantigens) onto nascent DR molecules. • Also, affects the ability to bind to Toll receptors in the lysosome. • Using this model, new through-put screening of new and better drugs Systemic Therapies-2 • Traditional DMARDs- What is new with methotrexate? • Alone or in combination with hydroxychlorquine to taper steroids; • Methotrexate polyglutamate may predict efficacy and toxicityhowever, methotrexate polyglutamate levels are still in trial in SLE and SS; • Most exciting are the reports of new SNPs to predict methotrexate responsive patients in RA; • (all the SNPs are in the de novo adenosine pathway). Systemic Therapies-2 Leflunomide and mycophenolic acidboth have mechanism of action that are similar and analogous to methotrexate • Methotrexate works on de novo synthesis for purine ribonucleotide pathway. • Leflunomide and Mycophenolic acid on de novo pyrimidine ribonucleotide pathway. • These ribonucleotides serve as energy source (mostly for glycosylation) that is required for cell division. • Unless, adequate rUMP, impaired G1-S transition. Take home lesson for Methotrexate, Azathioprine, Leflunomide, mycophenolic acid • All work by inhibiting synthesis of ribonucleotides that serve as an energy source (de novo synthesis pathway) required for G1-S transition of maturation. • This pathway links p52 and p21 driven apoptosis; p52 is the “sensor” for adequate ribonucleotide level. • Ribonucleotide synthesis as an energy source for cell membrane synthesis and glycosylation. • In future, it is likely that we can use SNPs to predict response to these agents based on their enzyme polymorphisms. Systemic Therapies-3 • Traditional steroids: • Prednisolone and methylprednisolone)—cheap and work but side effects • In general, the issue with steroids is the dose (less than prednisone 7.5 and duration of therapy) • Development of “soft steroids”—lotemax-like for effect on NFK-b ; this was the basis of p38 map kinase • Novel IKKB inhibitors that lack effect on weight, bone, etc. Biologics and Cytotoxics • Biologic Agents—the new “holy target” based on success in RA; however, biologics have been disappointing in SLE and SS (we will deal with these later in talk). • Cytotoxics such as cyclophosphamide—although we worry about cyclophosphamide, we need to ask how much is actually justified if we use carefully and limit cycles. • We worry about marrow depletion but yet hematologists use it to mobilize “stem cells” into the periphery. • In order to “cure” immune disease—we must reset the repertoire using cyotkines and growth factors. There will probably be a role for cyclophosphamide in this process. Available biologic therapy for Sjogren’s-1 • • TNF antagonists- one initial report of success with infliximab* Repeat studies not replicate early success Repeat infliximab study (multi-center, more patients)* Etanercept* • *Refs 43-47 • • Rituximab (anti-CD20 antibody)numerous reports in Sjogren’s that are multi-center and controlled • B-cell depletion efficient in periphery; • Decreased lymphocytes in gland biopsy; • Surprisingly, little change in serum BAFF or IgG levels; • Well tolerated. Rituximab failed the two pivotal FDA trials in lupus— both renal and non-renal • • • • These trials were poorly designed. The steroid dose was too high. The patients were too heterogeneous. The drug worked, but so did the placebo (standard of care). • The finding of several cases of PML (progressive neurodystrophy due to JC virus). Rituximab Most Consistent Role for Hematologic Features in SS *lymphadenopathy, *pseudolymphoma, *thrombocytopenia * mixed cryoglobulin *low grade lymphoma As it will not have “FDA label,” it will be an off-label use, and expense in US will limit its use-- as insurance will not cover. Rituximab Treatment 1. Only small changes in tear/saliva flow and only in patients with early disease; 2. Changes in salivary gland biopsy with improvement in foci score; 3. B-cell depletion as expected; 4. Change in T-cell repertoire (CD25+ T-reg) in some patients. Important lesson about biologics from Rituximab When you deplete B-cells (rituximab): 1. Create an excess of circulating BAFF in comparison to the number of B-cells that bear BAFF-Receptor; 2. This excess of ligand stimulates a round of cell division not only of B-cells but of B-cells; 3. Any round of cell division leads to activation induced cell death (AICD) and opportunity to re-shape the repertoire. The “cure” of autoimmune disease will depend on changing the repertoire-a) T-regs to modulate auto-immune cells; b) Alteration of homing receptors; c) Regeneration of damaged target organs. Humanized anti-CD20 (ocrelizumab) • Higher Affinity for B-cells; • Had Fc receptor for complement and B-cell depletion; • Clinical trials halted due to increased infection (although mostly at non-US sites). Other Biologics-1 • Anti-BAFF (Benlysta) antibody; • Approved for SLE by FDA; • The SS subset of SLE (SS-A) did not show significant improvement compared to SLE cohort; • Although the Benlysta subset did better than with no treatment, the patient and physician Global Assessment was not significantly different from placebo and marginally different than low dose. Other Biologics-2 • Anti-CD22 (Epratuzumab)—another B-cell marker; • Initial clinical trials in SS (and SLE) plagued by production of a uniform product (problems in glycosylation), so 6 different lots needed with interruption of protocol; • New Drug Manufacturer and preliminary studies indicate safety; • Any FDA approval for SS will require increased saliva and tears. Expect at best, results similar to rituximab. Other therapies in trial (biologic) 1 2 3 5. 6. 7. Anti-CD22 antibody: initial results inconclusive and repeat trials in progress* Antibody to IFN-a (Medi 545) in SLE* (Dan Wallace at ACR (2007) and recruiting in Japan) Antibody to type II (gamma) IFN (fontolizumab) Antibody to BAFF-R, April and TACI-Ig* Benlysta (free BAFF) and Ly2127399 (Lilly’s antiBAFF)(membrane and free) Bortezomib (protesome inhibitor) *Refs 60-61 and clinicaltrials.gov Additional Trials • • • • • Raptiva (stopped) Thalidomide (stopped) DHEA—past NIH trial vs. SLE trial Mycophenolic Acid Rituxan and biogeneric Fingolimod- a novel approach • The molecular biology of phosphofingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors Stromal cell has Sphingosine receptor Lymphocyte is retained in the lymph node until the sphingosine ligand is “removed” Fingolimod-2 (recently approved for multiple sclerosis) • It can sequester lymphocytes in lymph nodes, preventing them from moving to the central nervous system for autoimmune responses in multiple sclerosis, and was originally proposed as a anti-rejection medication indicated posttransplantation. • It has been reported to stimulate the repair process of glial cells and precursor cells after injury. • Fingolimod has also been reported to be useful in murine lupus and Sjogren’s. Problem will again be the risk of PML— a rare but devastating complication • May be acceptable in life threatening diseases such as multiple sclerosis; • Unclear if the FDA will approve such drugs for “quality of life” issues such as dryness or fatigue; • The global assessment by physician and patient has been the huge limitation in FDA approval. Fingolimod provides rationale for new therapies that interfere with homing 3. When the homing receptor encounters vascular adhesive molecules, the lymphocyte enters tissue. CD4+ Blood 2. Lymphs migrate through blood to tissues. B cell 1. T- and B-cells have surface “homing receptors” when generated in node or marrow. 4. Pearl: Failure to bind to homing receptor in 72 hours leads to obligate apoptosis of the lymphocyte. This is why we do not become one large lymph node. Caution: PML (progressive multifocal leukoencephalopathy) • Due to reactivation of polyoma virus (JC) in CNS • We have seen with agents: that alter homing: – – Natalazumab (Tsabri) Efalizumab (Raptiva), and • B-cell depleting agents (Rituximab); • SS and SLE patients already handle polyoma poorly, as evidenced by higher frequency pap smear abnormalities. Our most difficult problems 1. Neuropathy—peripheral and central; 2. Chronic fatigue and vague cognitive impairment; 3. Lymphoproliferation; 4. Accelerated cardiovascular complications. Neuropathy • Poor correlation between symptoms and objective findings: – Eye pain- does not correlate with tear flow; – Mouth pain-not correlate with saliva; – Peripheral neuropathy-not correlate with nerve biopsy; – Cognitive-not correlate with acute phase reactants. Fibromyalgia: The elephant in the Room Fatigue Cognitive Dry eyes and dry mouth Nerve pain As rheumatologists • We will need to learn a new vocabulary about the perception of pain and how it is modulated by cytokines. • The key term is the “plasticity” of the nervous system. How the perception of pain is modulated by cytokines of the “stress axis.” Neuroplasticity in Pain Processing1-3 100 Pain Sensation 80 Hyperalgesia3 Cytokines alter pain perception 60 40 Pain state Allodynia 20 0 innocuous noxious Stimulus Intensity 1. Woolf CJ, Salter MW. Science. 2000;288:1765-1768. 2. Basbaum AI, Jessell TM. The perception of pain. In: Kandel ER, et al, eds. Principles of Neural Science. 4th ed. 2000:479. 3. Cervero F, Laird JMA. Pain. 1996;68:13-23. Normal The Pain Roadmap: Peripheral and Central Nervous System Landmarks • The neural processing of pain involves the: – peripheral nervous system – spinal cord (central nervous system) – brain (central nervous system) Central Nervous System Brain image courtesy of ATI Peripheral Nervous System Brain Regions that May Modulate Pain and 1-4 and Mouth: Central Amplification ofEmotion Pain from Eyes Regions Found on Functional MRI Both Somatosensory Cortex Pain Insular Cortex Prefrontal Cortex Thalamus Hippocampus Take Home Lesson 1 1. Topical therapy and ability to stimulate saliva or tears remains inadequate. 2. Treatment of extraglandular manifestations such as arthritis, rashes, hemolytic anemia, or lymphomas is rapidly improving. 3. The treatment of the neuro-endocrine manifestations (cognitive impairment and fatigue) remains inadequate. Thank you for your time and attention I would be happy to entertain any questions now or later. The slides are available to you for your use at [email protected] Rituximab (anti-CD20)* 1. 2. • • • 3. 4. • Multiple studies of small number of patients and single center trials General Conclusion-a) useful in extra glandular manifestations including: -- mixed cryoglobulinemia -- pseudolymphoma (glands or lung) -- hemolytic anemia and thrombocytopenia b) results in tear/saliva flow not significant except in group of patients with early SS, where increase saliva was statistically increased but still modest improvement and biopsies showed improvement; Among SLE patients treated with anti-CD20, SS-A subset responded less frequently and had shorter remissions; After an NIH multi-center trial, company is not pursuing indication. *Refs 47-59 How does the process start? There may be many different triggers in the genetically predisposed individual… 1. Defective apoptosis of glandular cells and clearance of these autoantigens; 2. Viral infection including EBV (in Caucasion and Japanese) and Coxsackie (in Greek patients); 3. Other viral infections (examples of Hep C, HIV and HTLV-1) can mimic SS; 4. Activation of endogenous retroviral fragments. Ref 1 Role of Autoantibody: Anti-SS A Anti-SS A antibody (associated with HLA-DR3) binds to SS-A which complexed to hYRNA Antibody toisSS-A To the innate immune system (dendritic cells), hYRNA SS-A hYRNA (ds RNA) is a double-stranded RNA and looks like a viral RNA that binds to a specific Toll receptor. Salivary gland dendritic cells bind to the Fcg receptor to internalize the immune complexes containing SS-A/hYRNA 1. Immune complex antibody to SS-A hYRNA (ds RNA) 2. Fc-g R 3. Toll 3 receptor is in located in the cytoplasm Plasmacytoid Dendritic Cell SS-A 4. IFN Type 1 --The Vicious Cycle -of innate and acquired leads to IFN type I (links genetic and autoantibody response) 6. B-cell 4. Dendritic Cell 5. IFN-a with Toll Receptor and Fc-g Receptor 3. Toll receptor Fc-gamma R 2. Immune Anti-body response Anti-SS-A in HLA-DR3 pre-disposed female SS-A/hYRNA Complex containing… ______ 1.Apoptotic Cell Pearl: Rituxan does more than deplete B-cells a) • Alteration of T-cell subsets (especially appearance of CD25+/FoxP3 T-regs) after treatment indicates a role in “rebooting the computer.” • • • b) Lymphocytes remain present in the SG biopsy, probably due to BAFF secreted by dendritic cells. • *Refs 57-59 Typical Clinical Features of dry eyes, dry mouth and swollen glands Dryness results in the clinical appearance of keratoconjunctivitis sicca (KCS) characteristic of Sjogren’s syndrome The upper lid literally sticks to the surface epithelial surface and pulls surface mucin layers off. The Rose Bengal dye retention is like “rain water pooling in a street pothole” This test can be done at bedside and allows “triage” and rapid referral of patients to Ophthalmology For example IL-17 plays a key role in decreased secretion of water, proteins and mucin required in tears and saliva Severe Xerostomia with dry tongue Sjogren’s Syndrome- Cervical Dental Caries The Body’s 2 Distinct But Interconnected Immune Systems ACQUIRED INNATE HLA-DR4–dependent: HLA-DR–independent: T cells respond to peptide antigens and generate Dendritic cells respond to specific structures found on bacteria and apoptotic memory cells Products (Toll receptors) Lymphyocytes Dendritic Cells (Type 2 interferon signature) (Type 1 interferon signature) Beutler B et al. Blood Cells Mol Dis. 1998;24:216-230.