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Transcript
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) – 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 System 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 are 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 tear or saliva flow is a complex process that involves 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 6. Stimulation of gland water nutrients hormones 5. 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 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) is 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 signalling molecules) In Sjogren’s, only 50% of the acini and ducts are destroyed . Despite their retension 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. 1. 2. 3. 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. Homing Receptors are up-regulated on high endothelial venules in Sjogren’s Lip Biopsy A B Peripheral Lymph Node Addressin (PNA-d) (peanut agglutinin) Chemokine receptor CCL21 Ref 63 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. The interesting point is that the homing receptors expressed by salivary glands for T-cells, B-cells, and dendritic cells occur in NOD.scid mice so that they are independent of cytokines released from the lymphocytes. 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. 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 In patients whose minor salivary glands develop germinal centers, there is increased chance of lymphoma 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. 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 sex (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 Summary 1. Ability to stimulate saliva or tears remains inadequate involves a complex pathway. 2. Extraglandular manifestations reflect homing pathways, as well as factors that influence tissue retention and apoptosis. 3. Neuro-endocrine manifestations (cognitive impairment and fatigue) remain the frontier of research for the next decade. 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. [email protected] 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 Fcgreceptor 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 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 The Functional Circuit involves Known neural connections to the brain *Pflugfelder SC, et. al. Dry Eye and Ocular Surface Disorders. NY: Dekker, 2004. This 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. 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 Background 2 “The Danger Signal” The immune system is the 6th sense of the brain. Lymphocytes are sent out to detect foreign pathogens and clean up debris from dead (apoptotic) cells. Lymphocytes report back to the brain in the form of neurokines and cytokines. 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. Homing Receptors are up-regulated on high endothelial venules in Sjogren’s Lip Biopsy A B Peripheral Lymph Node Addressin (PNA-d) (peanut agglutinin) Chemokine receptor CCL21 Ref 63