systemic lupus erythematosis-spiderman vs superman

“LADY BETWEEN SPIDERMAN&SUPERMAN” : 

“LADY BETWEEN SPIDERMAN&SUPERMAN ” DR.KARUNAN KANNAMPOYILIL ( Prakashan KP) Dept: of Nephrology Govt Medical college Calicut Aug 2011

Introduction: 

Introduction A “Lady” between Spiderman and superman, that is Systemic Lupus Erythematosis (SLE) is a chronic inflammatory state that we encounter every day

Slide 4: 

Systemic Lupus Erythematosis , Tomorrow ?

Eurasian wolf (Canis lupus lupus): 

Eurasian wolf ( Canis lupus lupus )

Wolf (Lupus): 

Wolf ( Lupus)

Lupus: 

Lupus Wolf mutilates it’s pray before it eats without killing, in the similar way the SLE does. Ref:. Graves, Will (2007). Wolves in Russia: Anxiety throughout the ages . Detselig Enterprises. ISBN 1550593323 “ They kill large prey by biting large chunks of flesh from the soft perineum area, causing massive blood loss . Such bites can cause wounds 10–15 cm in length, with three such bites to the perineum usually being sufficient to bring down a large deer in optimum health”

SLE: 

SLE second most common human autoimmune disease in the world. Ref: Can morbidity and mortality of SLE be improved? Anurekha Bongu Elizabeth Chang Rosalind Ramsey-Goldman Best Practice & Research Clinical Rheumatology Volume 16, Issue 2 , April 2002, Pages 313-332 Northwestern University Medical School, ArthritisChicago Ave, Chicago, IL, 60611, USA. Available online 10 June 2002.

SLE: 

SLE SLE is the second most common autoimmune disorder (after thyroid disease) in women of childbearing age. Lupus is increasingly being recognized throughout the world's population. The incidence and prevalence of SLE varies among racial and ethnic groups. Lupus patient survival has significantly improved over the past five decades, but a three- to fivefold increased risk of death remains compared with the general population. As lupus patients survive longer, these individuals face a range of complications from the disease itself or consequent to its treatment. Emerging data from epidemiological studies underscore the importance of incorporating race and ethnicity in understanding the risk factors leading to the significant burden of mortality and morbidity associated with this disease; Anurekha Bongu Elizabeth

Prevalence of SLE India: 

Prevalence of SLE India A point prevalence of 3.2 per 100 000 (95% CI = 0-6.86 per 100 000). Ref:Prevalence of Systemic Lupus Erythematosus in India(North) A.N. Malaviya doi : 10.1177/096120339300200209. Lupus April 1993 vol. 2 no. 2 115-118

INDIA - FEMALE: 

INDIA - FEMALE Majority of the sufferers are females of the menstruating period. It affects predominantly women in their reproductive years. The median age of onset in Indian SLE is 24.5 years and the sex ratio (F:M) is 11:1 Ref: A Kumar J: INDIAN GUIDELINES ON THE MANAGEMENT OF SLE. Indian Rheumatol Assoc 2002 : 10 : 80 - 96

Slide 12: 

We are still in the dark to find out a cause for this illness but we know that it is an autoimmune disease. Large number of drugs that fight against the illness was already there in the armamentarium and more in the pipe line.

But alas! : 

But alas! Nothing found to be use full for the majority of SLE patients Who’s destiny is to land in the dialysis room or Kidney transplant arena with end stage Kidney failure and Those who escaped from suffering by reaching at the graveyards in the young age.

Americans: 

Americans Autoimmune diseases are common. Aaffecting > 23.5 million Americans. A Leading cause of death and disability

Unfortunate?: 

Unfortunate ? Unable to cut short Treatment cost Sufferings Morbidity Mortality Their future is bleak.

Some rays of hope : 

Some rays of hope Lande , Christian Goosmann , and various others Unveiling of the pathologic Cellular mechanism of the autoimmunity Ref: 1. Roberto Lande , et al.Peptide Complexes in Systemic Lupus Erythematosus Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self- DNA.Sci Transl Med 3, 73ra19 (2011 2. Volker Brinkmann , Britta Laube , Ulrike Abu Abed, Christian Goosmann , Arturo Zychlinsky.Neutrophil Extracellular Traps: How to Generate and Visualize Them. www.youtube.com/poyilil . Video Article 3.M. J. Shlomchik , Activating systemic autoimmunity: B’s, T’s, and tolls. Curr . Opin . Immunol.21, 626–633 (2009).

Autoimmunity: 

Autoimmunity By the breakdown of tolerance to nuclear self-antigens, which leads to activation of autoreactive Bcells that produce utoantibodies against self-nucleic acids and associated proteins.

Autoimmunity in SLE : 

Autoimmunity in SLE Results from hyper reactive B cells which initiate the T Helper/ suppressor deregulation results in the release of neutrophils characterized by chronic activation of plasmacytoid Dendritic Cells ( pDCs ) and production of autoantibodies against nuclear self-antigens. Ref: L. Rönnblom , V. Pascual , The innate immune system in SLE: Type I interferons and dendritic cells. Lupus 17, 394–399 (2008) .

Organ specific expressions: 

Organ specific expressions These autoantibodies bind self-nucleic acids released by dying cells, and form immune complexes that are deposited in different parts of the body, leading to detrimental inflammation and tissue damage.

Expressions of basic defects : 

Expressions of basic defects This results in various autoantibody production and deposition of immune complex in various organs.

Early event that triggers autoimmunity: 

Early event that triggers autoimmunity A key early event that triggers autoimmunity in SLE is the chronic innate activation of pDCs to secrete type I interferons (IFNs).

IFNs: 

IFNs The high levels of IFNs induce an unabated differentiation of monocytes into Dendritic cells that stimulate autoreactive B and T cells, and lower the activation threshold of autoreactive B cells, thereby promoting autoimmunity in SLE. Ref: A. N. Theofilopoulos, R. Baccala , B. Beutler , D. H. Kono , Type I interferons (a/b) in immunity and autoimmunity. Annu . Rev. Immunol . 23, 307–336 (2005). M. J. Shlomchik , Activating systemic autoimmunity: B’s, T’s, and tolls. Curr . Opin . Immunol.21, 626–633 (2009).

Slide 26: 

Neutrophil Extracellular Traps (Spiderman)

NET formation: 

NET formation These immunogenic complexes composed of neutrophil-derived antimicrobial peptides and self-DNA. These complexes were produced by activated neutrophils in the form of web-like structures known as Neutrophil Extracellular Traps (NETs) and

NET & BACTERIA: 

NET & BACTERIA

NET &Bacteria: 

NET &Bacteria

ScaningEMS view: 

ScaningEMS view

Toll-like receptor 9: 

Toll-like receptor 9 Efficiently triggered innate pDC activation via Toll-like receptor 9 (TLR9) Ref: Toll-like receptors in systemic autoimmune disease. A. Marshak -Rothstein, Nat. Rev. Immunol.6, 823–835 (2006).

1. Mechanisms for type I interferon induction in TLR7/9-stimulated dendritic cells: 

1. Mechanisms for type I interferon induction in TLR7/9-stimulated dendritic cells DCs sense nucleic acid adjuvants and produce type I interferon (IFN) in a subset-dependent manner. Among nucleic acid sensors, TLR7 and TLR9 are peculiar in that they recognize not only pathogen- but also host-derived nucleic acids. In fact, accumulating evidences suggest that TLR7/9-induced type I IFN production play important roles in pathogenesis of autoimmune disorders such as SLE. Therefore, clarifying the TLR7/9 signaling mechanisms should contribute to the development of therapeutic manipulation for such diseases.

IF Demo: 

IF Demo

Activated pDC- IF: 

Activated pDC - IF

Bacteria in Spidernet SEMS view: 

Bacteria in Spidernet SEMS view

Vicious cycle: 

Vicious cycle SLE patients were found to develop autoantibodies to both the self-DNA and antimicrobial peptides in NETs, indicating that these complexes could also serve as autoantigens to trigger B cell activation. Circulating neutrophils from SLE patients released more NETs than those from healthy donors.

VC: 

VC This catches the antimicrobial autoantibodies and chronic release of immunogenic complexes in SLE making a vicious cycle.

Vicious cycle: 

Vicious cycle

W-A-S-P: 

W-A-S-P This establish a link between cells, neutrophils, pDC activation, and autoimmunity in SLE, providing new potential targets for the treatment of this devastating disease. Even though the research thinks that the B cell defect is due to the genetic predilection of the individuals.

Spiderman: 

Spiderman There is some way to prevent the proliferation and multiplication of B-cells are prevented, we can control SLE and other auto immune disease to certain extend . The NET produced by neutrophils are like the Spiderman’s net.

NECROSIS, APOPTOSIS AND NETOSIS : 

NECROSIS, APOPTOSIS AND NETOSIS

CELL DEATH: 

CELL DEATH There are two ways of cell death either by necrosis or by apoptotic. In case of necrotic or inflammatory cell death various cell debris like DNA, nucleolus, chromatids etc are released in to the extracellular space which normally cached in the NET and removed from the tissues.

APOPTOSIS<>NECROSIS: 

APOPTOSIS<>NECROSIS

APOPTOSIS: 

APOPTOSIS Similarly apoptosis the cell debris are removed with out any immunological reactions . Ref:Hallmarks of the apoptotic and necrotic cell death process.( Pic ) Apoptosis includes cellular shrinking, chromatin condensation and margination at the nuclear periphery with the eventual formation of membrane-bound apoptotic bodies that contain organelles, cytosol and nuclear fragments and are phagocytosed without triggering inflammatory processes.The necrotic cell swells, becomes leaky and finally is disrupted and releases its contents into the surrounding tissue resulting in inflammation. Modified from [Van Cruchten , 2002].

APOPTOSIS: 

APOPTOSIS

Spiderman: 

Spiderman Thus playing a wonderful role by the NET (Spiderman). In the case of autoimmune diseases and SLE either the apoptosis is defective or after apoptotic cell death the removal of the debris are defective.

Activation pd: 

Activation pd

NETOSIS: 

NETOSIS It is proved that self-DNA in immune complexes of SLE patients contains Neutrophil antimicrobial peptide LL37 and HNP. These antimicrobial peptides were required for self-DNA to trigger TLR9 in pDCs by forming complexes with the DNA that is protected from extracellular degradation. Such immunogenic self-DNA–antimicrobial peptide complexes were released by dying neutrophils undergoing NETosis , a cell death process in which activated neutrophils extrude large amounts of nuclear DNA into the extracellular space in the form of web-like structures called NETs 8,9,10.

Net &Neutrophil: 

Net & Neutrophil NETs were abundantly released by neutrophils of SLE patients and were found to directly activate pDC to produce IFN-a. SLE patients developed autoantibodies to both the DNA and the antimicrobial peptides present in NETs, suggesting that NETs also trigger activation of autoreactive B cells.

CLINICAL IMPLICATIONS OF BASIC RESEARCH: 

CLINICAL IMPLICATIONS OF BASIC RESEARCH Thus, we @ identify the ability of neutrophils to activate pDCs through the release of NETs and suggest that a dysregulation of this pathway drives chronic pDC activation and autoimmunity in SLE. Recent studies, such as those by Lande et al. @ and Garcia- Romo et al., have pushed the neutrophil to the forefront of the pathogenesis of SLE and have provided insight into how the implicated biochemical and cellular events are linked. Ref: CLINICAL IMPLICATIONS OF BASIC RESEARCH Systemic Lupus Erythematosus and the Neutrophil Xavier Bosch, M.D., Ph.D. N Engl J Med 2011; 365:758-760 August 25, 2011

Slide 51: 

BIOSIMILARS (Superman)

Clinical<Failure> Basic : 

Clinical<Failure> Basic Once we failed to prevent the formation autoantibodies by the NET search continued to produce biologics (Superman ) against the antibodies produced by the SLE . One antibody fails try another it fails try another.....

In pockets and pipeline: 

In pockets and pipeline Autoantibodies seen in systemic lupus are directed against nuclear antigens such as nucleosomes, DNA, and histone proteins found within the body's cells and plasma . Autoantibodies are involved in disease development either by forming immune complexes that lodge in target organs, disrupting normal organ function, or by cross-reacting with targeted antigens and damaging tissue.

antibody: 

antibody Targets of autoantibodies in SLE include nuclear and cytoplasmic macromolecules, lipid components, and plasma proteins. The most frequently associated autoantibodies in SLE include smith ( Sm ), nucleosomes, histones, and double stranded (ds) DNA. Anti- ds DNA antibodies are the most frequently detected antibodies in SLE . Aberrancy in multiple components of the immune system including B cells, T cells, cytokines and growth factors.

Try try and try: 

Try try and try CD20 antibody. Rituximab, in SLE, reported an unexpected negative results. Belimumab , the monoclonal antibody against B-lymphocyte stimulator ( BLyS ), showed significant clinical benefit. Studies of a co-stimulation blocker ( abatacept ), tumor necrosis factor inhibitor (infliximab), and interleukin-6 inhibitor ( tocilizumab ) were either negative Studies of T cell and interferon inhibition remain in the early development phase.

TOMORROW? : 

TOMORROW? Excessive B cell function including autoantibody production is a common feature of SLE and considered to be intimately associated with spontaneous lymphokine secretion by themselves. To clarify roles of IL- 6/IL-6 receptor autocrine activation pathway in autoantibody production observed in patients with SLE, studied expression and function of IL- 6 receptors in comparison with those of IL-2 receptors, Tac on SLE B cells. IL-6 receptors and IL-2 receptors have been detected on B cells in the blood without any in vitro stimuli in most patients with SLE.

In pipeline: 

In pipeline The introduction of anti-IL-6 receptor antibody, which inhibits binding to the receptors of IL-6, and anti-IL-2 receptor antibody, anti- Tac to the cultures of SLE B cells resulted in potent inhibition of spontaneous production of polyclonal Ig and anti-DNA autoantibodies . In addition, fresh SLE B cells secreted high levels of IL-6 without any in vitro stimuli.

B cells the culprit?: 

B cells the culprit? These results indicate that constitutive expression of IL-6 receptors on B cells in conjunction with spontaneous IL-6 production by B cells induces autocrine B cell activation, which may lead to B cell hyperactivity and autoantibody secretion in SLE patients.

Future : 

Future Dysregulation of B cell activity observed in patients with SLE could thus be, at least in part, independent of T cell help. Several new targeted biologic agents for treating lupus nephritis are on the horizon; however, it is important to determine the circumstances in which they should be used, and how to optimally combine these agents with current or other new therapies.

hope@: 

hope@ Among the important ones are Tocilizumab a humanised monoclonal antibody that binds interleukin -6 (IL-6) receptors. Ustekunumab is a human immunoglobulin ( Ig ) G1 antibody that neutralizes IL-12 and IL-23 mediated common response.

Fusion proteins*: 

Fusion proteins* Alefacept a Fusion protein of the CD-2 blinding region of leukocyte function associated antigen -3 and the CH2 and CH3 domain lgG1 inhibit T-cells activation and induces apoptosis of memory T-cells. Abatacept modulates CD 80/CD86: CD28 Co-stimulatory signal needed for activation of T-cells.

Anakinra: 

Anakinra Anakinra competitively inhibit IL-1 binding to IL-1 type -1 receptor Retuximab . CD 20 directed cytotoxic antibody. Ref: Joanna m. Do biologics cause cancer? University of Michigan.17.08.2011.www.medscape.com.

Conclusion : 

Conclusion The war continues and warriors

The war and warriors: 

The war and warriors The presence of NET (Spider web like) in the extra cellular space which (The Spiderman helps in the elimination of enemy ) get neutralized by some weapons (Neutrophil antimicrobial peptide LL37 and HNP) produced by the enemy in SLE.

Futile Attempts- Nepotism?: 

Futile Attempts- Nepotism? The futile attempt in search of various biosimilars (Superman) to protect from SLE still continued.

-Hope for a good hope-: 

-Hope for a good hope-

REFERENCES : 

REFERENCES 1. Roberto Lande , et al.Peptide Complexes in Systemic Lupus Erythematosus Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self- DNA.Sci Transl Med 3, 73ra19 (2011 2. Volker Brinkmann , Britta Laube , Ulrike Abu Abed, Christian Goosmann , Arturo Zychlinsky.Neutrophil Extracellular Traps: How to Generate and Visualize Them. www.youtube.com/poyilil. Video Article 3.M. J. Shlomchik , Activating systemic autoimmunity: B’s, T’s, and tolls. Curr . Opin . Immunol.21, 626–633 (2009). 4. L. Rönnblom , V. Pascual , The innate immune system in SLE: Type I interferons and dendritic cells. Lupus 17, 394–399 (2008). 5. A. N. Theofilopoulos, R. Baccala , B. Beutler , D. H. Kono , Type I interferons (a/b) in immunityand autoimmunity. Annu . Rev. Immunol . 23, 307–336 (2005).

Slide 68: 

6. M. J. Shlomchik , Activating systemic autoimmunity: B’s, T’s, and tolls. Curr . Opin . Immunol.21, 626–633 (2009). 7. Toll-like receptors in systemic autoimmune disease. A. Marshak -Rothstein, Nat. Rev. Immunol.6, 823–835 (2006). 8. V. Brinkmann , U. Reichard , C. Goosmann , B. Fauler , Y. Uhlemann , D. S. Weiss, Y. Weinrauch , A. Zychlinsky , Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

Slide 69: 

9. T. A. Fuchs, U. Abed, C. Goosmann , R. Hurwitz, I. Schulze, V. Wahn , Y. Weinrauch , V. Brinkmann , A. Zychlinsky , Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 176, 231–241 (2007). 10. V. Brinkmann , A. Zychlinsky , Beneficial suicide: Why neutrophils die to make NETs. Nat. Rev. Microbiol . 5, 577–582 (2007). 11. Joanna m. Do biologics cause cancer? University of Michigan.17.08.2011.www.medscape.com.