Systemic  Lupus Erythematosus<br />By  Dr Bashir Ahmed Dar<br />Associate Professor of Medicine<br />Chinkipora  Sopore  K...
Dr Bashir and Dr yashodhora  leading group of medical students  to meet noble prize winner in medicine  at KL Malaysia<br />
Precious moments with noble prize winner<br />
Dr Bashir at PBL Conference<br />
My Son Yawer Bashir<br />
My Home in Kashmir<br />
SLE is an autoimmune inflammatory disease involving multisystem or multiorgans of the body.<br />
Systemic  Lupus Erythematosus<br />Basically, in autoimmune diseases, the human immune system wrongly recognizes tissues o...
Background on Systemic Lupus Erythematosus<br />Lupus is Latin for wolf, and "erythro" is derived from Greek for "red.“<br />
Background on Systemic Lupus Erythematosus<br />All explanations originate with the reddish, butterfly-shaped malar rash t...
Background on Systemic Lupus Erythematosus<br />In various accounts, some doctors thought the rash resembled the pattern o...
Background on Systemic Lupus Erythematosus<br />In other accounts, doctors thought that the rash, which was often more sev...
Background on Systemic Lupus Erythematosus<br />Another account claims that the term "lupus" did not come from Latin direc...
Background on Systemic Lupus Erythematosus<br />The term lupus is attributed to 12th-century physician Rogerius, who used ...
Background on Systemic Lupus Erythematosus<br />Four years later, the use of salicylates in conjunction with quinine was n...
Background on Systemic Lupus Erythematosus<br />Michael Jackson suffered from both SLE and vitiligo.Diagnosed in 1986, and...
Background on Systemic Lupus Erythematosus<br />Lady Gaga has been tested borderline positive for SLE, however she claims ...
Background on Systemic Lupus Erythematosus<br />In 1977 Charles Kuralt, former anchor of CBS Sunday Morning, died of SLE c...
Systemic  Lupus Erythematosus<br />Millions of Americans are afflicted with an autoimmune disease, mostly women of childbe...
Systemic  Lupus Erythematosus<br />Predominantly affects females at a rate of almost 9 to 1.<br />Though disease can affec...
Etiology<br />              Heredity/ Genetic<br />               Sex hormone status               <br />               En...
Heredity/ Genetic causes<br />The most important genes causing  SLE are located in the HLA region on chromosome 6, where m...
Heredity/ Genetic causes<br />14 of the genes where linked to SLE patients manifesting a severe form of the disease.<br />...
Heredity/ Genetic causes<br />The data show support for therapies that would block IFN pathways.  This may be able to help...
Heredity/ Genetic causes<br />Genetic predisposition<br />MHC genes: HLA DR2, DR3, DR4-DIL, DR5-   APS<br />Non-MHC genes:...
Heredity/ Genetic causes<br />Relatives of patients with autoimmune disease often show high incidence of same type of auto...
But Genetic predisposition is not enough ? need enviroNmental factors<br />
Environmental Factors Causing SLE<br />These factors  not only exacerbate existing  SLE conditions but also trigger the in...
Environmental Factors Causing SLE<br />They include certain medications (such as some antidepressants and antibiotics), ex...
Environmental Factors Causing SLE<br />UV radiation has been shown to trigger the photosensitive lupus rash and some evide...
Environmental Factors Causing SLE<br />Researchers have sought to find a connection between certain infectious agents (vir...
Environmental Factors Causing SLE<br />Some researchers have found that women with silicone gel-filled breast implants hav...
Environmental Factors Causing SLE<br />Drug-induced lupus erythematosus is a (generally) reversible condition that usually...
Environmental Factors Causing SLE<br />Drug-induced lupus mimics SLE. However, symptoms of drug-induced lupus generally di...
Environmental Factors Causing SLE<br />Wide range of possible infection; some genetic combinations result in autoimmunity....
Environmental Factors Causing SLE<br />Because of genetic variations in different components of the immune system, in some...
Environmental Factors Causing SLE<br />Researchers are now identifying the individual  genes, the proteins they produce, a...
Environmental Factors Causing SLE<br />Drugs such as hydralazine, methyldopa, and minocycline can induce lupus not associa...
Environmental Factors Causing SLE<br />       Even Provoking factors like<br />Sunlight, UV light<br />Infections<br />Dru...
HORMONAL FACTORS CAUSING SLE<br />Estrogen and other female hormones are considered to play a role since women are more li...
HORMONAL FACTORS CAUSING SLE<br />Testosterone reduces immunoglobulin production from peripheral blood   as well as mononu...
HORMONAL FACTORS CAUSING SLE<br />Flares of SLE are well known to occur during periods of rapid hormonal changes. These in...
HORMONAL FACTORS CAUSING SLE<br />Lupus activity tends to be reduced when patients undergo menopause. It has also been not...
HORMONAL FACTORS CAUSING SLE<br />The administration of exogenous estrogens in the form of OC pills and HRT may exacerbate...
HORMONAL FACTORS CAUSING SLE<br />Chronic hyperprolactinaemia induced by pituitary gland implantation stimulates primary h...
HORMONAL FACTORS CAUSING SLE<br />A dopamine agonist that selectively inhibits prolactin secretion from the pituitary, has...
HORMONAL FACTORS CAUSING SLE<br />Gonadotrophin releasing hormone (GnRH), a produced by the hypothalamus, regulates the re...
HORMONAL FACTORS CAUSING SLE<br />The administration of exogenous estrogens in the form of OC pills and HRT may exacerbate...
HORMONAL FACTORS CAUSING SLE<br />The exposure of humans to environmental estrogens is believed to increase over the years...
PATHOGENESIS OF SLE<br />To understand  further pathogenesis of SLE some idea about immune system is required.<br />
PHAGOCYTES<br />The granulocytes they attack any invaders in large numbers, and "eat" until they die. The pus in an infect...
PHAGOCYTES<br />The macrophages ("big eaters") are slower to respond to invaders have far greater capacities. Macrophages ...
PHAGOCYTES<br />The dendritic cells are "eater" cells  like the granulocytes and the macrophages..<br />
Professional antigen presenting cells <br />Common APC are<br />Macrophages<br />Dendritic cells<br />Please note that the...
PATHOGENESIS OF SLE<br />When antigen crosses the blood capillary and reaches to extracellular  space. <br />
After crossing of antigen the macrophage or B cell which are present in extracellular space then immediately come in conta...
The antigen is taken inside  the macrophage cell and broken into smaller fragments or peptides called epitopes.<br />
Antigen after being broken into peptides/smaller fragments combines with another protein inside the cell called major MHC-...
PATHOGENESIS OF SLE<br />
PATHOGENESIS OF SLE<br />
PATHOGENESIS OF SLE<br />
PATHOGENESIS OF SLE<br />Or if antigen-antibody has already formed  in blood and once it reaches extracellular space the a...
PATHOGENESIS OF SLE<br />Or it can also happen like this that when antigen reaches to extracellular space it unites with a...
PATHOGENESIS OF SLE<br />Because the B cell has antibody on its surface as a receptor that recognizes the antigen.<br />On...
First, the APC usually a macrophage  engulfs the antigen. Enzymes (peroxides) inside the APC break down the antigen into s...
The processed antigens are transported to the surface of the APC, where it binds with MHC (major histocompatibility comple...
This complex  (part of a foreign substance and MHC) is now presented to (CD4 T-helper cell ) or CD8 (cytotoxic T cell) whi...
Antigen with MHC-complex2,  combines with CD4 T helper cell otherwise with MHC-1 with CD8-T helper  cell.<br />
The macrophage or B cell also called as antigen presenting cell thus in this way presents small fragment of antigen to CD4...
<ul><li>As soon as APC  combines with T cell , the APC gets activated and secretes following cytokines.
Interleukin-1 (IL-1)
Interferon-alpha (IFN-a)
Interferon-gamma (IFN-g)
Tumor necrosis factor (TNF)
And other factors that activate lymphocytes and other immune cells to respond to the antigens.</li></li></ul><li>Effects o...
Effects of IL-1<br />Cells in vicinity also secrete  Chemokines.<br />So that more and more inflammatory cells  are attrac...
Effects of IL-1<br />
Effects of IL-1<br />Although peripheral  T cells are activated, both their capacity for proliferation in response to cyto...
IL-1 also causes increased production of inducible nitric oxide synthase and consequently high levels of nitric oxide resp...
IL-1 also activates endothelial cells and induces stimulation of adhesion molecule expression on endothelial cells.<br />
Firm Adhesion Rolling &Transmigration of neutrophilis & other cells to reach site of antigen by chemo attractants etc <br />
Effects of IL-1<br />The end result of these of IL-1 and TNF-a include activation and migration of leukocytes and lymphocy...
Tumor necrosis factor<br />Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-a...
Tumor necrosis factor<br />Suppressing appetite, induces neutrophil proliferation and increase in C-reactive protein and  ...
IL-10 in SLE<br />Also  in case of SLE, the Th2 helper cell role is much more prominent that secrete IL-10 than Th1 cells....
IL-10 & B cells<br />Now as said that IL-10 produced by Th2 cells etc stimulate proliferation of B cells and their transfo...
IL-10 & B cells<br />Even the B cell will have antibody as receptor on its surface which the T-helper cell will recognize ...
IL-10 & B cells<br />Antibodies are so enormously formed that they take antigens of normal tissue as non-self due to loss ...
IL-10 & B cells<br />IL-10 also acts as an anti inflammatory and immunosuppressive  cytokine on T- cells, and appears to u...
IL-10 & B cells<br />Promotes the development of immunologic tolerance.<br />Decreases production of inducible nitric oxid...
IL-10 & B cells<br />Therefore enhances B cell survival, proliferation, and antibody  formation.<br />The gene for IL-10 i...
IL-10 & B cells<br />Also it has been seen that the cells that normally suppress B cell activation, such as CD8+ suppresso...
Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9)<br />This enzyme is one of a group of metalloproteinase's (which inclu...
Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9)<br />Normal cells produce MMP-9 in an inactive, or latent form. The en...
Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9)<br />Breakdown of extracellular collagen and elastin etc pave easy way...
Elastin & collagen barriers are eaten away<br />
ROLE OF ANTIBODIES<br />Antibodies are released from the plasma cell so that they can seek out intruders and help destroy ...
ROLE OF ANTIBODIES<br />The attached antibodies serve as an appetizing coating for eater cells such as the macrophage. <br...
antigen-binding<br />sites<br />antigen<br />antigen binds<br />to binding site<br />V<br />V<br />V<br />V<br />light<br ...
ROLE OF ANTIBODIES<br />Each branch of the Y-shaped antibody can bind to a different antigen, so while one branch binds to...
Role of Complement Proteins<br />Bacteria and other pathogens /antigens covered with antibodies are also more likely to be...
Role of Complement Proteins<br />C1 binds to antibody that is bound to antigen (antigen-antibody [Ag-Ab complex) on the ta...
Role of Complement Proteins<br />The Ag-Ab complex catalyzes a series of chemical reactions that ends with inactive C3 con...
Once bound, C3b stimulates phagocytosis and promotes inflammation. C3b also triggers reactions that lead to the creation o...
In addition to destroying foreign invaders, complement causes degranulation of mast cells, and formation of the membrane a...
ROLE OF ANTIBODIES<br />The antibody has prepared the antigen for eating by the phagocytic cells. The term opsonin is used...
ROLE OF ANTIBODIES<br />Opsonization  can also happen due to coating of microbes with complement components, such as C3b. ...
ROLE OF ANTIBODIES<br />IgG is a good opsonin. Binding of IgG to Fc receptors on other types of cells results in the activ...
ROLE OF ANTIBODIES<br />Neutralization of toxins /antigen activity<br />Immobilization of microorganisms <br />Binding  wi...
ROLE OF ANTIBODIES<br />ACTIVATION OF COMPLIMENTS-LEADS TO CELL  LYSIS<br />Thus making also antigen immobile, inactive ha...
ROLE OF ANTIBODIES<br />But what happens in SLE the antibodies react with  normal antigens of normal cells of the body mak...
ROLE OF ANTIBODIES<br />Because due to consumption of compliments the level of compliments gets reduced even may be heredi...
Antibodies involved in SLE<br />So these antibodies act against almost all cells of the body to their nuclear, cytoplasmic...
Antibodies involved in SLE<br />The presence of autoantibodies can usually be determined by the antinuclear antibody also ...
Antibodies involved in SLE<br />Not all positive ANA tests indicate autoimmune disease, particularly when the titer is low...
Antibodies involved in SLE<br />Antibodies to double stranded DNA (dsDNA) are thought to be of importance in the pathogene...
Antibodies involved in SLE<br />Using serum from military personnel that was stored before any diagnosis with SLE, Arbuckl...
Antibodies involved in SLE<br />The Sm proteins were first discovered as antigens targeted by so called Anti-Sm antibodies...
Antibodies involved in SLE<br />The Sm antigen is designated as a small nuclear ribonucleoprotein (snRNP) and is composed ...
Antibodies involved in SLE<br />La protein is involved in RNA metabolism and plays a role in the transcription of RNA poly...
Antibodies involved in SLE<br />Anti-Ro/SSA and anti-La/SSB antibodies, which are directed against two extractable nuclear...
Antibodies involved in SLE<br />SSA/Ro are different epitopes on soluble cellular component nuclear and cytoplasmic polype...
Antibodies involved in SLE<br />Ribonucleoprotein (RNP) is a nucleoprotein that contains RNA, i.e. it is an association th...
Antibodies involved in SLE<br />Identification of a nuclear protein (Scl-70) recognized as topoisomerase I in 1986 with an...
Antibodies involved in SLE<br />Following detection of a high titer of ANAs (e.g. 1:160), various subtypes are determined....
Antibodies involved in SLE<br />A process for preparing nucleoproteic material which comprises immersing organic material ...
Antibodies involved in SLE<br />Anti-Ro/SSA and anti-La/SSB antibodies, which are directed against two extractable nuclear...
ANA classification<br />Anti-Ro (SS-A)<br />Anti-La (SS-B)<br />Anti-Sm (Smith antigen)<br />Anti-nRNP (nuclear ribonucleo...
Helper and Killer T Cells<br />Now coming again to the point that T cells as well as B cells are stimulated  when APC pres...
Helper and Killer T Cells<br />More and more helper T cells circulate in the body hunting for diseased or infected cells b...
Cytotoxic T cells<br />When the helper T cells find these unwanted cells, the helpers send a signal to the killer (cytotox...
Cytotoxic T cells<br />Activated killer T cells/(or "turned on") or cytotoxic T cells with CD8 receptor  recognizes antige...
Cytotoxic T cells/Killer T cells<br />
1  Cytotoxic T cell binds  to infected cell<br />Holeforming<br />Infecte cell<br />Infected cellis destroyed<br />Perfori...
Cytotoxic T cells/Killer T cells<br />
Suppressor T cells (also called Regulatory T cells)<br />limit responses of other cells (B & T cells) <br />Make immune re...
Defective Suppressor and Memory T cells in SLE<br />Suppressor T cells (also called regulatory T cells) tell the immune sy...
Defective Suppressor and Memory T cells in SLE<br />Regulatory T cells are important in preventing an overactive immune sy...
Defective clearance of apoptotic cells in SLE<br />Autoimmunity possibly results in defective clearance of apoptotic cells...
Defective clearance of apoptotic cells in SLE<br />B and T cell tolerance for apoptotic cells is abrogated, and the lympho...
Tingible Body Macrophages (TBM)<br />A Tingible body macrophage is a type of macrophage -- large phagocytic cells predomin...
Tingible Body Macrophages (TBM)<br />Tingible body macrophages normally engulf B cells and contain condensed (nuclear bits...
Tingible Body Macrophages (TBM)<br />In healthy conditions, apoptotic lymphocytes are removed in germinal centres by speci...
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Pathogenesis systemic lupus erythematosus by dr bashir ahmed dar associate professor medicine sopore kashmir

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Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and arthritis; malar and other skin rashes; pleuritis or pericarditis; renal or CNS involvement; and hematologic cytopenias.

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Pathogenesis systemic lupus erythematosus by dr bashir ahmed dar associate professor medicine sopore kashmir

  1. 1. Systemic Lupus Erythematosus<br />By Dr Bashir Ahmed Dar<br />Associate Professor of Medicine<br />Chinkipora Sopore Kashmir<br />Email-- drbashir123@gmail.com<br />
  2. 2. Dr Bashir and Dr yashodhora leading group of medical students to meet noble prize winner in medicine at KL Malaysia<br />
  3. 3. Precious moments with noble prize winner<br />
  4. 4. Dr Bashir at PBL Conference<br />
  5. 5.
  6. 6.
  7. 7.
  8. 8. My Son Yawer Bashir<br />
  9. 9.
  10. 10.
  11. 11.
  12. 12. My Home in Kashmir<br />
  13. 13. SLE is an autoimmune inflammatory disease involving multisystem or multiorgans of the body.<br />
  14. 14. Systemic Lupus Erythematosus<br />Basically, in autoimmune diseases, the human immune system wrongly recognizes tissues of the body as harmful antigens and so builds a response, targeting self-cells.<br />
  15. 15. Background on Systemic Lupus Erythematosus<br />Lupus is Latin for wolf, and "erythro" is derived from Greek for "red.“<br />
  16. 16. Background on Systemic Lupus Erythematosus<br />All explanations originate with the reddish, butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks.<br />
  17. 17. Background on Systemic Lupus Erythematosus<br />In various accounts, some doctors thought the rash resembled the pattern of fur on a wolf's face. <br />
  18. 18. Background on Systemic Lupus Erythematosus<br />In other accounts, doctors thought that the rash, which was often more severe in earlier centuries, created lesions that resembled wolf bites or scratches.<br />
  19. 19. Background on Systemic Lupus Erythematosus<br />Another account claims that the term "lupus" did not come from Latin directly, but from the term for a French style of mask that women reportedly wore to conceal the rash on their faces. The mask is called a "loup," French for "wolf."<br />
  20. 20. Background on Systemic Lupus Erythematosus<br />The term lupus is attributed to 12th-century physician Rogerius, who used it to describe the classic malar rash. <br />Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy.<br />
  21. 21. Background on Systemic Lupus Erythematosus<br />Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. <br />This was the best available treatment until the middle of the twentieth century, when Hench discovered the efficacy of corticosteroids in the treatment of SLE.<br />
  22. 22. Background on Systemic Lupus Erythematosus<br />Michael Jackson suffered from both SLE and vitiligo.Diagnosed in 1986, and confirmed by his dermatologist, Dr. Arnold Klein, who presented legal documents during court depositions.<br />
  23. 23. Background on Systemic Lupus Erythematosus<br />Lady Gaga has been tested borderline positive for SLE, however she claims not to be affected by the symptoms yet.Teddi King, American singer, died of SLE complications in<br />
  24. 24. Background on Systemic Lupus Erythematosus<br />In 1977 Charles Kuralt, former anchor of CBS Sunday Morning, died of SLE complications in 1997.Ferdinand Marcos, former Philippine president, who died of SLE complications in 1989.<br />
  25. 25. Systemic Lupus Erythematosus<br />Millions of Americans are afflicted with an autoimmune disease, mostly women of childbearing age. Generally, autoimmune diseases are lifelong conditions, although medication and treatment can make quality of life better for the patient.<br />
  26. 26. Systemic Lupus Erythematosus<br />Predominantly affects females at a rate of almost 9 to 1.<br />Though disease can affect all ages but most commonly begins from 20-45 years of age.<br />Common in Hispanic and African-American women than in Caucasian women.<br />The disease occurs in 1 out of 2,000 Americans and in as many as 1 out of 250 African-American women.<br />
  27. 27. Etiology<br /> Heredity/ Genetic<br /> Sex hormone status <br /> Environmental triggers /Immunological factor s <br /> Loss of ‘self-tolerance <br /> Complement deficiency<br />
  28. 28. Heredity/ Genetic causes<br />The most important genes causing SLE are located in the HLA region on chromosome 6, where mutations may occur randomly or may be inherited. HLA class I, class II, are associated with SLE.<br />
  29. 29. Heredity/ Genetic causes<br />14 of the genes where linked to SLE patients manifesting a severe form of the disease.<br />The 14 genes are collectively referred to as the interferon (or IFN) expression signature. The genes are turned on by interferon activity. IFN is a family of proteins that is involved in immune response regulation.<br />
  30. 30. Heredity/ Genetic causes<br />The data show support for therapies that would block IFN pathways. This may be able to help patients with a more severe form of the disease.<br />
  31. 31. Heredity/ Genetic causes<br />Genetic predisposition<br />MHC genes: HLA DR2, DR3, DR4-DIL, DR5- APS<br />Non-MHC genes: complement component, complement receptor, Fc receptors, CRP, cytokines, apoptotic genes (e.g., FAS)<br />
  32. 32. Heredity/ Genetic causes<br />Relatives of patients with autoimmune disease often show high incidence of same type of auto-Ab.<br />And may have some form of autoimmune disease.<br />
  33. 33. But Genetic predisposition is not enough ? need enviroNmental factors<br />
  34. 34. Environmental Factors Causing SLE<br />These factors not only exacerbate existing SLE conditions but also trigger the initial onset.<br />
  35. 35. Environmental Factors Causing SLE<br />They include certain medications (such as some antidepressants and antibiotics), extreme stress, exposure to sunlight, hormones, and infections. <br />
  36. 36. Environmental Factors Causing SLE<br />UV radiation has been shown to trigger the photosensitive lupus rash and some evidence suggests that UV light might be capable of altering the structure of the DNA, leading to the creation of autoantibodies.<br />
  37. 37. Environmental Factors Causing SLE<br />Researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no pathogen can be consistently linked to the disease.<br />
  38. 38. Environmental Factors Causing SLE<br />Some researchers have found that women with silicone gel-filled breast implants have produced antibodies to their own collagen, but it is not known how often these antibodies occur in the general population, and there is no data that show that these antibodies cause connective tissue diseases such as SLE. There is also a small but growing body of evidence linking SLE to lipstick usage,<br />
  39. 39. Environmental Factors Causing SLE<br />Drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being treated for a long-term illness.<br />
  40. 40. Environmental Factors Causing SLE<br />Drug-induced lupus mimics SLE. However, symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped. There are about 400 medications that can cause this condition, the most common of which are procainamide, hydralazine, quinidine, and phenytoin.<br />
  41. 41. Environmental Factors Causing SLE<br />Wide range of possible infection; some genetic combinations result in autoimmunity. The likely environmental triggers include ultraviolet light, drugs, and viruses. These stimuli cause the destruction of cells and expose their DNA, histones, and other proteins, particularly parts of the cell nucleus.<br />
  42. 42. Environmental Factors Causing SLE<br />Because of genetic variations in different components of the immune system, in some people the immune system attacks these nuclear-related proteins and produces antibodies against them.<br />In the end, these antibody complexes damage blood vessels in critical areas of the body, such as the glomeruli of the kidney; these antibody attacks are the cause of SLE.<br />
  43. 43. Environmental Factors Causing SLE<br />Researchers are now identifying the individual genes, the proteins they produce, and their role in the immune system. Each protein is a link on the autoimmune chain, and researchers are trying to find drugs to break each of those links.<br />
  44. 44. Environmental Factors Causing SLE<br />Drugs such as hydralazine, methyldopa, and minocycline can induce lupus not associated with anti-dsDNA. <br />Drug induced antibodies to histones.<br />
  45. 45. Environmental Factors Causing SLE<br /> Even Provoking factors like<br />Sunlight, UV light<br />Infections<br />Drugs<br />Isoniacid<br />Hidantoin<br />Hydralazin<br />Procainamide<br />D penicillinamin<br />Penicillins<br />Sulphonamids<br />TNF alpha blockers<br />Flare-ups can be induced by the contraceptive pill and hormone replacement therapy (HRT).<br />
  46. 46. HORMONAL FACTORS CAUSING SLE<br />Estrogen and other female hormones are considered to play a role since women are more likely to be affected.<br />Progesterone also have been shown to control the activity and production of MMP-9. Surprisingly, MMP-9 activity in females did not correlate strongly with SLE, but did so in male patients.<br />
  47. 47. HORMONAL FACTORS CAUSING SLE<br />Testosterone reduces immunoglobulin production from peripheral blood as well as mononuclear cells of both normal subjects and patients with SLE.<br />Improvement of SLE was noted in individual patients who had undergone menopause or ophorectomy.<br />
  48. 48. HORMONAL FACTORS CAUSING SLE<br />Flares of SLE are well known to occur during periods of rapid hormonal changes. These include pregnancy, puerperium, ovulation stimulation during in vitro fertilisation, and exogenous oestrogen administration.<br />
  49. 49. HORMONAL FACTORS CAUSING SLE<br />Lupus activity tends to be reduced when patients undergo menopause. It has also been noted that in many women disease flares are more common during the second half of the menstrual cycle, after the midcycle surge of oestrogen.<br />
  50. 50. HORMONAL FACTORS CAUSING SLE<br />The administration of exogenous estrogens in the form of OC pills and HRT may exacerbate the disease in patients with existing lupus.<br />
  51. 51. HORMONAL FACTORS CAUSING SLE<br />Chronic hyperprolactinaemia induced by pituitary gland implantation stimulates primary humoral antibody responses and accelerates autoimmune phenomena in lupus prone mice<br />Recent data suggest that the stimulatory actions of estrogens on auto reactive B cells require the presence of prolactin.<br />
  52. 52. HORMONAL FACTORS CAUSING SLE<br />A dopamine agonist that selectively inhibits prolactin secretion from the pituitary, has been shown to be useful in the treatment of non-life threatening SLE.<br />
  53. 53. HORMONAL FACTORS CAUSING SLE<br />Gonadotrophin releasing hormone (GnRH), a produced by the hypothalamus, regulates the release of LH and follicle stimulating hormone from the anterior pituitary. Recent animal studies show that GnRH is immunostimulatory.<br />
  54. 54. HORMONAL FACTORS CAUSING SLE<br />The administration of exogenous estrogens in the form of OC pills and HRT may exacerbate the disease in patients with existing lupus.<br />
  55. 55. HORMONAL FACTORS CAUSING SLE<br />The exposure of humans to environmental estrogens is believed to increase over the years through the consumption of meat and milk products of livestock that are fed with synthetic estrogens.<br />
  56. 56. PATHOGENESIS OF SLE<br />To understand further pathogenesis of SLE some idea about immune system is required.<br />
  57. 57. PHAGOCYTES<br />The granulocytes they attack any invaders in large numbers, and "eat" until they die. The pus in an infected wound consists chiefly of dead granulocytes.<br />
  58. 58. PHAGOCYTES<br />The macrophages ("big eaters") are slower to respond to invaders have far greater capacities. Macrophages start out as white blood cells called monocytes. Monocytes that leave the blood stream turn into macrophages in extracellular space.<br />
  59. 59. PHAGOCYTES<br />The dendritic cells are "eater" cells like the granulocytes and the macrophages..<br />
  60. 60. Professional antigen presenting cells <br />Common APC are<br />Macrophages<br />Dendritic cells<br />Please note that the B cells also act as antigen presenting cells.<br />
  61. 61. PATHOGENESIS OF SLE<br />When antigen crosses the blood capillary and reaches to extracellular space. <br />
  62. 62. After crossing of antigen the macrophage or B cell which are present in extracellular space then immediately come in contact with antigen.<br />
  63. 63. The antigen is taken inside the macrophage cell and broken into smaller fragments or peptides called epitopes.<br />
  64. 64. Antigen after being broken into peptides/smaller fragments combines with another protein inside the cell called major MHC-complex , and in this combination is brought to the surface of cell to be presented to T-helper cell or B cell<br />
  65. 65. PATHOGENESIS OF SLE<br />
  66. 66. PATHOGENESIS OF SLE<br />
  67. 67. PATHOGENESIS OF SLE<br />
  68. 68. PATHOGENESIS OF SLE<br />Or if antigen-antibody has already formed in blood and once it reaches extracellular space the antigen-antibody complex are taken together inside macrophage or B cell.<br />
  69. 69. PATHOGENESIS OF SLE<br />Or it can also happen like this that when antigen reaches to extracellular space it unites with antibody already present in extracellular space to form antigen-antibody complex.<br />
  70. 70. PATHOGENESIS OF SLE<br />Because the B cell has antibody on its surface as a receptor that recognizes the antigen.<br />Once the antigen (or antigen-antibody complex) are brought inside the cell, the antigen is broken into smaller fragments –the epitopes that combine with MHC-2 and brought to surface of B cell to be presented to T helper cell.<br />
  71. 71. First, the APC usually a macrophage engulfs the antigen. Enzymes (peroxides) inside the APC break down the antigen into smaller particles<br />
  72. 72. The processed antigens are transported to the surface of the APC, where it binds with MHC (major histocompatibility complex)<br />
  73. 73. This complex (part of a foreign substance and MHC) is now presented to (CD4 T-helper cell ) or CD8 (cytotoxic T cell) which the T-cell receptor (TCR) recognizes and binds to.<br />The T helper cell role is only to help and not to kill.<br />
  74. 74. Antigen with MHC-complex2, combines with CD4 T helper cell otherwise with MHC-1 with CD8-T helper cell.<br />
  75. 75. The macrophage or B cell also called as antigen presenting cell thus in this way presents small fragment of antigen to CD4 T helper cell or to CD8 T cell (cytotoxic T cell) which the T-cell receptor (TCR) recognizes and binds to.<br />The T helper cell role is only to help and not to kill, while as CD8 can kill the antigen and the cell that presents it..<br />
  76. 76. <ul><li>As soon as APC combines with T cell , the APC gets activated and secretes following cytokines.
  77. 77. Interleukin-1 (IL-1)
  78. 78. Interferon-alpha (IFN-a)
  79. 79. Interferon-gamma (IFN-g)
  80. 80. Tumor necrosis factor (TNF)
  81. 81. And other factors that activate lymphocytes and other immune cells to respond to the antigens.</li></li></ul><li>Effects of IL-1<br />On exposure to IL-1, the other inflammatory cells get affected and stimulated to produce following factors<br />Interleukin-6 (IL-6) <br />Prostaglandin's (e.g , PGE2) , and platelet-activating factor, which are involved in increased permeability ,vasodilatation and in the pain mechanism.<br />The mast cells in the vicinity also get activated to release histamine, heparin for capillary vaso- dilatation.<br />
  82. 82. Effects of IL-1<br />Cells in vicinity also secrete Chemokines.<br />So that more and more inflammatory cells are attracted and reach the site of antigen to deal with.<br />There also occurs activation of T cells their proliferation so that more T cells reach at the site of antigen along with neutrophilis and other inflammatory cells.<br />
  83. 83. Effects of IL-1<br />
  84. 84. Effects of IL-1<br />Although peripheral T cells are activated, both their capacity for proliferation in response to cytokine stimulation production are reduced in SLE.<br />Enhances activity of NK cells /cytotoxic T cells.<br />
  85. 85. IL-1 also causes increased production of inducible nitric oxide synthase and consequently high levels of nitric oxide responsible for dilatation of vessels.<br />Effects of IL-1<br />
  86. 86. IL-1 also activates endothelial cells and induces stimulation of adhesion molecule expression on endothelial cells.<br />
  87. 87. Firm Adhesion Rolling &Transmigration of neutrophilis & other cells to reach site of antigen by chemo attractants etc <br />
  88. 88. Effects of IL-1<br />The end result of these of IL-1 and TNF-a include activation and migration of leukocytes and lymphocytes from the blood into inflammatory tissues.<br />
  89. 89. Tumor necrosis factor<br />Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation.<br />Stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH)<br />
  90. 90. Tumor necrosis factor<br />Suppressing appetite, induces neutrophil proliferation and increase in C-reactive protein and induces insulin resistance result in cachexia, a wasting syndrome by protein catabolism, lipid depletion and necrosis of cells.<br />TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication. <br />
  91. 91. IL-10 in SLE<br />Also in case of SLE, the Th2 helper cell role is much more prominent that secrete IL-10 than Th1 cells.<br />Means there is switching of Th1 to Th2 response in SLE.<br />IL-10 is mainly produced by monocytes, activated macrophages, antigen-presenting cells and to a lesser extent by some activated B cells, subsets of CD4+ helper cells like TH1 cells,TH2 cells, mast cells and some non hematopoietic sources (e.g., keratinocytes, colon carcinoma, melanoma cells).<br />
  92. 92. IL-10 & B cells<br />Now as said that IL-10 produced by Th2 cells etc stimulate proliferation of B cells and their transformation into plasma cells.<br />The plasma cells in turn produce antibodies.<br />
  93. 93.
  94. 94. IL-10 & B cells<br />Even the B cell will have antibody as receptor on its surface which the T-helper cell will recognize when antigen binds to this B cell surface antibody.<br />The T-helper cell will then get it inside along with antibody as already said at the site of antigen.<br />
  95. 95. IL-10 & B cells<br />Antibodies are so enormously formed that they take antigens of normal tissue as non-self due to loss of tolerance and make these cells easily killed and destroyed due to antigen-antibody reaction and inflammation.<br />
  96. 96. IL-10 & B cells<br />IL-10 also acts as an anti inflammatory and immunosuppressive cytokine on T- cells, and appears to ultimately terminate inflammatory responses.<br />inhibits T cell proliferation. suppresses the antigen presentation capacity of antigen presenting cells. <br />inhibits synthesis of pro-inflammatory cytokines like IFN-?, IL-2, IL-3, TNFa, Chemokines.<br />
  97. 97. IL-10 & B cells<br />Promotes the development of immunologic tolerance.<br />Decreases production of inducible nitric oxide synthetase , a vasodilator.<br />The cumulative effect of these functions is to inhibit T cell-mediated immune inflammation, production of B cells and antibodies as well as decreased antigen presenting capacity.<br />
  98. 98. IL-10 & B cells<br />Therefore enhances B cell survival, proliferation, and antibody formation.<br />The gene for IL-10 is in chromosome region 1q31-q32<br />
  99. 99. IL-10 & B cells<br />Also it has been seen that the cells that normally suppress B cell activation, such as CD8+ suppressor T cells and NK cells are defective in their suppressive activity.<br />Because there is overall decrease in T cells as compared to B cells.<br />
  100. 100. Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9)<br />This enzyme is one of a group of metalloproteinase's (which includes collagenase and stromelysin) that are involved in connective tissue breakdown.. <br />
  101. 101. Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9)<br />Normal cells produce MMP-9 in an inactive, or latent form. The enzyme is activated by inflammatory mediators such as TNF-alpha and interleukin-1<br />
  102. 102. Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9)<br />Breakdown of extracellular collagen and elastin etc pave easy way and help cells to move easily in extracellular matrix to reach site of inflammation after migration of cells from vessels.<br />
  103. 103. Elastin & collagen barriers are eaten away<br />
  104. 104. ROLE OF ANTIBODIES<br />Antibodies are released from the plasma cell so that they can seek out intruders and help destroy them. Plasma cells produce antibodies at an amazing rate and can release tens of thousands of antibodies per second.<br />So that blood as well as extracellular spaces are flooded with antibodies.<br />
  105. 105. ROLE OF ANTIBODIES<br />The attached antibodies serve as an appetizing coating for eater cells such as the macrophage. <br />Antibodies also neutralize toxins /antigens and incapacitate viruses, preventing them from infecting new cells. <br />
  106. 106. antigen-binding<br />sites<br />antigen<br />antigen binds<br />to binding site<br />V<br />V<br />V<br />V<br />light<br />chain<br />C<br />C<br />shape of antigen fits<br />shape of binding site<br />C<br />C<br />heavy<br />chain<br />C = constant<br />V = variable<br />Antibody Structure<br />
  107. 107. ROLE OF ANTIBODIES<br />Each branch of the Y-shaped antibody can bind to a different antigen, so while one branch binds to an antigen on one cell, the other branch could bind to another antigen on other cell - in this way pathogens /antigens are gathered into larger groups that are easier for phagocyte cells to devour. <br />
  108. 108. Role of Complement Proteins<br />Bacteria and other pathogens /antigens covered with antibodies are also more likely to be attacked by the proteins from the complement system.<br />The complement system consists of 9 special proteins (designated C1-C9) that supplement/help or complement the action of antibodies<br />
  109. 109. Role of Complement Proteins<br />C1 binds to antibody that is bound to antigen (antigen-antibody [Ag-Ab complex) on the target cell surface.<br />
  110. 110. Role of Complement Proteins<br />The Ag-Ab complex catalyzes a series of chemical reactions that ends with inactive C3 converting to its active form, C3b, which then binds to the surface of the target antigen.<br />
  111. 111. Once bound, C3b stimulates phagocytosis and promotes inflammation. C3b also triggers reactions that lead to the creation of a membrane attack complex (MAC) that creates pores in the membrane of the target cell, like holes blown in the hull of a ship.<br />
  112. 112. In addition to destroying foreign invaders, complement causes degranulation of mast cells, and formation of the membrane attack complex – a group of lipid-soluble proteins that punch holes in the cell membrane of pathogens.<br />
  113. 113. ROLE OF ANTIBODIES<br />The antibody has prepared the antigen for eating by the phagocytic cells. The term opsonin is used to describe substances that enhance phagocytosis. <br />
  114. 114. ROLE OF ANTIBODIES<br />Opsonization can also happen due to coating of microbes with complement components, such as C3b. <br />Opsonized particles are more easily phagocytosed due to the presence of complement receptors on the plasma membrane of phagocytic cells.<br />
  115. 115. ROLE OF ANTIBODIES<br />IgG is a good opsonin. Binding of IgG to Fc receptors on other types of cells results in the activation of other functions.<br />
  116. 116. ROLE OF ANTIBODIES<br />Neutralization of toxins /antigen activity<br />Immobilization of microorganisms <br />Binding with soluble antigen , clumping of insoluble antigens (precipitation) , facilitates the ingestion of the antigen by phagocytic cells <br />Activating complement, complement components are also opsonins<br />
  117. 117. ROLE OF ANTIBODIES<br />ACTIVATION OF COMPLIMENTS-LEADS TO CELL LYSIS<br />Thus making also antigen immobile, inactive harmless and easily digestible by phagocytes.<br />
  118. 118. ROLE OF ANTIBODIES<br />But what happens in SLE the antibodies react with normal antigens of normal cells of the body making them prey for easy lyses by immune response as said already .<br />
  119. 119. ROLE OF ANTIBODIES<br />Because due to consumption of compliments the level of compliments gets reduced even may be hereditary deficiency of compliments in SLE.<br />
  120. 120. Antibodies involved in SLE<br />So these antibodies act against almost all cells of the body to their nuclear, cytoplasmic and cell-surface antigens.<br />To double-stranded DNA, histones and ribonuclear antigens in SLE.<br />
  121. 121. Antibodies involved in SLE<br />The presence of autoantibodies can usually be determined by the antinuclear antibody also known as anti-nuclear factor or ANF (ANA) test performed on patients serum from blood. The titer, or strength, of the ANA gives a rough indication of the severity of the disease.<br />
  122. 122. Antibodies involved in SLE<br />Not all positive ANA tests indicate autoimmune disease, particularly when the titer is low. After a positive screening ANA test, more specific tests for SLE include detection of auto-antibodies to double stranded DNA and to Smith antigen.<br />
  123. 123. Antibodies involved in SLE<br />Antibodies to double stranded DNA (dsDNA) are thought to be of importance in the pathogenesis of SLE. These antibodies are observed in approximately 60-70% of SLE patients.<br />
  124. 124. Antibodies involved in SLE<br />Using serum from military personnel that was stored before any diagnosis with SLE, Arbuckle et al. found that anti-dsDNA antibodies were present in the serum years before diagnosis of the actual disease. <br />This suggests that anti-dsDNA antibodies can be used as a marker for people who may be at risk for developing SLE.<br />
  125. 125. Antibodies involved in SLE<br />The Sm proteins were first discovered as antigens targeted by so called Anti-Sm antibodies in a patient with a form of systemic lupus erythematosus (SLE). <br />They were named Sm proteins in honor of this patient, Stephanie Smith. <br />
  126. 126. Antibodies involved in SLE<br />The Sm antigen is designated as a small nuclear ribonucleoprotein (snRNP) and is composed of a unique set of uridine rich RNA molecules bound to protein associated with the RNA molecules. <br />Anti-Sm antibodies react with snRNP core proteins.<br />
  127. 127. Antibodies involved in SLE<br />La protein is involved in RNA metabolism and plays a role in the transcription of RNA polymerase III, was originally defined by its reactivity with autoantibodies from patients with Sjogren syndrome.<br />
  128. 128. Antibodies involved in SLE<br />Anti-Ro/SSA and anti-La/SSB antibodies, which are directed against two extractable nuclear antigens, have been detected with high frequency in patients with Sjögren's syndrome.<br />
  129. 129. Antibodies involved in SLE<br />SSA/Ro are different epitopes on soluble cellular component nuclear and cytoplasmic polypeptides associated with small RNAs called scYRNA situated mostly in the cytoplasmic compartment (70%) and few in the nuclear compartment (30%).frequently produced in patients with Sjögren's syndrome and systemic lupus erythematosus. <br />
  130. 130. Antibodies involved in SLE<br />Ribonucleoprotein (RNP) is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together.<br />
  131. 131. Antibodies involved in SLE<br />Identification of a nuclear protein (Scl-70) recognized as topoisomerase I in 1986 with anti-centromere antibodies as a unique target of human antinuclear antibodies in scleroderma.<br />Topoisomerase is an enzyme that relaxes the strain on DNA by nicking and ligating the DNA. <br />
  132. 132. Antibodies involved in SLE<br />Following detection of a high titer of ANAs (e.g. 1:160), various subtypes are determined. These include:<br />Anti-ENA (Extractable nuclear antigen)<br />
  133. 133. Antibodies involved in SLE<br />A process for preparing nucleoproteic material which comprises immersing organic material into a suitable solvent for a sufficient time to extract nucleoproteins from said material, adding a sufficient amount of an acid to form a precipitate of nucleoproteic material, and recovering said nucleoproteic material precipitate. <br />
  134. 134. Antibodies involved in SLE<br />Anti-Ro/SSA and anti-La/SSB antibodies, which are directed against two extractable nuclear antigens, clinically by immunodiffusion, ELISA, or Western blot.<br />
  135. 135. ANA classification<br />Anti-Ro (SS-A)<br />Anti-La (SS-B)<br />Anti-Sm (Smith antigen)<br />Anti-nRNP (nuclear ribonucleoproteins)<br />Anti Scl-70 (topoisomerase I)<br />Anti-Jo<br />Anti-gp-210 (nuclear pore gp-210)<br />Anti-p62 (Nucleoporin 62)<br />Anti-dsDNA (double-stranded DNA)<br />Anti-centromere<br />
  136. 136. Helper and Killer T Cells<br />Now coming again to the point that T cells as well as B cells are stimulated when APC presents antigen to T helper cells.<br />In SLE B cell response is overwhelming due to IL-10 especially secreted by Th2 cells.<br />
  137. 137. Helper and Killer T Cells<br />More and more helper T cells circulate in the body hunting for diseased or infected cells bearing antigen or pathogen inside their cells. <br />
  138. 138. Cytotoxic T cells<br />When the helper T cells find these unwanted cells, the helpers send a signal to the killer (cytotoxic) T cells to come and kill the diseased or infected cells as well as degrade antigens and destroy these cells as well as cells bearing it.<br />
  139. 139. Cytotoxic T cells<br />Activated killer T cells/(or "turned on") or cytotoxic T cells with CD8 receptor recognizes antigens kill cells that contain foreign particles (antigens) by attaching to them and injecting a toxic chemical perforin so that holes form in these cells that then swells and bursts as well as antigen getting destroyed.<br />
  140. 140. Cytotoxic T cells/Killer T cells<br />
  141. 141. 1 Cytotoxic T cell binds to infected cell<br />Holeforming<br />Infecte cell<br />Infected cellis destroyed<br />Perforinmolecule<br />CytotoxicT cell<br />
  142. 142. Cytotoxic T cells/Killer T cells<br />
  143. 143. Suppressor T cells (also called Regulatory T cells)<br />limit responses of other cells (B & T cells) <br />Make immune response self-limiting <br />Prevents excessive immune response which might be detrimental to body <br />May also prevent immune system from attacking a person's own cells (= tolerance) <br />
  144. 144. Defective Suppressor and Memory T cells in SLE<br />Suppressor T cells (also called regulatory T cells) tell the immune system when the fight with the diseased or infected cells is over, and the killer T cells are no longer needed. <br />
  145. 145. Defective Suppressor and Memory T cells in SLE<br />Regulatory T cells are important in preventing an overactive immune system. There are problems with the regulatory T cells in SLE that lead to autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis as well.<br />
  146. 146. Defective clearance of apoptotic cells in SLE<br />Autoimmunity possibly results in defective clearance of apoptotic cells due to the extended exposure of large nuclear and intracellular autoantigens derived from enormous number of necrotic cells. <br />
  147. 147. Defective clearance of apoptotic cells in SLE<br />B and T cell tolerance for apoptotic cells is abrogated, and the lymphocytes get activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated.<br />
  148. 148. Tingible Body Macrophages (TBM)<br />A Tingible body macrophage is a type of macrophage -- large phagocytic cells predominantly found in germinal centers of lymph nodes, containing many phagocytosed, apoptotic cells in various states of degradation, referred to as tingible bodies (tingible meaning stainable).<br />
  149. 149. Tingible Body Macrophages (TBM)<br />Tingible body macrophages normally engulf B cells and contain condensed (nuclear bits) chromatin fragments.<br />
  150. 150. Tingible Body Macrophages (TBM)<br />In healthy conditions, apoptotic lymphocytes are removed in germinal centres by specialized phagocytes, the tingible body macrophages (TBM), which is why no free apoptotic and potential autoantigenic material can be seen.<br />
  151. 151. Tingible Body Macrophages (TBM)<br />But body macrophages (TBM) in SLE are few in number.<br />even show a definitely different morphology in SLE; they are smaller or scarce and die earlier there by engulfing of B cells is reduced B cells form plasma cells then antibodies. <br />
  152. 152. Tingible Body Macrophages (TBM)<br />The defect in apoptosis is thought due to inherited compliment deficiency like complement proteins, such as c1,C2, C4, or C1q.<br />
  153. 153. Tingible Body Macrophages (TBM)<br />Also, uningested apoptotic nuclei of cells can be found outside of TBMs.This material may present a threat and act as antigenic. <br />Defective apoptosis leading to the prolonged survival of pathogenic lymphocytes was thought to be one disease mechanism for SLE.which is associated with defective Fas (CD95) receptors on the surface of lymphocytes.<br />
  154. 154. THANK YOU SO MUCH<br />Trust the physician and the teacher, and drink his remedy in silence and tranquility. For his hand though heavy and hard is guided by tender hand of unseen. And the cup he brings, though it burn your lips has been fashioned of the clay which the potter have moistened with his tears and sacred feelings.<br />

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