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Dr Bashir Ahmed Dar Associate professor medicine chinkipora sopore kashmir presently working in malaysia writes on Systemic lupus erythematosus which 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.

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Systemic lupus erythematosus l.jpg
Systemic Lupus Erythematosus

By Dr Bashir Ahmed Dar

Associate Professor of Medicine

Chinkipora Sopore Kashmir

Email-- [email protected]


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Dr Bashir and Dr yashodhora leading group of medical students to meet noble prize winner in medicine at KL Malaysia


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Precious moments with noble prize winner students to meet noble prize winner in medicine at KL Malaysia


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Dr Bashir at PBL Conference students to meet noble prize winner in medicine at KL Malaysia


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My Son Yawer Bashir students to meet noble prize winner in medicine at KL Malaysia


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My Home in Kashmir students to meet noble prize winner in medicine at KL Malaysia


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SLE is an autoimmune inflammatory disease involving multisystem or multiorgans of the body.


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Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • 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.


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • Lupus is Latin for wolf, and "erythro" is derived from Greek for "red.“


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • All explanations originate with the reddish, butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks.


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • In various accounts, some doctors thought the rash resembled the pattern of fur on a wolf's face.


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • In other accounts, doctors thought that the rash, which was often more severe in earlier centuries, created lesions that resembled wolf bites or scratches.


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butterfly-shaped malar rash multisystem or multiorgans of the body


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • 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."


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • The term lupus is attributed to 12th-century physician Rogerius, who used it to describe the classic malar rash.

  • Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy.


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit.

  • 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.


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • 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.


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • 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


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Background on Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • 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.


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Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • 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.


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Systemic Lupus Erythematosus multisystem or multiorgans of the body

  • Predominantly affects females at a rate of almost 9 to 1.

  • Though disease can affect all ages but most commonly begins from 20-45 years of age.

  • Common in Hispanic and African-American women than in Caucasian women.

  • The disease occurs in 1 out of 2,000 Americans and in as many as 1 out of 250 African-American women.


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Etiology multisystem or multiorgans of the body

Heredity/ Genetic

Sex hormone status

Environmental triggers /Immunological factor s

Loss of ‘self-tolerance

Complement deficiency


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Heredity/ Genetic causes multisystem or multiorgans of the body

  • 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.


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Heredity/ Genetic causes multisystem or multiorgans of the body

  • 14 of the genes where linked to SLE patients manifesting a severe form of the disease.

  • 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.


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Heredity/ Genetic causes multisystem or multiorgans of the body

  • 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.


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Heredity/ Genetic causes multisystem or multiorgans of the body

  • Genetic predisposition

  • MHC genes: HLA DR2, DR3, DR4-DIL, DR5- APS

  • Non-MHC genes: complement component, complement receptor, Fc receptors, CRP, cytokines, apoptotic genes (e.g., FAS)


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Heredity/ Genetic causes multisystem or multiorgans of the body

  • Relatives of patients with autoimmune disease often show high incidence of same type of auto-Ab.

  • And may have some form of autoimmune disease.



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Environmental Factors Causing SLE enviroNmental factors

  • These factors not only exacerbate existing SLE conditions but also trigger the initial onset.


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Environmental Factors Causing SLE enviroNmental factors

  • They include certain medications (such as some antidepressants and antibiotics), extreme stress, exposure to sunlight, hormones, and infections.


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Environmental Factors Causing SLE enviroNmental factors

  • 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.


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Environmental Factors Causing SLE enviroNmental factors

  • Researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no pathogen can be consistently linked to the disease.


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Environmental Factors Causing SLE enviroNmental factors

  • 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,


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Environmental Factors Causing SLE enviroNmental factors

  • Drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being treated for a long-term illness.


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Environmental Factors Causing SLE enviroNmental factors

  • 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.


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Environmental Factors Causing SLE enviroNmental factors

  • 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.


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Environmental Factors Causing SLE enviroNmental factors

  • 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.

  • 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.


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Environmental Factors Causing SLE enviroNmental factors

  • 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.


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Environmental Factors Causing SLE enviroNmental factors

  • Drugs such as hydralazine, methyldopa, and minocycline can induce lupus not associated with anti-dsDNA.

  • Drug induced antibodies to histones.


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Environmental Factors Causing SLE enviroNmental factors

  • Even Provoking factors like

    • Sunlight, UV light

    • Infections

    • Drugs

      • Isoniacid

      • Hidantoin

      • Hydralazin

      • Procainamide

      • D penicillinamin

      • Penicillins

      • Sulphonamids

      • TNF alpha blockers

      • Flare-ups can be induced by the contraceptive pill and hormone replacement therapy (HRT).


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • Estrogen and other female hormones are considered to play a role since women are more likely to be affected.

  • 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.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • Testosterone reduces immunoglobulin production from peripheral blood as well as mononuclear cells of both normal subjects and patients with SLE.

  • Improvement of SLE was noted in individual patients who had undergone menopause or ophorectomy.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • 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.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • 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.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • The administration of exogenous estrogens in the form of OC pills and HRT may exacerbate the disease in patients with existing lupus.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • Chronic hyperprolactinaemia induced by pituitary gland implantation stimulates primary humoral antibody responses and accelerates autoimmune phenomena in lupus prone mice

  • Recent data suggest that the stimulatory actions of estrogens on auto reactive B cells require the presence of prolactin.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • 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.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • 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.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • The administration of exogenous estrogens in the form of OC pills and HRT may exacerbate the disease in patients with existing lupus.


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HORMONAL FACTORS CAUSING SLE enviroNmental factors

  • 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.


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PATHOGENESIS OF SLE enviroNmental factors

  • To understand further pathogenesis of SLE some idea about immune system is required.


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PHAGOCYTES enviroNmental factors

  • 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.


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PHAGOCYTES enviroNmental factors

  • 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.


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PHAGOCYTES enviroNmental factors

  • The dendritic cells are "eater" cells like the granulocytes and the macrophages..


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Professional antigen presenting cells enviroNmental factors

  • Common APC are

  • Macrophages

  • Dendritic cells

  • Please note that the B cells also act as antigen presenting cells.


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PATHOGENESIS OF SLE enviroNmental factors

  • When antigen crosses the blood capillary and reaches to extracellular space.


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After crossing of antigen the macrophage or B cell which are present in extracellular space then immediately come in contact with antigen.


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The antigen is taken inside the macrophage cell and broken into smaller fragments or peptides called epitopes.


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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


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PATHOGENESIS OF SLE 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


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PATHOGENESIS OF SLE 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


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PATHOGENESIS OF SLE 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


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PATHOGENESIS OF SLE 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

  • 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.


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PATHOGENESIS OF SLE 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

  • 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.


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PATHOGENESIS OF SLE 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

  • Because the B cell has antibody on its surface as a receptor that recognizes the antigen.

  • 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.


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First, the APC usually a macrophage engulfs the antigen. Enzymes (peroxides) inside the APC break down the antigen into smaller particles


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The processed antigens are transported to the surface of the APC, where it binds with MHC (major histocompatibility complex)


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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.

The T helper cell role is only to help and not to kill.


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Antigen with MHC-complex2, combines with CD4 T helper cell otherwise with MHC-1 with CD8-T helper cell.


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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.

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..


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As soon as 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.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.


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Effects of IL-1 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.

  • On exposure to IL-1, the other inflammatory cells get affected and stimulated to produce following factors

  • Interleukin-6 (IL-6)

  • Prostaglandin's (e.g , PGE2) , and platelet-activating factor, which are involved in increased permeability ,vasodilatation and in the pain mechanism.

  • The mast cells in the vicinity also get activated to release histamine, heparin for capillary vaso- dilatation.


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Effects of IL-1 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.

  • Cells in vicinity also secrete Chemokines.

  • So that more and more inflammatory cells are attracted and reach the site of antigen to deal with.

  • 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.


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Effects of IL-1 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.


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Effects of IL-1 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.

  • Although peripheral T cells are activated, both their capacity for proliferation in response to cytokine stimulation production are reduced in SLE.

  • Enhances activity of NK cells /cytotoxic T cells.


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Effects of IL-1 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.

  • IL-1 also causes increased production of inducible nitric oxide synthase and consequently high levels of nitric oxide responsible for dilatation of vessels.


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IL-1 also activates endothelial cells and induces stimulation of adhesion molecule expression on endothelial cells.


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Firm Adhesion Rolling &Transmigration of neutrophilis & other cells to reach site of antigen by chemo attractants etc


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Effects of IL-1 other cells to reach site of antigen by chemo attractants etc

  • 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.


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Tumor necrosis factor other cells to reach site of antigen by chemo attractants etc

  • Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation.

  • Stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH)


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Tumor necrosis factor other cells to reach site of antigen by chemo attractants etc

  • 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.

  • TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication.


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IL-10 in SLE other cells to reach site of antigen by chemo attractants etc

  • Also in case of SLE, the Th2 helper cell role is much more prominent that secrete IL-10 than Th1 cells.

  • Means there is switching of Th1 to Th2 response in SLE.

  • 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).


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IL-10 & B cells other cells to reach site of antigen by chemo attractants etc

  • Now as said that IL-10 produced by Th2 cells etc stimulate proliferation of B cells and their transformation into plasma cells.

  • The plasma cells in turn produce antibodies.


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IL-10 & B cells other cells to reach site of antigen by chemo attractants etc

  • 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.

  • The T-helper cell will then get it inside along with antibody as already said at the site of antigen.


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IL-10 & B cells other cells to reach site of antigen by chemo attractants etc

  • 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.


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IL-10 & B cells other cells to reach site of antigen by chemo attractants etc

  • IL-10 also acts as an anti inflammatory and immunosuppressive cytokine on T- cells, and appears to ultimately terminate inflammatory responses.

  • inhibits T cell proliferation. suppresses the antigen presentation capacity of antigen presenting cells.

  • inhibits synthesis of pro-inflammatory cytokines like IFN-?, IL-2, IL-3, TNFa, Chemokines.


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IL-10 & B cells other cells to reach site of antigen by chemo attractants etc

  • Promotes the development of immunologic tolerance.

  • Decreases production of inducible nitric oxide synthetase , a vasodilator.

  • 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.


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IL-10 & B cells other cells to reach site of antigen by chemo attractants etc

  • Therefore enhances B cell survival, proliferation, and antibody formation.

  • The gene for IL-10 is in chromosome region 1q31-q32


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IL-10 & B cells other cells to reach site of antigen by chemo attractants etc

  • 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.

  • Because there is overall decrease in T cells as compared to B cells.


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Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9) other cells to reach site of antigen by chemo attractants etc

  • This enzyme is one of a group of metalloproteinase's (which includes collagenase and stromelysin) that are involved in connective tissue breakdown..


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Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9) other cells to reach site of antigen by chemo attractants etc

  • 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


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Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9) other cells to reach site of antigen by chemo attractants etc

  • 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.


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Elastin & collagen barriers are eaten away other cells to reach site of antigen by chemo attractants etc


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ROLE OF ANTIBODIES other cells to reach site of antigen by chemo attractants etc

  • 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.

  • So that blood as well as extracellular spaces are flooded with antibodies.


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ROLE OF ANTIBODIES other cells to reach site of antigen by chemo attractants etc

  • The attached antibodies serve as an appetizing coating for eater cells such as the macrophage.

  • Antibodies also neutralize toxins /antigens and incapacitate viruses, preventing them from infecting new cells.


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antigen-binding other cells to reach site of antigen by chemo attractants etc

sites

antigen

antigen binds

to binding site

V

V

V

V

light

chain

C

C

shape of antigen fits

shape of binding site

C

C

heavy

chain

C = constant

V = variable

Antibody Structure


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ROLE OF ANTIBODIES other cells to reach site of antigen by chemo attractants etc

  • 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.


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Role of Complement Proteins other cells to reach site of antigen by chemo attractants etc

  • Bacteria and other pathogens /antigens covered with antibodies are also more likely to be attacked by the proteins from the complement system.

  • The complement system consists of 9 special proteins (designated C1-C9) that supplement/help or complement the action of antibodies


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Role of Complement Proteins other cells to reach site of antigen by chemo attractants etc

  • C1 binds to antibody that is bound to antigen (antigen-antibody [Ag-Ab complex) on the target cell surface.


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Role of Complement Proteins other cells to reach site of antigen by chemo attractants etc

  • 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.


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ROLE OF ANTIBODIES 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.

  • The antibody has prepared the antigen for eating by the phagocytic cells. The term opsonin is used to describe substances that enhance phagocytosis.


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ROLE OF ANTIBODIES 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.

  • Opsonization can also happen due to coating of microbes with complement components, such as C3b.

  • Opsonized particles are more easily phagocytosed due to the presence of complement receptors on the plasma membrane of phagocytic cells.


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ROLE OF ANTIBODIES 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.

  • IgG is a good opsonin. Binding of IgG to Fc receptors on other types of cells results in the activation of other functions.


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ROLE OF ANTIBODIES 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.

  • Neutralization of toxins /antigen activity

  • Immobilization of microorganisms

  • Binding with soluble antigen , clumping of insoluble antigens (precipitation) , facilitates the ingestion of the antigen by phagocytic cells

  • Activating complement, complement components are also opsonins


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ROLE OF ANTIBODIES 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.

  • ACTIVATION OF COMPLIMENTS-LEADS TO CELL LYSIS

  • Thus making also antigen immobile, inactive harmless and easily digestible by phagocytes.


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ROLE OF ANTIBODIES 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.

  • 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 .


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ROLE OF ANTIBODIES 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.

  • Because due to consumption of compliments the level of compliments gets reduced even may be hereditary deficiency of compliments in SLE.


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Antibodies involved in SLE 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.

  • So these antibodies act against almost all cells of the body to their nuclear, cytoplasmic and cell-surface antigens.

  • To double-stranded DNA, histones and ribonuclear antigens in SLE.


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Antibodies involved in SLE 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.

  • 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.


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Antibodies involved in SLE 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.

  • 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.


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Antibodies involved in SLE 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.

  • 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.


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Antibodies involved in SLE 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.

  • 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.

  • This suggests that anti-dsDNA antibodies can be used as a marker for people who may be at risk for developing SLE.


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Antibodies involved in SLE 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.

  • 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).

  • They were named Sm proteins in honor of this patient, Stephanie Smith.


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Antibodies involved in SLE 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.

  • 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.

  • Anti-Sm antibodies react with snRNP core proteins.


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Antibodies involved in SLE 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.

  • 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.


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Antibodies involved in SLE 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.

  • 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.


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Antibodies involved in SLE 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.

  • 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.


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Antibodies involved in SLE 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.

  • Ribonucleoprotein (RNP) is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together.


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Antibodies involved in SLE 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.

  • 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.

  • Topoisomerase is an enzyme that relaxes the strain on DNA by nicking and ligating the DNA.


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Antibodies involved in SLE 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.

  • Following detection of a high titer of ANAs (e.g. 1:160), various subtypes are determined. These include:

  • Anti-ENA (Extractable nuclear antigen)


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Antibodies involved in SLE 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.

  • 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.


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Antibodies involved in SLE 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.

  • Anti-Ro/SSA and anti-La/SSB antibodies, which are directed against two extractable nuclear antigens, clinically by immunodiffusion, ELISA, or Western blot.


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ANA classification 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.

  • Anti-Ro (SS-A)

  • Anti-La (SS-B)

  • Anti-Sm (Smith antigen)

  • Anti-nRNP (nuclear ribonucleoproteins)

  • Anti Scl-70 (topoisomerase I)

  • Anti-Jo

  • Anti-gp-210 (nuclear pore gp-210)

  • Anti-p62 (Nucleoporin 62)

  • Anti-dsDNA (double-stranded DNA)

  • Anti-centromere


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Helper and Killer T Cells 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.

  • Now coming again to the point that T cells as well as B cells are stimulated when APC presents antigen to T helper cells.

  • In SLE B cell response is overwhelming due to IL-10 especially secreted by Th2 cells.


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Helper and Killer T Cells 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.

  • More and more helper T cells circulate in the body hunting for diseased or infected cells bearing antigen or pathogen inside their cells.


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Cytotoxic T cells 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.

  • 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.


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Cytotoxic T cells 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.

  • 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.


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Cytotoxic T cells/Killer T cells 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.


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1 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.Cytotoxic T cell binds to infected cell

Holeforming

Infecte cell

Infected cellis destroyed

Perforinmolecule

CytotoxicT cell


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Cytotoxic T cells/Killer T cells 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.


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Suppressor T cells (also called Regulatory T cells) 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.

  • limit responses of other cells (B & T cells)

  • Make immune response self-limiting

  • Prevents excessive immune response which might be detrimental to body

  • May also prevent immune system from attacking a person's own cells (= tolerance)


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Defective Suppressor and Memory T cells in SLE 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.

  • 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.


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Defective Suppressor and Memory T cells in SLE 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.

  • 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.


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Defective clearance of apoptotic cells in SLE 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.

  • 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.


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Defective clearance of apoptotic cells in SLE 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.

  • 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.


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Tingible Body Macrophages (TBM) 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.

  • 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).


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Tingible Body Macrophages (TBM) 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.

  • Tingible body macrophages normally engulf B cells and contain condensed (nuclear bits) chromatin fragments.


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Tingible Body Macrophages (TBM) 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.

  • 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.


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Tingible Body Macrophages (TBM) 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.

  • But body macrophages (TBM) in SLE are few in number.

  • 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.


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Tingible Body Macrophages (TBM) 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.

  • The defect in apoptosis is thought due to inherited compliment deficiency like complement proteins, such as c1,C2, C4, or C1q.


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Tingible Body Macrophages (TBM) 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.

  • Also, uningested apoptotic nuclei of cells can be found outside of TBMs.This material may present a threat and act as antigenic.

  • 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.


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THANK YOU SO MUCH 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.

  • 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.


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