Presentation on theme: "(from Webster’s Online)"— Presentation transcript:
1 (from Webster’s Online) Autoimmunity“n. of, relating to, or caused by autoantibodies or lymphocytes that attack molecules, cells, or tissues of the organism producing them.”(from Webster’s Online)
2 The Study of Autoimmunity Molecular Mechanisms of AutoimmunityAnimal Models for Autoimmune DysfunctionTreatments for Autoimmune DiseasesGender Differences in AutoimmunityThree Common Autoimmune Diseases
3 Molecular Mechanisms of Autoimmunity How is autoimmunity induced?What could go wrong here?
4 Molecular Mechanisms of Autoimmunity Cross-reactivity (Molecular and Viral Mimicry)Viral and nonviral peptides can mimic self-peptides and induce autoimmunityExample: papilloma virus (HPV) and insulin receptor
6 Molecular Mechanisms of Autoimmunity Release of Sequestered AntigenAntibodies in blood can attack Myelin Basic Protein if Blood-Brain barrier is breached.
7 Molecular Mechanisms of Autoimmunity Inappropriate MHC expressionType I Diabetes: Pancreatic β cells express abnormally high levels of MHC I and MHC II (?)MHC II – APC only! This may hypersensitize TH cells to β cell peptides.
8 Inappropriate MHC Expression Normal Pancreas Pancreas with InsulitisFig. 20-3
9 Molecular Mechanisms of Autoimmunity Polyclonal B Cell Activation by Viruses and BacteriaIf B cells reactive to self-peptides are activated, autoimmunity can occur.Example: Epstein-Barr Virus, which is the cause of infectious mononucleosis.
10 Putting it all together…the big picture Autoimmunity can be caused by immunological, genetic, viral, drug-induced, and hormonal factors.There are 4 immunological mechanisms of autoimmunity.All mechanisms cause abnormal B or T cell activation.Centrality of the Ternary ComplexMost instances of autoimmune diseases occur with multiple mechanisms, which makes treatment difficult.
11 Animal Models for Autoimmune Diseases Why have them?Animal models of autoimmune diseases contribute valuable insights into the mechanisms of autoimmunity and to our understanding of autoimmunity in humans and how we may treat autoimmune diseases.
12 Autoimmunity in Animals is Spontaneous or Induced Spontaneous: Autoimmunity develops spontaneously in some inbred strains of animalsInduced: Autoimmunity develops after being induced by certain experimental manipulation
13 Spontaneous Autoimmunity in Some Animals Exhibits important clinical and pathogenic similarities to certain autoimmune diseases in humansExample: New Zealand Black Mice (NZB) and F1 hybrids of NZB and New Zealand White Mice (NZW) spontaneously develop autoimmune diseases that closely resemble lupus erythematosusIncidence of autoimmunity in hybrids is more common in females than in males
14 New Zealand MiceNZB spontaneously develops autoimmune hemolytic anemia between 2-4 months of ageAt this point various antibodies can be detected. These antibodies include antibodies to erthyocytes, nuclear proteins, DNA and T lymphocytesF1 hybrids develop glomerulonephritis from immune-complex deposits in the kidneys and die within 18 monthsGlomerulonephritis: nephritis marked by inflammation of the capillaries of renal glomeruliGlomeruli: a tuft of capillaries at the point of origin of each vertebrate nephron that passes a protein-free filtrate to the surrounding Bowman’s capsule
15 Mouse MRL/lpr/lpr (Mouse strain) Systemic Lupus Erthematosus develops in the mouse strain MRL/lpr/lprMice are homozygous for the lpr gene, which has been identified as a defective fas gene.The fas/lpr gene product is a cell surface protein in the TNF familyWhen the normal fas protein interacts with its ligand, signals are sent out leading to apoptic death of the fas bearing cells: target of CTLsFas is also known to be important for the death of hyperactive CD4+ cellsWithout fas mature peripheral T cells do not die, and they continue to proliferate and produce cytokines that result in enlarged lymph nodes and spleen
16 Nonobese Diabetic (NOD) Mouse Model Found to develop a form of diabetes that resemble human insulin dependent mellitusAs in humans, NOD in mice begins with lymphatic infiltration into the islets of the pancreasThere is an association between certain MHC and development of diabetes in the miceExperiments have shown that t cells from diabetic mice can transfer diabetes to nondiabetic miceWhen bone marrow of a normal mouse is replaced with NOD bone marrow, diabetes developsWhen bone marrow from NOD mouse is replaced with healthy bone marrow, diabetes doesn’t develop
17 Spontaneous Autoimmunity A final example….- Other animals: Obese strain chickens can develop humoral and cellmediated reactivity thyroglobulin resembling Hashimoto’s Thyroiditis
18 Induced Autoimmunity in Animals Autoimmune dysfunctions that are similar to human autoimmune disease can be induced into animals
19 Myasthenia Gravis1973: rabbits were immunized with acetylcholine receptors purified from electric eels. The rabbits then developed muscular weakness similar to myasthenia gravisMyasthenia gravis: disease characterized by progressive weakness and exhaustibility of voluntary muscles without atrophy or sensory disturbance and caused by an autoimmune attack on acetylcholine receptors at the neuromuscular junctionExperimental myasthenia gravis resulted when the antibodies to the acetylcholine receptors blocked muscle stimulation by the acetylcholine in the synapseFrom this experiment: the discovery that auto-antibodies to the acetylcholine receptors were the cause of myasthenia gravis in humans
20 CFA: Complete Freund’s Adjuvant An effective means of potentiating humoral antibody response to injected immunogensCFA is considered to be an emulsion consisting of equal volumes of CFA to antigen (1 part CFA or less to 1 part antigen).Improper or unnecessary use leads to excessive inflammation, induration, and/or necrosis in laboratory animals.
21 Experimental Autoimmune Encephalomyelitis (EAE) Experimental autoimmune encephalomyelitis (EAE): one of the best studied models of autoimmune diseasesEncephalomyelitis: concurrent inflammation of the brain and spinal cordEAE is mediated by T cells and can be induced in many species by immunization with a myelin basic protein (MBP) or protolipid protein (PLP) in complete Freund’s adjuvant (20-7)Within 2-3 weeks animals develop cellular infiltration of the myelin sheaths of the central nervous system: resulting in demyelination or paralysis.Most animals die, but some have milder symptoms. Some develop chronic symptoms that resemble multiple sclerosis in humans.Animals that recover are resistant to more MBP injectionsEAE model is used to investigate treatment testing for human MSRecent mouse experiments suggest that orally administered MBP may make these antigen-specific peripheral T cell clones self-tolerantPaved the way for clinical trials in MS patients
22 Experimental AutoimmuneThyroiditis (EAT) Induced in a number of animals by immunizing them with thyroglobulin using CFA: humoral and Tdth cell responses cause inflammation of the thyroid.EAE resembles human hashimoto’s thyroiditisAutoimmune Arthritis is induced by immunizing rats with Mycobacterium tuberculosis in CFAAnimals develop symptoms similar to human rheumatoid arthritis
24 Treatment of Autoimmune Diseases Current Therapies- aimed at reducing symptoms by providing non-specific suppression of the immune systemII. Experimental Therapeutic Approaches - try to induce specific immunity
25 I. Current Therapies Immunosuppressive drugs Cyclosporin A Thymectomy - corticosteroids, azathioprine- slows the proliferation of lymphocytesCyclosporin A- blocks signal transduction mediated by the TCR (inhibits only antigen-activated T cells while sparing non-activated ones)Thymectomy- removal of thymus from patients with myasthenia gravisPlasmapheresis- removes antigen-antibody complexes for a short- term reduction in symptoms
26 II. Experimental Therapeutic Approaches T-cell Vaccination- autoimmune T-cell clones elicit regulator T-cells that are specific for the TCR on the autoimmune T- cells- results in suppression of the autoimmune cellsPeptide Blockade of MHC molecules- a synthetic peptide is used to bind in place of the regular peptide on the MHC- induces a state of clonal anergy in the autoimmune T-cells
27 (Experimental Therapies continued) Monoclonal-Antibody Treatment- monoclonal antibody against the IL-2 receptor blocks activated TH-cells- blockage of preferred TCRs with monoclonal antibodies- monoclonal antibody against an MHC molecule that is associated with autoimmunity while sparing the othersOral antigens- tend to induce tolerance- still in early clinical trials
28 Sex-based Differences in Autoimmunity Differences can be traced to sex hormones- hormones circulate throughout the body and alter immune response by influencing gene expression- (in general) estrogen can trigger autoimmunity and testosterone can protect against itDifference in immune response- ♀ produce a higher titer of antibodies and mount more vigorous immune responses than ♂- ♀ have a slightly higher cortisol secretion than ♂- ♀ have higher levels or CD4+ T-cells and serum IgM
29 Sex-based Differences Estrogen- causes autoimmunity (generally)- stimulates prolactin secretion (helps regulate immune response)- stimulates the gene for CRH (corticotropin- releasing hormone) that promotes cortisol secretion- causes more TH1-dominated immune responses(promotes inflammation)Testosterone- can cause autoimmunity or protect against it
30 Sex-based Differences Pregnancy- during this, ♀ mount more of a TH2-like response- the change in hormones creates an anti inflammatory environment (high cortisol levels)- diseases enhanced by TH2-like responses are exaggerated and diseases that involve inflammatory responses are suppressed- fetal cells can persist in the mother’s blood or the mother’s cells may appear in the fetus (microchimerism)- can result in autoimmunity if the fetal cells mount an immune response in the mother’s body (or vice versa)
31 Rheumatoid Arthritis (RA) Cause (s) and DemographicsMolecular MechanismMechanism of Tissue DamageTreatment Options
32 Cause and Demographics Cause is unknown!Affects 1-2% of worldwide populationPatients are 75% Women, between years of age
36 Grave’s DiseaseProduction of thyroid hormones is regulated by thyroid-stimulating hormones (TSH)The binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of two thyroid hormones: thyroxine and triiodothyronineA person with Grave’s Disease makes auto-antibodies to the receptor for TSH. The binding of these auto-antibodies to the receptor mimics the normal action of TSH, without the regulation, leading to overstimulation of the thyroidThe auto-antibodies are called long-acting thyroid stimulating hormones
37 Grave’s DiseaseBeta-blockers such as propranolol are often used to treat symptoms of rapid heart rate, sweating, and anxiety until the hyperthyroidism is controlled.Hyperthyroidism is treated with antithyroid medications, radioactive iodine or surgery.Both radiation and surgery result in the need for lifelong use of replacement thyroid hormones, because these treatments destroy or remove the gland.
38 Autoimmune Anemias What is it? What causes it? Pernicious AnemiaWhat is it?- deficiency in vitamin B12What causes it?- auto-antibodies to intrinsic factorWhat happens?- B12 remains in the stomach and is excretedTreatment- treated with injections of B12
39 Hemolytic Anemia- results from monoclonal antibodies to normal RBC constituents- antibodies coat the erythrocytes, causing clumping, lysis, and premature clearance by the spleen- can be induced by an “offending” agent (parasite, drug, or toxin) that adheres to the RBC- Drug-induced Hemolytic Anemia- drug binds to RBC’s and causes them to become antigenic- antibodies that develop from the drug recognize these cells and they are lysed