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  • LymphocyteEosinophilErythrocyteBasophilNeutrophil polymorphMonocyte

  • B Lymphocytes:Immunocompetency occurs in bone marrowProduce AntibodiesConduct Humoral Immunity

    T Lymphocytes:Immunocompetency occurs in thymusNon antibody producing cellsConduct Cellular Immunity

    www.academic.brooklyn.cuny.edu/biology/bio4fv/page/aviruses/cellular-immune.html

  • Antibody Mediated ImmunityHelper T cells recognize non self antigens and stimulate B cells to produce antibodiesB cells release antibodies which bind to non self antigens present on infected cellsB cells complete their maturation upon binding to non self antigens and destroying infected cellsCell Mediated ImmunityMacrophages phagocytize pathogensUpon phagocytosis macrophages present non self antigens on their membranesHelper T cells recognize non self antigens and recruit cytotoxic T cellsCytotoxic T cells destroy infected cells

  • Animation of Antibody Mediated Immunity

    What kind of cell does the macrophage activate in the humoral immune response?

    What occurs during the effector phase of the humoral response?

  • We normally do not mount a strong immune response against our own (self) antigens, a phenomenon called self-tolerance. When the immune system recognizes a self antigen and mounts a strong response against it, autoimmune disease develops. Nonetheless, the immune system has to recognize self-MHC (Major histocompatibility complex) to mount a response against a foreign antigen. Thus, the immune system is constantly challenged to discriminate self vs non-self and mediate the right response.

  • Autoimmune disease occurs when a specificadaptive immune responseis mounted againstself antigens. The normal consequence of an adaptive immune response against a foreignantigenis the clearance of the antigen from the body. Virus-infected cells, for example, are destroyed bycytotoxic T cells, whereas soluble antigens are cleared by formation of immune complexes ofantibodyand antigen, which are taken up by cells of the mononuclear phagocytic system such as macrophages. When an adaptive immune response develops against self antigens, however, it is usually impossible for immune effector mechanisms to eliminate the antigen completely, and so a sustained response occurs. The consequence is that the effector pathways of immunity cause chronic inflammatory injury to tissues, which may prove lethal. The mechanisms of tissue damage inautoimmune diseasesare essentially the same as those that operate in protective immunity and in hypersensitivity diseases.

  • Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self. Such an immune response may not always be harmful (e.g., anti-idiotype antibodies). However, in numerous autoimmune diseases it is well recognized that products of the immune system cause damage to the self.

    5 % to 7% adult affected.

    Two third women.

    Over 80 conditions linked to autoimmunity 15 diseases directly linked to autoimmune response

  • Autoimmunity occurs when the body is unable to differentiate self from non-selfResults in overactive immune response against own cells and tissuesAffects 5%-8% of the population78% affected are femalesLow level autoimmunity is normal

  • Both antibodies and effector T cells can be involved in the damage in autoimmune diseases.Organ specificimmune response is directed against antigen(s) associated with the target organ being damaged Non-organ specificantibody is directed against an antigen not associated with the target organ

  • 20/11/08Dr Ekta, MicrobiologyCessation of tolerance to self Ag.

    Enhanced helper T-cell and decreased suppressor T-cell functions

    Dr Ekta, Microbiology

  • 20/11/08Dr Ekta, Microbiologytolerance to self Ag.

    Dr Ekta, Microbiology

  • 2. Mechanism(1) Alteration of self-proteins (modification of the molecule)

    Partial degradation of autoantigens.

    Complexing of self-antigens with drugs or microorganisms. (2) Hidden antigens exposure

  • (3) Cross-reactions (molecular mimicry)

    Antibodies to streptococcal antigens may react with constituents of cardiac muscle or connective tissue in rheumatic fever.

    Rabies vaccine may rise to encephalitis

  • (4) Breakdown of tolerance Bypass of helper T cell tolerance Imbalance of suppressor-helper T cell function Genetic factors Emergence of a sequestered antigen Polyclonal lymphocyte activation

  • Autoimmune disorders fall into two general types:Systemic Autoimmune DiseasesLocalized Autoimmune Diseases

  • Dr Ekta, Microbiology

    Dr Ekta, Microbiology

  • 2 - 7 % of the population suffers from autoimmune diseaseAutoimmune diseases are tissue and antigen specific

  • Some autoantibody- mediated diseases

  • HLA human leukocyte antigen

  • DiseaseOrganAntibody toDiagnostic TestOrgan-SpecificHashimoto's thyroiditisThyroidThyroglobulin, thyroid peroxidase (microsomal)RIA, Passive, CF, hemagglutinationPrimary MyxedemaThyroidCytoplasmic TSH receptorImmunofluorescence (IF)Graves' diseaseThyroidBioassay, Competition for TSH receptorPernicious anemiaRed cellsIntrinsic factor (IF), Gastric parietal cellB-12 binding to IF immunofluorescenceAddison's disease AdrenalAdrenal cellsImmunofluorescencePremature onset menopauseOvarySteroid producing cellsImmunofluorescenceMale infertilitySpermSpermatozoaAgglutination, Immunofluorescence

  • Insulin dependent juvenile diabetesPancreasPancreatic islet beta cellsInsulin resistant diabeticSystemicInsulin receptorCompetition for receptorAtopic allergySystemicbeta-adrenergic receptorCompetition for receptorMyasthenia gravesMuscleMuscle, acetyl choline receptorImmunofluorescence, competition for receptorGoodpasture's syndromeKidney, lungRenal and lung basement membraneImmunofluorescence (linear staining)PemphigusSkinDesmosomesImmunofluorescencePemphigoidSkinSkin basement membraneImmunofluorescence Phacogenic uveitisLensLens proteinAI hemolytic anemiaRed cells PlateletRed cellsPassive hemagglutinationDirect Coomb's testIdiopathic thrombocytopeniaPlateletImmunofluorescence

  • Primary biliary cirrhosisLiverMitochondriaImmunofluorescenceIdiopathic neutropeniaNeutrophilsNeutrophilsImmunofluorescenceUlcerative colitisColonColon lipopolysaccharideImmunofluorescenceSjogren's syndromeSecretory glands Duct mitochondriaImmunofluorescenceVitiligoSkin JointsMelanocytes ImmunofluorescenceRheumatoid arthritisSkin, kidney, joints etcIgGIgG-latex agglutinationSystemic lupus erythematosusjoints, etc.DNA, RNA, nucleoproteinsRNA-, DNA-latex agglutination, IF (granular in kidney)

  • TirednessDepressionWeight gainWeight lossMuscle weaknessCrampsIrritabilitySweatingShakySwellingRashBody painsTremorsNumbnessFatigueLoss of appetiteInsomniaCoordination lossMany different symptoms make autoimmune diseases hard to diagnoseMany times there are no symptoms!

  • Autoantibodies against blood cells promote their destructionIgGorIgMresponses to antigens located on the surface of blood cells lead to the rapid destruction of these cells. Autoimmune Hemolytic Anemia where antibodies againstself antigenson red blood cells trigger destruction of the cells, leading to anemia. This can occur in two ways. Red cells with bound IgG or IgMantibodyare rapidly cleared from the circulation by interaction with Fc orcomplementreceptors, respectively, on cells of the fixed mononuclear phagocytic system; this occurs particularly in thespleen. Alternatively, the autoantibody-sensitized red cells are lysed by formation of themembrane-attack complexof complement.

  • Signs and Symptoms Related to anemia and hemolysisDyspnea, fatigue, tachycardiaScleral icterus, splenomegaly

    Related to cold exposureAcrocyanosis

  • Hemolytic anemiaElevated LDH, indirect bilirubin, reticulocyte countDecreased haptoglobinSpurious macrocytosis RBC agglutination due to cooling during automated counting Agglutination on peripheral smear

  • Direct antiglobulin test (Coombs test)

    Cold agglutinins titer Upper limits of normal 1:40Hemolysis usually occurs at titers >1:500

  • Autoantibodies against receptors cause disease by stimulating or blocking receptor functionA special class of type II hypersensitivity reaction occurs when the autoantibody binds to a cell-surface receptor. Antibody binding to a receptor can either stimulate the receptor or block its stimulation by its natural ligand. In Graves' disease, autoantibody against the thyroid-stimulating hormone receptor on thyroid cells stimulates the excessive production of thyroid hormone. The production of thyroid hormone is normally controlled by feedback regulation; high levels of thyroid hormone inhibit release of thyroid-stimulating hormone (TSH) by the pituitary. In Graves' disease, feedback inhibition fails because the autoantibody continues to stimulate the TSH receptor in the absence of TSH, and the patients become hyperthyroid

  • Graves' disease is caused byautoantibodiesspecific for the receptor for thyroidstimulating hormone (TSH). Normally, thyroid hormones are produced in response to TSH and limit their own production by inhibiting the production of TSH by the pituitary. In Graves' disease, the autoantibodies are agonists for the TSH receptor and therefore stimulate production of thyroid hormones (right panels). The thyroid hormones inhibit TSH production in the normal way but do not affect production of the autoantibody; the excessive thyroid hormone production induced in this way causes hyperthyroidism.

  • Graves disease involves antibodies to thyroid stimulating hormone receptor

  • In some cases, it is clear that antibodies are pathogenic

  • Selective destruction of pancreatic cells in insulin-dependent diabetes mellitus (IDDM) indicates that the autoantigen is produced in cells and recognized on their surface

  • In IDDM, there is highly specific destruction of insulin-producing cells in the pancreatic islets of Langerhans, sparing other islet cell types ( and ). This is shown schematically in the upper panels. In the lower panels, islets from normal (left) and diabetic (right) mice are stained for insulin (brown), which shows the cells, and glucagon (black), which shows the cells. Note thelymphocytesinfiltrating the islet in the diabetic mouse (right) and the selective loss of the cells (brown) whereas the cells (black) are spared. The characteristic morphology of the islet is also disrupted with the loss of the cells.

  • Selective destruction of pancreatic cells in insulin-dependent diabetes mellitus (IDDM) indicates that the autoantigen is produced in cells and recognized on their surface. In IDDM, there is highly specific destruction of insulin-producing

  • Autoantibodiesagainst the chain of the nicotinic acetylcholine receptor, which is present on skeletal muscle cells at neuromuscular junctions, can block neuromuscular transmission. The antibodies are believed to drive the internalization and intracellular degradation of acetylcholine receptors. Patients with myasthenia gravis develop potentially fatal progressive weakness as a result of their autoimmune disease. Diseases caused by autoantibodies that act as agonists or antagonists for cell-surface receptors

  • In normal circumstances, acetylcholine released from stimulated motor neurons at the neuromuscular junction binds to acetylcholine receptors on skeletal muscle cells, triggering muscle contraction (left panel).Myasthenia gravisis caused byautoantibodiesagainst the subunit of the receptor for acetylcholine. These autoantibodies bind to the receptor without activating it and also cause receptor internalization and degradation (right panel). As the number of receptors on the muscle is decreased, the muscle becomes less responsive to acetylcholine.

  • Antibody responses to extracellular matrix molecules are infrequent, but can be very damaging when they occur. In Goodpasture's syndrome, an example of a type II hypersensitivity reaction, antibodies are formed against the 3chain of basement membrane collagen (type IV collagen). These antibodies bind to the basement membranes of renal glomeruli and, in some cases, to the basement membranes of pulmonary alveoli, causing a rapidly fatal disease if untreated. Theautoantibodiesbound to basement membrane ligateFc receptors, leading to activation of monocytes, neutrophils, and tissue basophils and mast cells. These release chemokines that attract a further influx of neutrophils into the glomeruli, causing severe tissue injury. The autoantibodies also cause local activation ofcomplement, which may amplify the tissue injury.

  • Autoantibodies reacting with glomerular basement membrane cause the inflammatory glomerular disease known as Goodpasture's syndrome. The panels show sections of renal glomeruli in serial biopsies taken from patients with Goodpasture's syndrome.

  • Immune complexes are produced whenever there is anantibodyresponse to a soluble antigen. Normally, they are cleared efficiently by red blood cells bearingcomplementreceptors and by phagocytes of the mononuclear phagocytic system that have both complement andFc receptors, and such complexes cause little tissue damage.

  • This clearance system can, however, fail in three circumstances. The first follows the injection of large amounts of antigen, leading to the formation of large amounts of immune complexes that overwhelm the normal clearance mechanisms. An example of this is serum sickness, which is caused by injection of large amounts of serum proteins. This is a transient disease, lasting only until the immune complexes have been cleared.

  • The second circumstance is seen in chronic infections such as bacterial endocarditis, where theimmune responsetobacterialodged on a cardiac valve is incapable of clearing infection. The persistent release of bacterial antigens from the valve infection in the presence of a strong antibacterial antibody response causes widespread immune-complex injury to small blood vessels in organs such as the kidney and the skin.

  • The third type of failure to clear immune complexes is seen in SLE. This is animmune complex-mediated disease characterized by chronicIgGantibodyproduction directed at ubiquitousself antigenspresent in all nucleated cells. In SLE, a wide range ofautoantibodiesare produced to common cellular constituents. The main antigens are three intracellular nucleoprotein particlesthe nucleosome, the spliceosome, and a small cytoplasmic ribonucleoprotein complex containing two proteins known as Ro and La

  • In SLE, large quantities ofantigenare available, so large numbers of small immune complexes are produced continuously and are deposited in the walls of small blood vessels in the renal glomerulus, in glomerular basement membrane, in joints, and in other organs. This leads to activation of phagocytic cells through thei rFc receptors. The consequent tissue damage releases more nucleoprotein complexes, which in turn form more immune complexes. Eventually, the inflammation induced in small blood vessel walls, especially in the kidney, can cause sufficient damage to kill the patient.

  • Panel a, a section through a renal glomerulus from a patient with SLE, shows that the deposition of immune complexes has caused thickening of the glomerular basement membrane, seen as the clear canals running through the glomerulus. Panel b, a similar section stained with fluorescent anti-immunoglobulin, reveals immunoglobulin deposits in the basement membrane. Panel c, by electron microscopy the immune complexes are seen as dense protein deposits between the glomerular basement membrane and the renal epithelial cells. Polymorphonuclear neutrophilic leukocytes are also present, attracted by the deposited immune complexes.

  • Slide 7.24Lupus nephritis. There are two focal necrotizing lesions at 11 and 2 oclock. (H&E stain.)

  • Slide 7.25Lupus nephritis, diffuse proliferative type. Note the marked increase in cellularity throughout the glomerulus. (H&E stain.)

  • Slide 7.26Immunofluorescence micrograph stained with fluorescent anti-IgG from a patient with diffuse proliferative lupus nephritis. One complete glomerulus and part of another one are seen. Note the mesangial and capillary wall deposits of IgG.

  • Slide 7.28Lupus nephritis showing a glomerulus with several wire loop lesions representing extensive subendothelial deposits of immune complexes. (Periodic acid-Schiff [PAS] stain.)

  • Slide 7.29Systemic lupus erythematosus involving the skin. A, An H&E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction. (Dr. Jag Bhawan) B, An immunofluorescence micrograph stained for IgG reveals deposits of immunoglobulin along the dermoepidermal junction.

  • Slide 7.30Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are easily seen.

  • (i) Immunologically, the disease involves a bewildering array of auto-antibodies, particularly antinuclear antibodies (ANAs).(ii) Anatomically, all sites of involment have in common vascular lesions with fibrinoid deposits.(iii) Clinically, it is an unpredictable remitting, relapsing disease of acute or insidious in the body, but principally affects the skin, kidneys, serosal membranes, joints and heart

  • Sjogrens syndrome

    It is a clinicopathologic entity characterized by dry eyes and dry mouth resulting from immunologically mediated destruction of the lacrimal and salivary glands.

  • Slide 7.31Sjogrens syndrome. A, Enlargement of the salivary gland. (Dr. Richard Sontheimer). B, The histologic view shows intense lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia.

  • Scleroderma Rheumatoid arthritis Polymyositis Polyarteritis nodosa

  • Slide 7.33 Note the extensive deposition of dense collagen in the dermis with virtual absence of appendages and thinning of epidermis.

  • Slide 7.34 The extensive subcutaneous fibrosis has virtually immobilized the fingers, creating a clawlike flexion deformity. Loss of blood supply has led to cutaneous ulcerations.

  • Slide 7.35 Note the rash affecting the eyelids. B, Dermatomyositis. The histologic appearance of muscle shows perifascicular inflammation and atrophy. C, Inclusion body myositis showing a vacuole within a myocyte.

  • Auto-immune disorder which results in inflammation of the synovial lining of the joint and cartilage destruction.

    This result in loss of function.

    Affects 1% of adults.

  • *Disease appears without warning or causeHormone levels have been shown the affect severity of diseaseLow level autoimmunity- aid in recognition of neoplastic cells by T cells, reducing incidence of cancer - allows rapid immune response in early stages on infection when the availability of foreign antigens limits the response**