HYPERSENSITIVITY REACTIONSInnocous materials can cause hypersensitivity in certain individualsunwanted inflammationdamaged cells and tissuesNon-proper reaction of the immune system to foreign substances Mainly harmless substances after second or multiple times
TYPES OF HYPERSENSITIVITY REACTIONSmostly appear together with autoimmune diseases
Type IimmediateType IIType IIIType IVdelayedAntibody mediatedT cell mediatedspecific IgEcell surface antigen specifically reacting with antibodyaspecificallydeposited soluble immuncomplexMHC restricted T cell activationmediators produced by mast cellsFcR mediated inflammation, inhibition of cell functionsFcR mediated complement activation, inflammationcytokines, cytotoxicityclassical allergynewborn haemolytic anaemia, penicillin sensitivity, M. gravisSerum sickness, SLEContact dermatitis
ANTIBODY MEDIATED HYPERSENSITIVITY REACTIONSHay feverAsthmaSystemic anaphylaxisCertain drug allergies(penicillin)Serum sicknessArthus reaction
TYPE I HYPERSENSITIVITY REACTIONALLERGY
DIFFERENCES OF IMMUNE RESPONSES INDUCED BY ALLERGENS AND PATHOGENSALLERGENNon devidingAct together with other environmental effects DANGER SIGNALNi, Mn, Co, Sn chloridesIon channel inhibitorsEnergy homeostasisDC/TISSUE DEMAGETNCB, DNCBDer p1 cisztein protezpapain meat processing CD25, CD23 cleavageStructure of epithelial tight junction is demagedBee bite (toxin)Substilyzin washing powderPATHOGENDevivingEscape mechanismDANGER SIGNALMicrobial DNS, CpG-ODNdsRNS IFNLPS (Gram-), PG (Gram+)HSPInflammatory cytokinTNF-, IL-1DC/TISSUE DEMAGEActivation of innate immunityInflammation, neurotransmitters (VIP)
B cell ALLERGENS USUALLY ENTER THE BODY VIA MUCOSAL SURFACES AND THEY ARE PRESENT AT A LOW DOSEantigen presentationT cell priming and polarization soluble proteins on te surface of small particles (pollen, dust mite drops) small molecular weight, soluble trans-mucosal entry, enzymatic activity low dose (ragweed: 1g/year)
IL-4IL-4IL-10MucosaAllergenMechanism of the initiation of Th2 responseCD4+ T
chromosome 11q FcR chain genechromosome 11qIL-3-5 IL-9, IL-13 GMCSFHLAII DRB1*015allergy Inproper immunregulation Th1/Th2 inbalanceregulation of IgE synthesisimmunodeficiencyhigh eosinophil countsEnvironmental factorslack of toleranceGENETIC/ENVIRONMENTAL PREDISPOSITION TO ALLERGYGenetic factors
Mast cell degranulation, wheel and flare reactionRagweedSalineHistamine
MAST CELL RESPONSE TO SURFACE FcRI CROSSLINKINGEARLY MEDIATORSBiogenic amins histaminEnzymes triptase, chymase, carboxypeptidaseLATE MEDIATORS
The effect of mast cell degranulation varies with the tissue exposed to allergen
Systemic anaphylaxis is caused by allergens that reach the blood stream
Types of IgE-derived allergic response
Short/Common ragweed (Ambrosia artemisiifolia)
Short/Common ragweed (Ambrosia artemisiifolia)Mugwort (Artemisia vulgaris) Green leaf backWhite leaf back
Mugwort (Artemisia vulgaris)
Mugwort (Artemisia vulgaris) ?
Wormwood (Arthemisia absinthium) Absinthe (thujone: max 35 mg/l)
cells expressing the antigen become sensitive to complement mediated lysis or to opsonized phagocytosis
frustrated phagocytosiss tissue demage
the antibody inhibits or stimulates target cell function no tissue damage (e.g. M. gravis receptor blocker antibodies)Type II hypersensitivityIgG tpye antibodies bound to the cell surface or to tissue antigensHYPERSENSITIVITY REACTIONS INDUCED BYIMMUNE COMPLEXESTYPES II and III
MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONSHemolytic anemia of newbornsErythroblastosis fetalis
Drug induced Hemolytic anemiaTrombocytopeniaAgranulocytosisPenicillin-based antibiotics Anti-arythmic quinidin
Goodpasture syndrome (type IV collagen)Pemphigus vulgaris(desmosomal antigens)Damage of epidermal and mucosal junctions, acantholysis
Healthy cellDrug-modified cell surface proteinIgG type antibodiesDEVELOPMENT OF DRUG SENSITIVITY
The tissue, which can not be phagocytosed, is damagedInternal or absorbed antigen (drug)FRUSTRATED PHAGOCYTOSIS MEDIATED BY IgG TYPE ANTIBODIESBinding Opsonization Internalization Enzyme release Opsonized surface Binding Frustrated Enzyme release phagocytosis
Examples - Type II hypersensitivityNewborn haemolytic anaemiaTransfusion reactionHyperacut allograft rejection
Drug-derived Haemolitic anaemiaThrombocytopeniaAgranulocitosis
Penicillin-based antibioticsAnti-arithmic quinidin
Goodpasture syndrome (kidney, membrane basalis, collagen type IV)
Myasthaenia gravis (anti-acetyl-choline receptor antibodies)
Basedow-disease (anti-TSH-receptor antibodies)
Pemphigus vulgaris (mucosal bubbles) against desmosomal antigens, interruption of epidermal and mucosal connections, acantolysis (desintegration into single cells)
TYPE III HYPERSENSITIVITY
Antibodies binding to soluble antigensSmall circulating immune complexesDepends on:Size of immune complexes Antigen-antibody ratio Affinity of antibodyIsotype of antibody
Pathogenic immune complexes Formed in the blood and than are deposited in tissues Formed in situ at the site of antigen localization Mechanisms of tissue demage is independent on the site of depositionSteps of tissue demageFormation immune complexes in the blood Deposition depends on the size, composition and cytophylic properties of the antibody (IgM, IgG, IgA)FcRIII has a pivotal role expressed by basophylic granulocytes, NK cellsPermeability of endothelium Tissue demage Increased permeability of blood vessels Reqruitment of neutrophils enzymes, chemoattractans, dilatators, prostaglandinsfibrosisConsequences of tissue demage depends on the site of deposition Arthus reaction local reaction in skinInfectious diseases morbilli erythema, vasculitisAcute serum disease 7 10 daysPolyclonal antibodies against snake venom produced in horses (anti-streptococcal)Immune suppresszive anti-lymphocyte globulin Bacterial trombolytic streptokinase treatment of miocardial infarctionSubacute bacterial endocarditis pathogens are not eliminatedChronic viral hepatitis SLE small vessels, kidney, joints, skin, heart, serosal surfaces PATHOGENICITY OF IMMUNE COMPLEXES
THE PROCESS OF TISSUE DAMAGE CAUSED BY IMMUNE COMPLEXESImmune complexes activate the complement system, neutrophils, bazophil granulocytes and thrombocytesBlood vessel wall permeabilityFrustrated phagocytosis
Arthus-reactionLocalized Type III hypersensitivity Local vasculitis develops as a result of immune complex deposition Inhaled antigens (fungi, animal feces) may induce similar reaction in the lungIgG type antibody Farmer lung and piegeon breeder lung
MANIFESTATION OF TYPE III HYPERSENSITIVITY IN SLE
Facial, malar "butterfly" rash with characteristic shape across the cheeks. Discoid lupus erythematosus (DLE) involves mainly the skin, it is relatively benign compared to systemic lupus erythematosus (SLE). In either case, sunlight exposure accentuates this erythematous rash. A small number (5 to 10%) of DLE patients go on to develop SLE (usually the DLE patients with a positive ANA).
Here is a more severe inflammatory skin infiltrate in the upper dermis of a patient with SLE in which the basal layer is undergoing vacuolization and dissolution, and there is purpura with RBC's in the upper dermis (which are the reason for the rash).
DEPOSITION OF IMMUNE COMPLEXES IN THE SKIN OF SLE PATIENTS
When immunofluorescence staining with an antibody to complement or immunoglobulin is performed, a brightly fluorescent signal staining the dermal epidermal junction is visable indicating immune complex deposition.
Immunofluorescence staining pattern with antibody to IgG staining immune complexes at the dermal-epidermal junction. If such a pattern is seen only in skin involved by a rash, then the diagnosis is probably DLE, but if this pattern appears even in skin uninvolved by a rash, then the diagnosis is SLE.
RENAL FAILURE IN IMMUNECOMPLEX DISEASES
One of the feared complications of the rheumatic diseases is renal failure. This is most likely to occur in SLE. Here is a glomerulus in which the capillary loops are markedly pink and thickened such that capillary lumens are hard to see. This is lupus nephritis.
Here is a glomerulus with thickened pink capillary loops, the so-called "wire loops", in a patient with lupus nephritis. The surrounding renal tubules are unremarkable.
ANAAnti -nuclear antibody
This is the so-called "rim" pattern that is more characteristic of SLE.
This is the so-called "speckled" pattern of staining which is more characteristic of the presence of autoantibodies to extractable nuclear antigens, particularly ribonucleoprotein. This pattern is not very specific, but may be seen with an entity called "mixed connective tissue disease" which is a mix between SLE, scleroderma, and polymyositis, but without serious renal or pulmonary disease. The autoimmune diseases are very hard to classify, even for the experts.
This is the so-called "nucleolar pattern" of staining in which the bright fluorescence is seen within the nucleoli of the Hep2 cells. This pattern is more suggestive of progressive systemic sclerosis.
TYPE IV HYPERSENSITIVITY REACTION
T CELL MEDIATED PROCESSMACROPHAGES ARE INVOLVED
Type IV hypersensitivity reactionChemokines, cytokines,cytotoxins
Delayed-type (TYPE IV) Hypersensitivity
Delayed-type (Type IV) Hy