Immunological bas ic s of allergic diseases

1. Immunological basics of allergic diseases Magdalena Żbikowska Gotz

2. Immune system(IS)- function Defense against pathogens IS properly functioning protect the body against potentially harmful influences from outside (antigens) – viruses, bacteria, fungi, parasites IS -2 stages defence operation: -innate immunity or natural resistance -adaptive immunity or antigen specific immunity- aquired

3. innate immunity -nonspecific response -response is directed against various patogens -absence immunological memory adaptive immunity -after contact with antigen, specific response -very quick reaction -very effective response -presence immunological memory

5. Immunological response can be: advantageous –it offers quick mobilization offorces to fight against diseases disadvantageous- immune disorders -insufficient response - immunodeficiency diseases -excessive response: directed against external factors – allergy directed against own tissues – autoimmune diseases Inflammation is one of the first responses of the immune system to infection and can be: advantageous - when run accross deterioration of microorganism or slowing their growth disadvantageous – leads to damage of tissues

6. Hypersensitivity Allergichypersenstivity Nonallergichypersenstivity

7. Nonallergic hypersensitivity - mechanism nonimmunological -clinical symptoms are identical as in allergic hypersensitivity -reaction is taking place during first contact with specific factor -the strength of the pseudoallergic reaction depends on the dose of substance -examples: reaction after NSAID (non steroidal antiinflamatory drugs), morphine, antibiotics, neuromuscular-blocking drug and others.

8. Allergic hypersensitivity Allergy is a hypersensitivity reaction initiated byimmunological mechanisms. Allergic reaction is an exaggerated or wrong immune reaction and causes damage to the host

9. Allergic hypersensitivity -can be defined as repeatable symptoms from organs and systems -to acquire allergy there has to be a cooperation of genetic and environmental agents (allergen/ pollution) -allergic reactions occur when a person’s immune system reacts to normally harmless substances in the environment Substance that causes a reaction is called an allergen. Allergic reactions are acquired, predictable, and rapid.

10. Allergic hypersensitivity -immunesystem responds to antigen/allergen stimulation by producing allergen specific antibodies (asIg) and allergen specific lymphocytes (asL) -allergic reaction can be local or systemic -2 phases of allergic reaction: I phase – specific reactionAg-Ab, Ag-asL II phase – nonspecific response, clinical symptoms are due to nonspecific mediators

11. Allergy is a systemic disorder affected organs allergic diseases Allergic rhinitis Asthma Nose Pharynx Lungs Oesophagus Stomach Inhalatory and Food allergy Skin Eczema Urticaria Allergic dermatitis “Global diseases” – due to the large spectrum of symptoms affecting the whole body

12. Allergic hypersensitivity -inadequate, uncontrolled course of reaction, involves defects of regulatory mechanism -specific immunological response -caused by allergens not taking place during the first contact with allergen -first contact with allergen causes sensitization without clinical symptoms, production of specific lymphocytes and antibodies) -next contact results with clinical symptoms -result – damage of organs and tissues, and symptoms of disease

13. . . Sensitization - presence Ab, asLT Allergic reaction–involves clinical sympt.

14. Allergic hypersensitivity -divisioncriteria- 1 time of reaction after exposition -immediate allergic reaction– minutes after contact with allergen -half-late reaction – it will be visible 6-8 hours after contact -late reaction – several hours, days after contact 2 different immunological response mechanism -humoral reaction – antibodies -cell reaction - asLT

15. Allergic hypersensitivity-Gell-Coombs classification- Type I: allergy reaction - mediated by IgE antibodies, which trigger the mast cells and basophils to release pharmacologically active agents. Type II: cytotoxic reaction - IgM or IgG antibodies bind to antigen on the surface of cells and activate complement cascade.

16. Allergic Hypersensitivity-Gell-Coombs classification- Type III: Immune complex reaction - complexes of antigen and IgM or IgG antibodies accumulate in the circulation or in tissue and activate the complement cascade. Granulocytes are attracted to the site of activation and release lytic enzymes and reactive form of oxygen (RFO) Type IV: cell-mediated immunity reaction - mediated by T cells, which release cytokines upon activation to cause accumulation and activation of macrophages.

17. Allergic Hypersensitivity Types I, II,III -depend on the interaction of antigen with antibody humoral type reactions Type IV - involves T-cell recognition cellular type sensitivity

18. Antigen Immunological reactant Effector mechanism Example of hypersensitivity reaction

19. Hypersensitivity Type I known as: Immediate hypersensitivity Anaphylaxis IgE-associated immune responses

20. HypersensitivityType I Atopy or atopic syndromeis a geneticpredisposition toward producing specific IgE as a response to low concentration of allergen in the environment. -itis not a disease! -it is a predisposition to develop disease! -term „atopy” has a prognostic value. Allergy is a atopic disease with clinical symptoms.

21. HypersensitivityType I-stages of allergic reaction- -APC presents allergen to lymphocytes T -differention of lymphocyte Th0 to Th1/Th2 clones -activation of lymphocytes B and production of IgE -stimulation, degranulation of effector cells, production and release of mediators -intensification of reaction and inflow of proinflamatory cells -participation of regulatory cells – expiry of reaction

22. HypersensitivityType I1 - APCAntigen presenting cells function: • take up antigen, • process antigen/allergen • present antigen to T cells- TCR APC includes: macrophage, monocyte, dendritic cell, B lymphocyte and another cells - MHC ag classII (major histocompatibility complex) important part - takes place in presentation of allergen

23. HypersensitivityTYPE I1 - presentation of antigens to T cells -proteins (peptides) from inside the cell are presented by MHC I molecules to Tc cells. -proteins (peptides/allergens) from the outside are presented by MHC II molecules to Th 2 cells. -MHC I on almost all cells -MHC II on specialized antigen-presenting cells

25. Allergen in native form - not immunogenic

27. HypersensitivityTYPE I2 - CD4+ T lymphocyte -differention of lymphocyte Th0 to Th1/Th2 clones depends on the presence cytokines in environment LTh subsets based on distinct cytokines produced Th1: -produce IL-2, IL-12, interferon (IFN)- gamma -activate Tcs cells, natural killer cells, and macrophage -funktion -elimination of intracellular pathogen, facilitate delayed hypersensitivity

28. HypersensitivityTYPE I2CD4+ T lymphocyte Th2: -produce ,secrete IL-4, IL-5, IL-10. IL13 -IL activate B cells and switch antibody synthesis to IgE mediate allergic inflammation -preferentially activate Th2 cells leading to development of allergic disease Th1 and Th2 inhibit the development of each other thanks to the released cytokines Allergy is called a Th2 disease

29. HypersensitivityTYPE I3 – activation of B lymphocytes and production IgE antibodies- B lymphocyte needs 2 signals to mature to IgE producing plasma cell. -IL-4 secreted by Th2 cells -presence of costymulatory molecules on Th2 and B cells (interaction of CD40 ligand on the surface of T-cell with the CD40 receptor on the B cell) IgE -form free - half life in serum estimated for 2-3 days -form bound to receptor on the surface of mast cell, basophil, dendritic cell, and eosinophil - half life of several weeks

30. HypersensitivityTYPE I4 stimulation, degranulation of effector cells, production and release of mediators

31. HypersensitivityType I5-participation of regulatory cells, expiry of reaction -in thehealthyadults and childrenthereactionisfinishedwithparticipation of regulatory cells (RCs) -RC populationconsists of cellswithcharacteristicphenotype -main of theRCshave on thesurfaceantigen CD4 and CD25 and intranuclearpresence of FOXP3 (nTREG), anothersubset of RCsareinducecells Th3 and Tr1

32. HypersensitivityTYPE I5 -participation of regulatory cells, expiry of reaction -RCs inhibit the proliferation of effectory cells by contact or inhibit release of proinflamatory cytokines -nTreg, acquired Treg: Tr1 – IL10, Th3 –TGFβ -in allergic diseases is a disorder between number of RCs and Th2 (decrease RCs) or reduction of activity reduction of their activity associated with lack of FOXP3

33. Regulatory cells areactiveintheexpiry of reaction

34. HypersensitivityType I-elements of allergic reaction- -allergens (there is no allergens allergies) -lymphocyte T (Th2) -IgE antibodies -receptors for IgE -effector cells (mastocytes, basophiles), mediators -cytokines -chemokines -cell adhesion molecules -proinflamatory cells, mediators

35. HypersensitivityType I allergens -induce specific immunological response theIgE dependent and clinical symptoms allergens: -enter the organism through: mucose membrane of the respiratory system, digestive system, skin - food allergens, inhalatory allergens, contact allergens -allergens may be seasonal (grass,tree,weeds) and perennial (food,house dust, animal dander and epithelium)

36. Allergens -proteins or glycoproteins (weight from several to 50 kDa). -enzyme proteins, Der p 1 – cysteine protease -one allergen can have few or many epitopes recognized by immune system -sometimes allergens cross react - cross reactivity is relates to similar structures

37. Allergens Der p1 Der p1 is an enzyme allergen from the fecal pellets of the dust mite. Dermatophagoides pteronyssinus (common dust mite)

39. Allergens-source of sensitization,consist of components From the large number of compononents only several are allergenic Some of them with high level of similarity may decide about cross-reactivity Allergens-components-epitops Epitops: linear -amino acid sequences,conformational -tertiary structure, overlapping

40. T lymphocyte -subtype Th2 -activated Th2 produces cytokines: IL 3, 4, 5, 10, 13, 25, GM-CSF(granulocyte- macrophage colony stimulating factor) -Th2 cytokines profile initiate IgE production. -activation of Th1 results in repression of Th2 and other way around – immunological polarization. Th17- IL17A,IL17F(Th1) and IL17E(Th2) Th-9

42. IgE Izshizaka and Johanson in 1967 -cytofile antibody (easily connects with the cells) -very low level in serum (below 250 ng/ml; less then 0,001 % of all immunoglobulin concentration). -do not access through placenta -synthesis starts during the11 week of fetal life. -combine with the surface of cell through receptors -is produced by: plasmatic cells of respiratory system, digestive system, lymphatic nods

44. IgE receptor FcRI–large affinity FcRII –small affinity FcRI receptor - takes part in allergic reaction - combines IgE to the surface of mast cells, basophiles, eosinophils, Langerhans cells - receptor construction: 4 chains - , , 2 . - induction of effector cell – antigen encourage creating a bridge between 2 IgE on the surface of mast cell – release of allergic reaction mediators Allergen Cell

45. Mechanisms of allergic responseFceRI structure High affinity IgE Fc Receptor

46. Effector cells Mast cells (MC) Basophiles Mastocytes - metachromatic granulationswith different natural serine protease: tryptase and chymase 2 mainphenotypes MC: - MCT – MC mucosal tissue - MCTC – MC connective tissue

47. Mast cells and Basophils

48. Degranulation of a Mast Cell Small explosion

50. primary mediators - pre-formed/stored mediators in granules mediators released immediately in course of allergic reaction -histamine:smooth muscules contraction,increase vasculit permeability,excessive secretion of mucus -cytokines TNF-a, IL-1, IL-6. -chemoattractants for neutrophils and eosinophils. -serine proteases: tryptase, chymase, cathepsin lead to changes in connective tissue matrix, tissue breakdown.