HYPERSENSITIVITY REACTIONS

Innocous materials can cause hypersensitivity in certain individuals unwanted inflammation damaged cells and tissues Non-proper reaction of the immune system to foreign substances Mainly harmless substances – after second or multiple times

TYPES OF HYPERSENSITIVITY REACTIONS Type I „immediate” Type IIType IIIType IV „delayed” Antibody mediated T cell mediated specific IgEcell surface antigen specifically reacting with antibody aspecifically deposited soluble immuncomplex MHC restricted T cell activation mediators produced by mast cells FcR mediated inflammation, inhibition of cell functions FcR mediated complement activation, inflammation cytokines, cytotoxicity „classic allergy”newborn haemolytic anaemia, penicillin sensitivity, M. gravis Serum sickness, SLEContact dermatitis mostly appear together with autoimmune diseases

TYPES OF HYPERSENSITIVITY REACTIONS IgE Mast cell IgG – immune complex FcγR+ cells NK, macrophage IgG – immune complex FcγR+ cells Complement Hay fever Asthma Systemic anaphylaxis Certain drug allergies (penicillin) Serum sickness Arthus reaction

TYPE I HYPERSENSITIVITY REACTION ALLERGY

allergy response Th2 B cell Th2 DC ALLERGENES USUALLY ENTER THE BODY VIA MUCOSAL SURFACES AND THEY ARE PRESENT AT A LOW DOSE antigen presentation T cell priming and polarization  soluble proteins on te surface of small particles (pollen, dust mite „drops”)  small Mol. Weight, soluble  trans mucosal entry, enzymatic activity  low dose (ragweed: 1µg/year)

IL-4 IL-10 Mucosa Allergen Mechanism of the initiation of Th2 response CD4+ T

Mast cell degranulation, wheel and flare reaction Ragweed Saline Histamine

MAST CELL RESPONSE TO SURFACE FcRεI CROSSLINKING EARLY MEDIATORS Biognic amins – histamin Enzymes – triptase, chymase, carboxypeptidase LATE 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

chromosome 11q FcERβ chain gene chromosome 11q IL-3-5 IL-9, IL13 GMCSF HLAII DRB1*150 allergy Improper immunregulation Th1/Th2 inbalance regulation of IgE synthesis immunodeficiency high eosinophil counts Environmental factors lack of tolerance GENETIC/ENVIRONMENTAL PREDISPOSITION TO ALLERGY Genetic factors

Types of IgE-derived allergic response SYNDROME ALLERGENSROUTE OF ENTRYRESPONSE systemic anaphylaxis drugs anti-serum peanuts intravenous peroral edema, increased vascular permeability tracheal occlusion circulatory collapse, death acute utricaria bug bite allergy test subcutan local increase in blood flow and vascular permeability allergic rhynitis pollen dust mite drops inhaled irritation and edema of nasal mucosa airway inflammation asthmaanimal fur pollen dust mite drops inhaled bronchial constriction, increased mucus production food allergynut, peanuts, fish, shellfish milk, eggs peroral vomiting, diarrhea pruritis (itching) urticaria (hives) anaphylaxia (rare)

Short/Common ragweed (Ambrosia artemisiifolia)

Mugwort (Artemisia vulgaris) levélfonák zöld levélfonák fehéresen molyhos

Mugwort (Artemisia vulgaris)

Mugwort (Artemisia vulgaris) –? Wormwood (Arthemisia absinthium) – Absinthe (thujone: max 35 mg/l)

Type II hypersensitivity IgG tpye antibodies bound to the cell surface or to tissue antigens 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) HYPERSENSITIVITY REACTIONS INDUCED BY IMMUNE COMPLEXES TYPES II and III

MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS Hemolytic anemia of newborns Erythroblastosis fetalis Drug induced Hemolytic anemia Trombocytopenia Agranulocytosis Penicillin-based antibiotics Anti-arythmic quinidin Goodpasture syndrome (type IV collagen) Pemphigus vulgaris (desmosomal antigens) Damage of epidermal and mucosal junctions, acantholysis

Healthy cell Drug-modified cell surface protein Th B IgG type antibodies MECHANISM OF THE DEVELOPMENT OF DRUG SENSITIVITY

The tissue, which can not be phagocytosed, is damaged Internal or absorbed antigen (drug) FRUSTRATED PHAGOCYTOSIS MEDIATED BY IgG TYPE ANTIBODIES Binding Opsonization Internalization Enzyme release Opsonized surface Binding Frustrated Enzyme release phagocytosis

Examples - Type II hypersensitivity Newborn haemolytic anaemia Transfusion reaction Hyperacut allograft rejection Drug-derived Haemolitic anaemia Thrombocytopenia Agranulocitosis Penicillin-based antibiotics Anti-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)  atoantibody against desmosomal antigen desmoglein-3, interruption of epidermal and mucosal connections, acantolysis (disintegration into single cells)

Transplantation - hyperacut allograft rejection HLA-A, B, C, DR, DQ, DP, minor histocompatibility antigens foreign MHC-antigens recognized by T cells Direct: self T cells - donor APCs (CD8+ T cells) Indirect: self APC presents donor MHC-molecule fragments (CD4+ T cells) cytokine release Hyperacut rejection Causes: immunization against alloantigens, preformed anti- HLA-antibodies, blood group incompatibility antibodies bound to endothel activation of complement system thrombosis of venules vascularis necrosis Therapy resistent

HLA typing - used for transplantations (generally the -B and -DR is the most important and the -C does not matter) - diagnostical value (connections between the HLA alleles and the diseases) MHC I: HLA-A, HLA-B, HLA-C MHC II:HLA-DP, HLA-DQ, HLA-DR Serotyping (microcitotoxicity tests) Based on the serological reaction between the examined cells and the typing serum. Complement mediated lysis with the help of MHC I and/or MHC II antigen recognizing antibody containing serum. There are no reaction in the case of serotype identity (dead cells can be visualized by specific dye) Typing sera containing antibodies to Class I and II proteins were collected from multiparous women, or individuals who had received multiple blood transfusions. (immunized against multiple alleles). The specificity identification have been done on international workshops. The procedures have been done on microtiter plates (with 10µl working aliquots – Terasaki plates) because of the available quantity of the typing sera were always limited. Sera have been replaced by monoclonal antibodies later.

HLA-D (MHC II) antigenes had been examined on nylon column separated B cells Serotyping (2.) The polymorphism of the MHC II antigens could be examined by mixed lymphocyte reactions (MLR). (A normal person can have 1-10% alloreactive lymphocytes.) Microtiter plates

serotyping have some limits – crossreactions (HLA-B27 – HLA-B7) – there is no sera against HLA-C because of the low immunogenicity – some subtype cannot be discriminated Genomic DNA based examinations - PCR-SSP is using the PCR amplification reaction directly to detect HLA polymorphisms. Primers can be constructed specifically to complement HLA polymorphisms; if the primers bind the complementary polymorphism and amplify the gene segment, then the PCR product can be detected by standard techniques. An array of PCR primers complementary to the range of HLA polymorphisms has been constructed. HLA-A …

-PCR-SSOP (sequence specific oligonucleotid probe) The examined HLA genes are amplified by PCR with non allele specific primer pairs. The amplificates are immobilized on nitrocellulose membranes or microtiter plates and are hybridized by HLA allele specific labeled oligonucleotides. The label can be enzimatic, fluorescent or radioactive -SBT (sequence based typing) allotypes can be evaluated by sequencing MHC region of the genomic DNA (minor mutations can be examined)

ref: Klinikai immunológia (II. klinikum) (OHVI 1990 szerk.: Szegedi, Gergely, Sipka, Szemere) Stenszky Valéria: Autoimmun betegségek genetikai vonatkozásai Diseases (autoimmune) HLA frequency concernedcontrol SLE DR35520 B85020 Hydralazine(?) induced lupus erythematosus DR47332 Basedow-disease DR35625 B84320 Active chronic hepatitisDR35521 Sclerosis multiplex DR26030 B73724 Myasthenia gravisB84420 Autoimmune IgA glomerulonephritis DR45319 Type I diabetes DR37224 DR34922 B84021 Addison-disease (idiotopic, autoimmune) DR37020 B84623 Sjörgen-syndrome DR37020 B85022 Coeliaca DR37922 DR76015 B86822 Goodpasture-syndromeDR28829 IgA lossDR38120 Dermatitis herpetiformis DR38220 B87522 De Qervain-thyreoiditisB Reiter-syndromeB27799 Felty-syndromeDR49520 DiseasesHLA frequency concernedcontrol NarcolepsiaDR Bechterew-diseaseB27899 Adrenogenitális syndrome salt lost late virilizing Bw47361 B14574 B54810 Psoriasis vulgaris Cw65615 B13248 B17278 DR74823 Idiophatic haemochromatosisA37628 Bechet-diseaseB Gold induced thrombocytopeniaDR35013 Gold induced leucopeniaDR34713 HLA allotypes and diseases

HLA-A alleles described until october

Type IV hypersensitivity reaction Chemokines, cytokines, cytotoxins

Delayed-type Hypersensitivity (Type IV Hypersensitivity) Delayed-type Hypersensitivity (Type IV Hypersensitivity)

Delayed-type Hypersensitivity (Type IV Hypersensitivity) Delayed-type Hypersensitivity (Type IV Hypersensitivity)

Delayed-type hypersensitivity (DTH) (e.g., tuberculin skin test) T H 1 from a previous immunization (memory)

Tuberculin skin test

Chemical Mediators of DTH

*a contact-sensitizing agent is usually a small molecule that penetrates the skin then binds to self-proteins, making them “look” foreign Contact Dermatitis

Poison ivy Anacardiaceae (family), Toxicodendron (genus) Toxicodendron radicans or Rhus toxicodendron

(Type IV hypersensitivity) Delayed-type hypersensitivity is mediated by T cells

Delayed-type Hypersensitivity A positive tuberculin skin test is a DTH reaction

TYPE III HYPERSENSITIVITY Antibodies binding to soluble antigens Small circulating immune complexes Depends on: Size of immune complexes Antigen-antibody ratio Affinity of antibody Isotype of antibody

THE PROCESS OF TISSUE DAMAGE CAUSED BY IMMUNE COMPLEXES Immune complexes activate the complement system, neutrophils, bazophil granulocytes and thrombocytes Blood vessel wall permeability Frustrated phagocytosis

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). MANIFESTATION OF TYPE III HYPERSENSITIVITY IN SLE

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. DEPOSITION OF IMMUNE COMPLEXES IN THE SKIN OF SLE PATIENTS

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. RENAL FAILURE IN IMMUNECOMPLEX DISEASES

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. ANA Anti -nuclear antibody