Hypersensitivity Reaction

DefinisiReaksi imunologik (humoral atau diperantarai seluler) terhadap antigen, baik yang bersumber endogen maupun eksogen, dapat menyebabkan beberapa reaksi perusakan jaringan.

Classification

The four-group classification was expounded by P. H. G. Gell and Robin Coombs in 1963.

Additional Type V

Comparison

Hypersensitivity Reactions Gell and Coombs classification:

Type I – IgE mediated (allergy) Type II – Antibody-mediated cytotoxic Type III – Immune Complex mediated Type IV – Delayed-Type Hypersensitivity (DTH) Type V – Autoimmune Disseases

Types I, II and III are “immediate” Type IV is delayed

Type I Hypersensitivity

Antigens are called “allergens” Unknown why people get allergies, but there

is a strong genetic predisposition (called atopy)

Hallmark is inappropriate production of IgE against allergens that cause mast cell degranulation

Normally IgE/mast cell activity should be directed against parasitic infections

Type I Hypersensitivity

Mediators of Type I hypersensitivites Mast cell granule contents (early effects)

Histamine and Heparin - ↑ vascular permeability, smooth muscle contraction (intestines, bronchi), mucus secretion

Chemotactic factors – attract eosinophils and neutrophils Proteases – mucus secretion, complement activation,

degradation of blood vessel basement membrane Later Effects

Leukotrienes and prostaglandins – secreted after tissue disruption caused by mast cell degranulation, effects are similar to histamine

Arrival of proinflammatory eosinophils and neutrophils

Reaksi Hipersensitivitas Tipe I ( Tipe Anafilaksis )

Rx hipersensitivitas tipe cepat IgE

Co : asma, rinitis, dermatitis atopi, urtikaria,

anafilaksis.

Ag sel B untuk membentuk Ig E dengan

bantuan sel Th. Ig E diikat oleh mastosit pd

reseptor Fc.

Bila terpajan ulang, maka Ag tersebut IgE

yang sudah ada pada permukaan mastosit

degranulasi mastosit histamin.

Clinical Manifestations of Type I Systemic anaphylaxis

Allergen gets into the blood stream Dyspnea, ↓BP, bronchole constriction, GI and

bladder smooth muscle contration, shock, death within minutes if untreated

Treatment - epinephrine Allergic rhinitis (hay fever)

Inhaled allergen triggers reaction in nasal mucosa Watery exudate from nose, eyes, upper

respiratory tract, sneeezing and coughing

Clinical Manifestations of Type I Asthma

Allergic asthma – due to inhaled airborne allergens (pollens, dust, fumes, etc)

Intrinsic asthma – triggered by cold, exercise Reaction develops in lower respiratory tract Bronchoconstriction, airway edema, mucus secretion,

inflammation Food allergies

Ingestion of allergen Vomiting and diarrhea If allergens are absorbed into bloodstream, reactions can occur

where allergen deposits asthma-like symptoms Urticaria (hives, wheal & flare response)

Triad asma Hipertrofi muscularis bronchial (1)

spasme bronchial Produksi mukus berlebihan (2)

obstruksi alveoli tertutup emphysema

Edema membran mukus (3) infiltrasi eosinofil mediator inflamasi membran edema kristalisasi enzym eosinofil diamond-shaped Charcot-Leyden crystals (4)

Clinical Manifestations of Type I Atopic Dermatitis (allergic eczema)

Often occurs in young children Red skin rash Strong hereditary predisposition

Type I Hypersensitivity

Treatment Avoid allergen if possible Antihistamines, or anti-prostaglandins Hyposensitization – injections of low doses of

allergen may cause a shift from IgE to IgG as the dominant antibody formed.

Type II Hypersensitivity

Antibody-mediated Cytotoxic HS Antibodies (IgM or IgG) bind to cell surface

antigens. Antigen/antibody complex may lead to: Complement activation lysis ADCC Opsonization phagocytosis

These are normal reactions, but when they cause unwarranted tissue damage, they are considered a hypersensitivity.

Reaksi Hipersensitivitas Tipe II ( Tipe Sitotoksik)

Antigen terikat pada sel sasaran.

Antibodi IgG dan IgM dengan adanya komplemen akan berikatan dengan antigen, sehingga dapat mengakibatkan hancurnya sel tersebut.

Reaksi ini merupakan reaksi yang cepat.

Type II Hypersensitivity

Examples of Type II HS: Transfusion reactions

To ABO blood groups To other RBC blood groups

Hemolytic disease of the newborn (erythroblastosis fetalis)

Drug-induced hemolytic anemia (penicillin)

Reaksi Hipersensitivitas Tipe III (diperantarai kompleks imun)

Antibodi berikatan dengan antigen dan komplemen membentuk kompleks imun.

Keadaan ini menimbulkan neuro-trophic chemotactic factor yang dapat menyebabkan terjadinya peradangan atau kerusakan lokal.

Pada umumnya terjadi pada pembuluh darah kecil. Pengejawantahannya di kornea dapat berupa keratitis herpes simpleks, keratitis karena bakteri (stafilokok, pseudomonas) dan jamur.

Type III Hypersensitivity

Immune Complex Disease Antibody (IgG) / attaching to soluble antigen leads

to complex formation Immune complexes may deposit in:

Blood vessel walls (vasculitis) Synovial joints (arthritis) Glomerular basement membrane (glomerulonephritis) Choroid plexus

Type III Hypersensitivity

Damage occurs due to: Anaphylatoxin release due to complement

activation (C3a, C5a) which then attracts neutrophils, and causes mast cell degranulation

Neutrophils have trouble phagocytosing “stuck” immune complexes so they release their granule contents leading to more inflammation

Platelet aggregation also results from complement activation

These effects are also known as the Arthus reaction

Type III Hypersensitivity

Localized reactions edema and redness (erythema) and tissue

necrosis of the affected tissue Can occur in the skin following insect bites Can occur in the lungs

E.g. “farmer’s lung” from inhaling particles from moldy hay

Type III Hypersenstivity

Generalized reactions: Serum sickness (following treatment with

antiserum to a toxin) Autoimmune diseases

SLE Rheumatoid arthritis

Drug reactions (penicillin) Infectious diseases

Meningitis, hepatitis, malaria, mono etc.

Reaksi Hipersensitivitas Tipe IV (diperantarai sel)

Reaksi terjadi melalui sel ketimbang melalui antobodi.

Terdapat reaksi yang termasuk ke dalam hipersensitivitas IV ini, yaitu hipersensitivitas lambat dan sitotoksisitas diperantarai sel.

Type IV Hypersensitivity

Delayed type hypersensitivity (DTH) TH cells that have been “sensitized” by an antigen

develop a TH1 and (sometimes a TC response) leading to macrophage recruitment and activation.

First noticed with reaction to tuberculosis bacteria (tuberculin reaction)

Hallmarks of type IV is the large number of macrophages at the reaction site, and that it takes an average of 24 hrs to manifest after repeat exposure.

Type V : Hypersensitivity

Inflammation

Inflamasi

Reaksi lokal pada jaringan karena adanya injuri.

Reaksi proteksi komples Penyebab : berbagai stimulus exogen /

endogen Agen penyebab : dihancurkan oleh tubuh

Mechanisme local systemic 3 major:

1. alteration2. exsudation - inflammatory exsudate

liquid (exsudate)cellular (infiltrate)

3. proliferation (pembentukan granulasi dan jaringan fibrosa)

Classification several points of view length:

acute × chronic (+ subacute, hyperacute)

according to predominant component 1. alterative (predominance of necrosis - diphtheria) 2. exsudative (pleuritis) 3. proliferative (cholecystitis - thickening of the wall by

fibrous tissue)

Classification

according to histological features nonspecific (not possible to trace the etiology) - vast

majority specific (e.g. TB)

according to causative agent aseptic (sterile) - chemical substances, congelation,

radiation - inflammation has a reparative character septic (caused by living organisms) - inflammation has

a protective character

Acute inflammation important role in inflammation has

microcirculation! supply of white blood cells, interleukins, fibrin,

etc.

Local symptomatology classical 5 symptoms (Celsus 1st c. B.C.,

Virchow 19th c. A.D.) 1. calor - heat 2. rubor - redness 3. tumor - swelling 4. dolor - pain 5. functio laesa - loss (or impairment) of

function

Systemic symptomatology fever (irritation of centre of thermoregulation)

TNF, IL-1 IL-6 – high erythrocyte sedimentation rate

leucocytosis - increased number of WBC bacteria – neutrophils parasites – eosinophils viruses - lymphocytosis

leucopenia viral infections, salmonella infections, rickettsiosis

immunologic reactions - increased level of some substances (C-reactive protein)

Vascular changes vasodilation

increased permeability of vessels due to widened intercell. junctions and contraction of endothelial cells (histamin, VEGF, bradykinin)

protein poor transudate (edema) protein rich exsudate

leukocyte-dependent endothelial injury proteolysis – protein leakage

platelet adhesion thrombosis

Cellular events

leukocytes margination rolling adhesion transmigration

emigration of: neutrophils (1-2 days) monocytes (2-3 days)

chemotaxis endogenous signaling molecules - lymphokines exogenous - toxins

phagocytosis - lysosomal enzymes, free radicals, oxidative burst

passive emigration of RBC - no active role in inflamm. - hemorrhagic inflammation

Phagocytosis adhesion and invagination into cytoplasm engulfment lysosomes - destruction in highly virulent microorganisms can die

leucocyte and not the microbe in highly resistant microorganisms -

persistence within macrophage - activation after many years

Outcomes of acute inflammation 1. resolution - restoration to normal, limited injury

chemical substances neutralization normalization of vasc. permeability apoptosis of inflammatory cells lymphatic drainage

2. healing by scar tissue destruction fibrinous inflammtion purulent infl. abscess formation (pus, pyogenic

membrane, resorption - pseudoxanthoma cells - weeks to months)

3. progression into chronic inflammation

Chronic inflammation reasons:

persisting infection or prolonged exposure to irritants (intracell. surviving of agents - TBC)

repeated acute inflamations (otitis, rhinitis) primary chronic inflammation - low virulence,

sterile inflammations (silicosis) autoimmune reactions (rheumatoid arthritis,

glomerulonephritis, multiple sclerosis)

Chronic inflammation

chronic inflammatory cells ("round cell" infiltrate) lymphocytes plasma cells monocytes/macrophages activation of macrophages by

various mediators - fight against invaders lymphocytes plasma cells, cytotoxic (NK) cells,

coordination with other parts of immune system plasma cells - production of Ig monocytes-macrophages-specialized cells

(siderophages, gitter cells, mucophages)

Morphologic patterns of inflammation 1. alterative 2. exsudative

2a. serous 2b. fibrinous 2c. suppurative 2d. pseudomembranous 2e. necrotizing, gangrenous

3. proliferative primary (rare) x secondary (cholecystitis)

Morphologic patterns of inflammation 2a. serous - excessive accumulation of fluid, few

proteins - skin blister, serous membranes - initial phases of inflamm.

modification - catarrhal - accumulation of mucus

2b. fibrinous - higher vascular permeability - exsudation of fibrinogen -> fibrin - e.g. pericarditis (cor villosum, cor hirsutum - "hairy" heart

fibrinolysis resolution; organization fibrosis scar

2c. suppurative (purulent) - accumulation of neutrophillic leucocytes - formation of pus (pyogenic bacteria)

interstitial phlegmone – diffuse soft tissue abscess - localized collection

acute – border – surrounding tissue chronic – border - pyogenic membrane Pseudoabscess – pus in lumen of hollow organ

formation of suppurative fistule accumulation of pus in preformed cavities - empyema

(gallbladder, thoracic)

complications of suppurative inflamm.: bacteremia (no clinical symptoms!; danger of formation

of secondary foci of inflamm. (endocarditis, meningitis) sepsis (= massive bacteremia) - septic fever, activation

of spleen, septic shock thrombophlebitis - secondary inflammation of wall of the

vein with subsequent thrombosis - embolization - pyemia - hematogenous abscesses (infected infarctions)

lymphangiitis, lymphadenitis

2d. pseudomembranous - fibrinous pseudomembrane (diphtheria - Corynebacterium, dysentery - Shigella) - fibrin, necrotic mucosa, etiologic agens, leucocytes

2e. necrotizing - inflammatory necrosis of the surface - ulcer (skin, gastric) gangrenous - secondary modification by bacteria - wet

gangrene - apendicitis, cholecystitis - risk of perforation - peritonitis

Granulomatous inflammation

distinctive chronic inflammation type cell mediated immune reaction (delayed) aggregates of activated macrophages

epithelioid cell multinucleated giant cells (of Langhans type x of foreign body type)

NO agent elimination but walling off intracellulary agents (TBC)

Granulomatous inflammation

1. Bacteria TBC leprosy syphilis (3rd stage)

2. Parasites + Fungi 3. Inorganic metals or dust

silicosis berylliosis

4. Foreign body suture (Schloffer „tumor“), breast prosthesis

5. Unknown - sarcoidosis