Immunology

Lecture 7 Dr,HUDAHypersensitivity Types II-IV

Type II: Cytotoxic Type III: Immune Complex Type IV: T Cell-Mediated (DTH)

Hypersensitivity II & III(antibody mediated diseases)

Antibodies (other than IgE) may cause tissue injury & diseases by binding directly to their target organs & extracellular matrix (type II) or by forming immune complexes that deposit mainly in blood vessels (type III) .

Cytotoxic hypersensitivity

Characteristics of Cytotoxic Hypersensitivity
Antibodies directed against cell surface or tissue antigen Characterized by complement cascade activation and various effector cells


Complement Activated C3 forms opsonin recognized by phagocytes Formation of membrane attack complex (lytic enzymes Formation of chemotactic factors Effector cells possess Fc and complement receptors macrophages/monocytes neutrophils

Mechanisms of tissue injury

Antibodies specific for cell & tissue antigens may deposit in tissue and cause injury by inducing local inflammation , or may interfere with normal cellular functions. IgG bind to neutrophil & macrophages Fc receptors and activate these leukocytes , resulting in inflammation.



The same antibodies ,as well as IgM , activate the complement system by the classical pathways , resulting in the production of complement by-products that recruit leukocytes & induce inflammation. If antibodies bind to cells , such as erythrocytes & platelets ,the cells are opsonized and may be ingested & destroyed by host phagocytes.


Some antibodies may cause disease without directly inducing cell injury. Some antibodies against hormone receptors & inhibit receptor function (Myasthenia Gravis). Other antibodies may activate receptors e.g.,Graves disease in which antibodies against the receptor for the TSH will stimulate thyroid cell even in absence of hormone.

Examples of Type II Hypersensitivity

Blood transfusion reactions Hemolytic disease of the newborn (Rh disease) Autoimmune hemolytic anemias Drug reactions Myasthenia gravis (acetylcholine receptor) Pemphigus vulgaris Goodpasture s syndrome Graves disease (TSH receptor ,hyperthyroidism) Pernicious anemia


The Rh system and hemolytic disease of the newbornRh antigenCommon to red blood cells of humans and rhesus monkeysAbout 85% of humans are Rh positive (Rh+)Rh– woman carrying an Rh+ fetus may be at risk for hemolytic disease

Hemolytic Disease of the Newborn

RhD positive red cells
RhD negative mother
RhD positive fetus
LysisOfRBC’s B cell
anti-RhD
first birth
post partum
subsequent
anti-RhD
RhD positive fetus


Hypersensitivities
Drug-induced cytotoxic reactions Some drug molecules bind larger molecules Stimulate the production of antibodies Can produce various diseases Immune thrombocytopenic purpura Agranulocytosis Hemolytic anemia

Drug-Induced Reactions:Adherence to Blood Components

complement
blood cell adsorbed drug or antigen drug metabolite

antibody to drug
lysis

Immune (Toxic )Complex Hypersensitivity (Type III)

Hypersensitivities
Type III (Immune Complex–Mediated) HypersensitivityInvolve reactions against soluble antigens circulating in serum.Caused by formation of immune complexesCan cause localized reactionsHypersensitivity pneumonitisPost streptococcal glomerulonephritisCan cause systemic reactionsSystemic lupus erythematosusRheumatoid arthritis

Diseases associated with immune complexes

Persistent infection microbial antigens deposition of immune complexes in kidneys Autoimmunity self antigens deposition of immune complexes in kidneys, joints, arteries and skin Extrinsic factors environmental antigens deposition of immune complexes in lungs

Inflammatory Mechanisms in Type III

Complement activation anaphylatoxins Chemotactic factors Neutrophils attracted difficult to phagocytize tissue-trapped complexes frustrated phagocytosis leads to tissue damage

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* Immune Complex Mediated Hypersensitivity

Disease Models

Serum sickness Arthus reaction

* Arthus Reaction

Localized manifestation of generalized hypersensitivityAg+Ab precipitates cause C activation and release of inflammatory molecules. Leads to ↑ vascular permeability & neutrophil infiltrate. Leucocyte-platelet thrombi formed which reduce blood supply leading to necrosis.Clinical example – Farmer’s lung & other hypersensitivity pneumonitis following inhaled Ag like Actinomycetes.

* Arthus reaction

Arthus reaction Type-III
Weal & flare reaction Type-I



* Serum Sickness
–Systemic form of Type III reaction.Takes place following serum therapye.g., Hyperimmune globulin, Anti Snake venum.Clinically Fever, lymphadenopathy, splenomegaly, arthritis, glomerulonephritis, endocarditis, vasculitis, urticarial rashes, abdominal pain, nausea, vomiting.Pathogenesis – Formation of immune complexes, its deposition on the endothelial lining of BVs all over the body, leads to inflammation.

* Serum Sickness (contd)

*Plasma concentration of C falls due to massive activation and fixation to Ag+Ab complexes. *Disease self limited. *Can also be seen after administration of penicillin or other antibiotics. Immune complexes occur in many bacterial, e.g. pos-tstreptococcal glomerulonephritis .Also in Hepatitis B & Malaria. Also seen in disseminated malignancies & autoimmunity.*

* Serum sickness

T-Cell Mediated Hypersensitivity(Type IV / Delayed-Type)

Manifestations of T-Cell Mediated Hypersensitivity

Allergic reactions to bacteria, viruses and fungi Contact dermatitis due to chemicals Rejection of tissue transplants

General Characteristics of DTH

An exaggerated interaction between antigen and normal CMI-mechanisms Requires prior priming to antigen Memory T-cells recognize antigen together with class II MHC molecules on antigen-presenting cells Stimulated T-cells release soluble factors (cytokines) Cytokines attract and activate macrophages and/or eosinophils help cytotoxic T-cells become killer cells, which cause tissue damage

Types of Delayed Hypersensitivity

Delayed Reaction maximal reaction time Contact 48-72 hours tuberculin 48-72 hours granulomatous at least 14 days

Contact Hypersensitivity

Predominantly an epidermal reaction Langerhans cells are the antigen presenting cells Associated with hapten-induced eczema nickel salts in jewellry picryl chloride acrylates p-Phenylene diamine in hair dyes chromates chemicals in rubber poison ivy (urushiol)

* Contact dermatitis

Ag possibly enters thru’ sebaceous glandsLesions vary from macules & papules to vesicles which subsequently breakdown leaving weeping surface typical of acute eczematous dermatitis.

* Contact dermatitis reaction

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* Allergic Contact Dermatitis Response to Poison Ivy Hapten

Atopy Patch Tests

*

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* The food allergen is applied to the skin under an occlusive cover (called a Finn chamber) and the skin is assessed after 48 and 72 hours for a wheal reaction. Any redness or micro-blistering is then measured and graded as a positive reaction.

Tuberculin Hypersensitivity

Maximum at 48-72 hours Inflitration of lesion with mononuclear cells Responsible for lesions associated with bacterial allergy cavitation, caseation, general toxemia seen in TB May progress to granulomatous reaction in unresolved infection

Granulomatous Hypersensitivity

Clinically, the most important form of DTH, since it causes many of the pathological effects in diseases which involve T cell-mediated immunity Maximal at 14 daysContinual release of cytokinesLeads to accumulation of large numbers of macrophagesGranulomas can also arise from persistence of “indigestible” antigen such as talc (absence of lymphocytes in lesion)

* Granuloma in a leprosy patient

Examples of Microbial-Induced DTH
Viruses (destructive skin rashes) smallpox measles herpes simplex Fungi candidiasis dematomycosis coccidioidomycosis histoplasmosis Parasites (against enzymes from the eggs lodged in liver) leishmaniasis schistosomiasis

* Type-IV

Type-III
Type-II
Type-I
characteristic
Comparison of hypersensitivity reactions
TB test, poison ivy, granuloma
farmers’ lung, SLE pemphigus, Goodpasture
hay fever, asthma
examples
antibody
IgE
IgG, IgM
IgG, IgM
none
antigen
exogenous
cell surface
intracellular
soluble
response time
15-30 min.
Min.-hrs
3-8 hours
48-72 hours or longer
appearance
Weal & flare
Lysis & necrosis
Erythema & edema
Erythema & induration
baso- and eosinophils
Ab and complement
histology
PMN and complement
Monocytes & lymphocytes
T-cells
antibody
antibody
antibody
transfer with