1. Hypersensitivity Types II-IV
Type II: Cytotoxic
Type III: Immune Complex Type
IV: T Cell-Mediated (DTH)

2. 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) .

3. Cytotoxic hypersensitivity

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

5. Activated C3 forms opsonin recognized by phagocytes
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

6. 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.

7. The same antibodies ,as well as IgM , activate the complement system by the classical pathways , resulting in the production of complement anaphylatoxins(C3a, and C5a), and complement membrane attack complex that recruit leukocytes and induce inflammation.
and attack cells .
If antibodies bind to cells , such as erythrocytes & platelets ,the cells are opsonized and may be ingested & destroyed by host phagocytes.

8. 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.

9. 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

10. 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

11. Drug-Induced Reactions: Adherence to Blood Components
blood cell adsorbed drug
or antigen drug metabolite
antibody to drug
complement
drug can bind to red blood cells, causing them to be recognized as different.B cell proliferation to produce IgG,IgM,bind to these antigens to form complexes that activate the classical pathway
lysis

13. Immune (Toxic )Complex Hypersensitivity (Type III)
Study Guide
What is the difference between Type II and Type III?

15. Hypersensitivities Type III (Immune Complex–Mediated) Hypersensitivity
Involves immune reactions against soluble antigens circulating in serum.
Leads to formation of immune complexes( Ag-Ab complexes)
Can cause localized reactions
Hypersensitivity pneumonitis
Post streptococcal glomerulonephritis
Can cause systemic reactions
Systemic lupus erythematosus
Rheumatoid arthritis

16. 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

17. Inflammatory Mechanisms in Type III
Complement activation
Anaphylatoxins ( C3a and C5a)
C3b and C4b release( opsonizing and chemotactic factors)
MAC formation( membrane attack complex C5b-C9)
Neutrophils attracted
difficult to phagocytoze tissue-trapped complexes
frustrated phagocytosis leads to tissue damage

18. Immune Complex Mediated Hypersensitivity
Kher

19. Disease Models
Serum sickness
Arthus reaction

20. Arthus Reaction
Localized manifestation of generalized hypersensitivity
Ag+Ab precipitates cause C activation and release of inflammatory molecules. It 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.

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

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

23. Serum Sickness (contd)
*Plasma concentration of C3 falls due to massive activation and fixation to Ag+Ab complexes.
*Disease is 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.*

24. Serum sickness

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

26. Manifestations of T-Cell Mediated Hypersensitivity
Allergic reactions to bacteria, viruses and fungi
Contact dermatitis due to chemicals
Rejection of tissue transplants

27. 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

28. Types of Delayed Hypersensitivity
Delayed Reaction maximal reaction time
Contact hours
tuberculin hours
granulomatous at least 14 days

29. 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)
Study Guide
What is the circulating equivalent of the Langerhans cell?
What is the carrier in hapten-induced eczema?

30. Contact dermatitis Ag possibly enters sebaceous glands
Lesions vary from macules & papules to vesicles which subsequently breakdown leaving weeping surface typical of acute eczematous dermatitis.
Detected by patch test

31. Contact dermatitis reaction

32. Allergic Contact Dermatitis Response to Poison Ivy Hapten
Kher

33. Atopy Patch Tests
Atopy Patch Tests (APT) on the skin can detect delayed hypersensitivity reactions to foods, but are usually employed to identify trigger contact allergens such as nickel, rubber, dyes and cosmetics

34. 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.
Kher

35. Tuberculin Hypersensitivity
Maximum at 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

36. 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 days
Continual release of cytokines
Leads to accumulation of large numbers of macrophages
Granulomas can also arise from persistence of “indigestible” antigen such as talc (absence of lymphocytes in lesion)
Study Guide
Are you familiar with tuberculosis?

37. Granuloma in a leprosy patient

38. 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

39. Comparison of hypersensitivity reactions
Type-IV
Type-III
Type-II
Type-I
characteristic
antibody
IgE
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
transfer with
TB test, poison ivy, granuloma
farmers’ lung, SLE
pemphigus, Goodpasture
hay fever, asthma
examples