2. Type I
IgE Mediated
ClassicAllergy
Type IV
T cell
Delayed
Type
Hypersensitivity
Gel and Coombs classification of hypersensitivities.
Type II
IgG/IgM
Mediated
rbc lysis
Type III
IgG Mediated
Immune
complex
Disease
4. TYPE-3 HYPERSENSITIVITY
• The reaction of antibody with antigen -- immune
complexes -- clearance of antigen by phagocytic cells.
Large amounts of immune complexes -- tissue-
damaging type III hypersensitive reactions.
• The severity -- the quantity of immune complexes
and their distribution within the body.
• When the complexes are deposited in tissue very
near the site of antigen entry, a localized reaction
develops.
5. • Antigen involved:
– Exogenous antigens such as bacteria and viruses
– Endogenous antigens such as DNA.
• Removal of immune complexes:
– Mere formation of immune complexes does not result in type Ill
hypersensitivity reaction.
– Immunocomplexes -- rapidly cleared by activation of
complement system.
– Coated with complements are either phagocytosed by
macrophages/ monocytes or are bound to RBCs and carried to
liver and spleen where they are phagocytosed.
– Immune system may be exposed to excess dose of antigen over
long period of time -- chronic infection, autoimmune diseases,
and repeated exposure to environmental pollutants.
– Leads to formation of excessive immune complexes.
6. • Complex deposition –
– blood-vessel walls,
– in the synovial membrane of joints,
– on the glomerular basement membrane of the kidney, and
– on the choroid plexus of the brain.
• The deposition of these complexes recruitment of
neutrophils granular release from the neutrophil
tissue injury
7. • Soluble vs Insoluble lmmunocomplexes
• Localised reaction
– Antibody excess or antigen-antibody equivalence, --
immune complexes are large and insoluble; -- localise
near site of antigen
– deposited on the basement membrane of blood
vessel walls or glomeruli,
• Generalised
– Antigen excess -- small soluble complexes are formed
-- tend to travel through blood and get deposited in
various sites
– smaller complexes may pass through the basement
membrane and deposited in the sub epithelium.
8. MECHANISM OF TISSUE INJURY
• Classical Complement Activation
• Ag-Ab-immune complexes stimulate classical
pathway of complement;
• the products -- mediate the tissue injury
– Anaphylatoxin: Complement by-products C3a and C5a
being anapbylactic; induce localized mast cell
degranulation with increase in vascular permeability.
– Chemoattractant : C3a and C5a -- causing recruitment
of neutrophils to the site of immune complex
deposition.
– Role of neutrophils: attempt to phagocytose large
immune complexes, but fail in doing so.
– Release large number of lytic enzymes from secretory
granules ( through frustrated phagocytosis) which
causes extensive tissue damage.
9. • The C3b complement component acts as an
opsonin in this FRUSTRATED
PHAGOCYTOSIS(sloppy eating)
• Because the complex is deposited on the
basement membrane surface, phagocytosis is
impeded, so that lytic enzymes are released
during the unsuccessful attempts of the
neutrophil to ingest the adhering immune
complex.
10. Disorders of the Immune System:
Immune Complex Disease
Glomerul
membrane of
Large complex
Endothelial cell
Small complex 10
12. • Platelet Activation
– Immunocomplexes + Fc receptors on platelets –
platelet activation.
• Platelet aggregation -- leads to microthrombi
formation
• vasoactive amines released from activated platelets,
• Tissue ischemia leading to further tissue damage.
• Activation of Hageman Factor
– Activation of kinin, which in turn causes causes
vasodilatalion and edema.
14. Type III Reactions Can Be Localized
• ARTHUS REACTION
• Localized area of tissue necrosis due to
vasculitis resulting from acute immune
complex deposition at the site of inoculation
of antigen
• Injection of an antigen intradermally or
subcutaneously into an animal with high
levels of circulating antibody specific for that
antigen -- formation of localized immune
complexes acute Arthus reaction within 4–
8 h.(Nicholas Maurice Arthus, 1903)
15. • Microscopic examination -- neutrophils adhering to the
vascular endothelium and then migrating into the
tissues at the site of immune complex deposition.
• As the reaction develops, localized tissue and vascular
damage results in an accumulation of fluid (edema)
and red blood cells (erythema) at the site.
• The severity of the reaction can vary from mild swelling
and redness to tissue necrosis.
16. • In skin – following insect bite, during allergic
desensitisation
• In lung –
– Reactions induced by bacterial spores, fungi, or dried fecal
proteins can also cause pneumonitis or alveolitis.
– These reactions are known by common names reflecting
the source of the antigen.
– For example :- “farmer’s lung”-
“pigeon fancier’s disease”
17. Type III Reactions Can Also Be
Generalized
• When large amounts of antigen enter the blood
stream and bind to antibody, circulating immune
complexes can form.
• If antigen is in excess, small complexes form;
because these are not easily cleared by the
phagocytic cells, they can cause tissue- damaging
type III reactions at various sites
• generalized type III reactions were often observed
after the administration of antitoxins containing
foreign serum, such as horse antitetanus or anti
diphtheretic serum.
18. SERUM SICKNESS
• The recipient -- develops antibodies specific for the
foreign serum proteins; -- form circulating immune
complexes with the foreign serum antigens.
• Within days or weeks after exposure -- begins to
manifest a combination of symptoms that are called
serum sickness
– fever,
– weakness,
– generalized vasculitis (rashes) with edema and erythema,
– arthritis,
– lymphadenopathy, and
– sometimes glomerulonephritis.
19. OTHER EXAMPLES
• Autoimmune Diseases –
– Systemic lupus erythematosus
– Rheumatoid arthritis
– Goodpasture’s syndrome
• Drug Reactions-
– Allergy to penicillin and sulfonamides
• Infections-
– Poststreptococcal glomerulonephritis
– Meningitis,Hepatitis,Mononucleosis
– Malaria,Trypanosomiasis
20. Factors affecting clearance of
immune complexes
• Complement deficiency impairs clearance of
complexes.
• Size of immune complexes.
• Immunoglobulin classes
• Phagocyte defects
22. • When some subpopulations of activated TH cells
encounter certain types of antigens, they secrete
cytokines that induce a localized inflammatory
reaction called delayed-type hypersensitivity (DTH)
• large influxes of nonspecific inflammatory cells, in
particular,macrophages.
• Robert Koch in 1890 -- individuals infected with
Mycobacterium tuberculosis developed a localized
inflammatory response when injected intradermally
with a filtrate derived from a mycobacterial culture
23. • It is delayed type (occurs after 48-72 hours of
antigen exposure)
• It is cell- mediated; characteristic cells– TDTH
cells-- principal mediators of type reactions.
• Tissue injury -- due to activated macrophages.
25. PHASES OF THE DTH RESPONSE
• SENSITISATION PHASE
• 1–2 weeks after primary contact with an antigen.
• TH cells -- activated and clonally expanded by antigen
together with the class II MHC molecule on antigen
presenting cell
• APC Langerhans cells and macrophages.
• Langerhans cells -- pick up antigen that enters
through the skin and transport it to regional lymph
nodes, where T cells are activated by the antigen.
26. • Most TDTH cells -- derived from TH1 cells;
• Occasionally other T cells, such as CD8 T cells and
CD4' TH 17 can also act as TDTH cells.
• EFFECTOR PHASE
• The TDTH cells, on subsequent contact with the
antigen, secrete variety of cytokines which attract
and recruit various inflammatory cells ( e.g.
macrophages) at the site Of DTH reaction
27. • TH1 cells secrete a variety of cytokines that recruit
and activate macrophages and other nonspecific
inflammatory cells.
• A DTH response become apparent only after 24 h
and peaks 48–72 h after second contact.
• The delayed onset of this response reflects the time
required for the cytokines to induce localized influxes
of macrophages and their activation
30. CYTOKINES PARTICIPATING IN DTH
• TH1 cells secrete cytokines that attract and activate
macrophages to the site of infection.
• IL-3 and GM-CSF localized hematopoiesis of the
granulocyte-monocyte lineage.
• IFN-γ and TNF-β (together with macrophage-derived
TNF-α and IL-1) act on nearby endothelial cells
facilitate extravasation of monocytes and other
nonspecific inflammatory cells.
31. • Circulating neutrophils and monocytes adhere to the
adhesion molecules displayed on the vascular
endothelial cells and extravasate into the tissue
spaces.
• Neutrophils appear early in the reaction, peaking by
about 6 h and then declining in numbers.
• The monocyte infiltration occurs 24 to 48 h after
antigen exposure
32. MCAF (Monocyte Chemotactic and Activating
Factor)
• Monocytes enter the tissues to become
macrophages,
• Chemotactically drawn to the site of the DTH
response by chemokines such as monocyte
chemotactic and activating factor (MCAF).
33. MIF(Migration Inhibiting factor)
• Inhibits macrophages from migrating beyond the
site of a DTH reaction.
• As macrophages accumulate at the site of a DTH
reaction, they are activated by cytokines,
particularly IFN-√ and membrane bound TNF-β
produced by TH1 cells.
• macrophages become more effective as antigen-
presenting cells upon activation activation of
more T cells Secretion more cytokines
recruit and activate even more macrophages.
34. PATHOLOGY OF DTH REACTION
• Continuous DTH reaction for killing the
intracellular microbes (especially persistent
and/or nondegradable antigens) -- formation of
granuloma (e.g. tubercles in leprosy and
tuberculosis).
• The initial TH1 cell infiltrate is progressively
replaced by macrophages in 2-3 weeks.
• Macrophages transform into two type of cell5:
• 1. They become large, flat, and eosinophilic --
epithelioid cells.
• 2. The epithelioid cells occasionally fuse (induced
by IFN-y) -- multi nucleated giant cells.
35. • Granuloma consists of an inner zone of epithelioid cells,
typically surrounded by a collar of lymphocytes and a
peripheral rim of fibroblasts and connective tissue
36. Tuberculin Test-detect DTH Reaction
• A positive skin-test reaction after intradermal injection of
antigen indicates that the individual has a population of
sensitized TH1 cells specific for the test antigen.
• PPD, a protein derived from cell wall of mycobacterium.
• Development of a red, slightly swollen, firm lesion at the site
between 48 and 72 h later indicates previous exposure.
• The skin lesion results from intense infiltration of cells to the site
of injection during a DTH reaction.
• a positive test doesn’t allow one to conclude whether due to a
pathogenic form of M. tuberculosis or to a vaccine form received through
immunization,.
37. Contact Dermatitis Is a Type
of DTH Response
• Many contact-dermatitis reactions are mediated
by TH1 cells.
– formaldehyde,
– trinitrophenol,
– nickel,
– turpentine, and
– active agents in various cosmetics and hair dyes,
– poison oak, and poison ivy,
• Most of these substances are small molecules
that can complex with skin proteins
38. • This complex is internalized by antigen-presenting
cells in the skin (e.g., Langerhans cells) processed
and presented together with class II MHC molecules
activation of sensitized TH1 cells induce
Cytokine production
• Approximately 48–72 h after the second exposure,
the secreted cytokines cause macrophages to
accumulate at the site.
• Activation of these macrophages and release of lytic
enzymes result in the redness and pustules.
40. • The therapy for T cell-mediated hypersensitivity
disorders is designed to reduce inflammation, using:
corticosteroids and antagonists against cytokines such
as TNF, and to inhibit T cell responses with
immunosuppressive drugs such as cyclosporine.
• Antagonists of TNF have proved to be beneficial
in patients with rheumatoid arthritis and
inflammatory bowel disease.
• Many newer agents are being developed to inhibit T
cell responses. These include: agents that block
costimulators such as B7 and antagonists against
receptors for cytokines such as IL-2.
41. Type V Hypersensitivity / Auto immune
• This is an additional type that is sometimes (often in
Britain) used as a distinction from Type 2
• Instead of binding to cell surface components, the
antibodies recognize and bind to the cell surface
receptors , which either prevents the intended ligand
binding with the receptor or mimics the effects of
the ligand, thus impairing cell signaling.
42. Examples of Type V
• Grave's disease
• Myasthenia Gravis
• Hashimoto's thyroiditis
• Systemic lupus erythematosus
