This document discusses Type IV hypersensitivity reactions, which are mediated by T cells. It describes how CD4+ T cells can differentiate into Th1 and Th17 effector cells that promote inflammation through cytokine production. It also explains the three pathways through which CD8+ T cells exert their cytotoxic effects: cytotoxin mediated killing, Fas-mediated apoptosis, and cytokine production. Finally, it provides several clinical examples of conditions involving CD4+ and CD8+ T cell-mediated hypersensitivity, such as tuberculosis and autoimmune diseases.

1. TYPE – IV HYPER SENSITIVITY
Moderator: Dr. Sanchita Ghosh
Speaker: Dipayan Das

2. INTRODUCTION
 Immunity is the balanced state having adequate
biological defense against infections and diseases
while having adequate tolerance to inflammation,
allergy and autoimmune diseases.
 The response is how our body recognizes and
defends itself against foreign and harmful
substances.

3.  Hypersensitivity reactions are a set of
undesirable reactions produced by
normal immune system and the resulting
diseases are called hypersensitivity
diseases.
 Persons who mount immune responses
against an antigen are said to be
“sensitized” to that antigen.
 So pathologic or excessive reactions
represent a “hypersensitive” state.
INTRODUCTION

4. FEATURES OF HYPERSENSITIVITY
 Elicited by exogenous environmental antigens (microbial
and nonmicrobial) or endogenous self antigens.
 Allergy : caused by environmental antigens.
 Autoimmune diseases : Immune responses against
self or autologous antigens.
 It results from an imbalance between the effector
mechanisms of immune responses and the control
mechanisms that serve to normally limit such responses.

5.  The development of hypersensitivity diseases
(both allergic and autoimmune) is often
associated with the inheritance of particular
susceptibility genes (both HLA and non-HLA
genes).
 The mechanisms of tissue injury in
hypersensitivity reactions are the same as the
effector mechanisms of defense against
infectious pathogens.
FEATURES OF HYPERSENSITIVITY

6. CLASSIFICATION
 Coombs and Gell classification of hypersensitivity
reaction(1963)
o 1-Type I - immediate ( atopic, or anaphylactic)
o 2-Type II - antibody-dependent
o 3-Type III - immune complex mediated
o 4-Type IV - cell-mediated or delayed type

8. TYPE-IV HYPERSENSITIVITY
 Caused by inflammation resulting from
cytokines produced by CD4+ T cells and
cell killing by CD8+ T cells.
 Also known as T cell mediated hyper
sensitivity.
 CD4+T cell mediated hypersensitivity:
Major role in autoimmunity.
 CD8+T cell mediated hypersensitivity :
Predominantly acts against viral infection,
tumor cells and graft rejection.

9. CD4+T CELL MEDIATED HYPERSENSITIVITY
 In CD4+ T cell–mediated hypersensitivity
reactions, cytokines produced by the T cells
induce inflammation that may be chronic
and destructive.
 The prototype of T cell–mediated
inflammation is delayed-type
hypersensitivity(DTH).
 Both Th1 and Th17 are involved in immune
mediated destruction.

10. The inflammatory reactions stimulated
by CD4+ T cells can be divided into two
stages :
 Activation of CD4+T cells.
 Responses of differentiated effector T cells.

11. CD4+T cells recognize
peptides displayed by APC
 Activation of CD4+T cells :
IL-2 secreted by CD4+T cells
Proliferation of
CD4+T cells and
activation of
APC(macrophages &
dendritic cells)

12. Production of cytokines by
the APCs(IL-12,6,23)
IL-12
Differentiation
of CD4+T cells
into Th1 cells
Differentiation
of CD4+T cells
into Th17 cells
IL-6, IL-23
Secretion of INF-γ
Further Th1 development

13. Responses of Differentiated Effector T
Cells :
Th1 secretes INF-γ
Activation of
macrophage
(Classical
pathway)
Increased ability
to phagocytose
and kill
microorganism
Expression of
more MHC-II
Facilitating
further antigen
presentation
IL-12
Amplification of the
TH1 response
TNF, IL-1, and
chemokines
Promote
inflammation

14. Responses of Differentiated Effector T
Cells :
Th17 secretes IL-17,
IL-22, chemokines &
other cytokines
Recruitment of
neutrophils and
monocytes
Promote
inflammation

16.  CLINICAL EXAMPLES OF CD4+ T
CELL– MEDIATED
HYPERSENSITIVITY :
 Tuberculin reaction : Intracutaneous
injection of PPD in a previously sensitized
individual
Accumulation of mononuclear
cells(CD4+T cells and macrophages)
around the venules
Perivascular cuffing Release of
cytokines Hyprtrophy of venules
Reddening and induration of the site in 8-
12 hrs Peak in 24hrs and thereafter
subside slowly

17. Delayed hypersensitivity reaction in the skin. A, Perivascular
accumulation (“cuffing”) of mononuclear inflammatory cells (lymphocytes
and macrophages), with associated dermal edema and fibrin deposition.
B, Immunoperoxidase staining reveals a predominantly perivascular
cellular infiltrate that marks positively with anti-CD4 antibodies.

18.  Granulomatous inflammation : CD4+T
cells(Th1 & Th2) releases high level of INF-Y
Sustained activation of macrophages
Transformed to epithelioid cells Granuloma
formation
 CLINICAL EXAMPLES OF CD4+ T
CELL– MEDIATED
HYPERSENSITIVITY :

19.  Contact dermatitis : Contact with urushiol,
antigenic component of poison ivy or oak
Bind and structurally modifies some self
protiens and/or HLA molecules These
altered protien are recognized as foreign by
CD4+T cells Activation and cytokine
production Inflammation Vesicular
dermatitis
 Rheumatoid arthritis : Th17 acts against
collagen and citrullinated self protien leading to
chronic arthrits with inflammation and
destruction of articular cartilage.
 CLINICAL EXAMPLES OF CD4+ T
CELL– MEDIATED
HYPERSENSITIVITY :

20.  Multiple sclerosis : Th1 and Th17 act against
myelin causing demyelination in CNS with
perivascular inflammation and paralysis.
 Inflammatory bowel disease : Th1 and Th17
act against enteric bacteria or a self antigen
leading to chronic intestinal inflammation and
obstruction.
 Psoriasis : Here CD4+T cells get activated
against unknown antigen and differentiated into
Th17 which prdoces destructive plaques in the
skin.
 CLINICAL EXAMPLES OF CD4+ T
CELL– MEDIATED
HYPERSENSITIVITY :

21. CD8+T CELL MEDIATED HYPERSENSITIVITY

22.  EFFECTOR FUNCTIONS OF CD8+T CELLS :
There are three different ways by which CD8+T
cells exert their functions.
(1) Cytotoxin mediated : When exposed to
infected / dysfunctional somatic cells, CTLs
release the cytotoxins - perforin, granzymes,
granulysin and calreticulin.
 Through the action of perforin, granzymes and
other cytotoxins enter into the cytoplasm of the
target cells.

23. EFFECTOR FUNCTIONS CONT…
(a) Granzymes :
Granzymes have two
subunits – Granzyme A and
Granzyme B.
 Granzyme B is a serine
protease which triggers the
caspase cascade, which is
a series of cysteine
proteases that eventually
lead to apoptosis.

24. EFFECTOR FUNCTIONS CONT…
 Granzyme A is a tryptase and induces caspase-
independent cell death.
 It concentrates in the nucleus of the target cells
and degrades histone H1 into small fragments.
 Histone digestion provides a mechanism for
unfolding compacted chromatin and facilitating
endogenous DNAase access to DNA during T cell
granule-mediated apoptosis.

25. EFFECTOR FUNCTIONS CONT…
(b) Perforin (Cytolysin)
: Perforin is a 65 to 75 kD
glycoprotein with
homology to C9
complement component.
 It is synthesized as an
inactive precursor, which
is cleaved to yield a 60
kD active form.

26. EFFECTOR FUNCTIONS CONT…
 The C-terminal portion of this active form is
cleaved by proteolytic enzymes, activating
the C2 domains for phospholipid binding.
 The N-terminal is involved in interaction with
the membrane and polymerization.
 Finally, aggregation of such 10-20 perforin
monomers forms polyperforin pores.

27. EFFECTOR FUNCTIONS CONT…
(c) Granulysin : It is active against Gram-
positive and Gram-negative bacteria, fungi and
parasites.
 It disrupts artificial liposomes.
 Damages mitochondria.
 Activates caspase 9 to induce apoptosis.It kills
extracellular M. tuberculosis and decreases
their viability inside the cells.

28. EFFECTOR FUNCTIONS CONT…
(d) Calreticulin : It is a Ca2+ binding
protein and acts as a chaperone for
perforin. It protects CTL from autodigestion
during biogenesis of the granules.
(e) Other components : Chondroitin
sulfate is a negatively charged molecule
which helps in delivery of granzymes into
the target cells.

29. EFFECTOR FUNCTIONS CONT…
(2) Fas mediated:
Activation of CTL
Expression of the surface protein FasL
Engagement of Fas with FasL
Recruitment of DISC
FADD translocate to DISC
Recruitment and activation of procaspases 8 and 10
Activation of effector caspase 3,6 and 7

30. EFFECTOR FUNCTIONS CONT…
(2) Fas mediated:
Cleavage of death substrates such as laminin A, B1 & B2
Apoptosis of target cells

31. EFFECTOR FUNCTIONS CONT…
(3) Cytokine mediated : CTLs also produce cytokines,
notably IFN-Y following viral infections and exposure
to some contact sensitizing agents. INF-Y is produced
in two pathways:
(a) Major pathway : The majority of INF-Y is
produced when TCR of CTL bind with an anitgen. So
it is antigen-dependent pathway.
(b) Minor pathway : The innate cytokines type-1 INF
and IL-12 can also induce INF-Y production through
STAT-4. It is antigen-independent and so it makes
CTL able to take part in innate immunity.

32.  CLINICAL EXAMPLES OF CD8+ T
CELL– MEDIATED
HYPERSENSITIVITY :
(1) Graft versus Host Disease and Graft versus
Leukemia Reaction : CTL is implicated for both
graft vs host disease and graft vs leukemia
reaction.
 The first one is attributed to both perforin and Fas
pathway but later is mediated predominantly by
perforin pathway.
(2) Type-I Diabetes Mellitus : Here CTLs act against
antigens of pancreatic β cells(insulin, glutamic
acid decarboxylase) leading to inflammation and
destruction of islet cells.

33.  CLINICAL EXAMPLES OF CD8+ T
CELL– MEDIATED
HYPERSENSITIVITY :
(3) Familial hemophagocytic lymphohistiocytosis
:
Perforin prevents uncontrolled expansion and
activation of T cells.
 Homozygous loss of function defect in perforin gene
(PRF1) causes familial hemophagocytic
lymphohistiocytosis(FHL2).
 It is due to uncontrolled activation of T cells and
macrophages with overproduction of inflammatory
cytokines.

34.  CLINICAL EXAMPLES OF CD8+ T
CELL– MEDIATED
HYPERSENSITIVITY :
 The disease is mapped on chromosome
10q21-22 (i.e., the location of PRF1).

35.  CLINICAL EXAMPLES OF CD8+ T
CELL– MEDIATED
HYPERSENSITIVITY :
(4) Hepatic injury during HBV infection : CTL kills
the infected hepatocytes leading to liver injury.
(5) Arthritis : CTL causes depletion of articular
cartilage macromolecule, glycosaminoglycan.

36. TAKE HOME MESSAGE
 Hypersensitivity is of four types: Type-I, Type-II, Type-III and
Type-IV.
 Type-IV Hypersensitivity is mediated by CD4+T cells and
CD8+T cells.
 In CD4+T cell mediated hypersensitivity, CD4+T cells
differentiate into Th1 and Th17 cells which exerts their effect
by producing cytokines.
 In CD8+T cell mediated hypersensitivity, CD8+T cells
produce their effect by three pathways cytotoxin mediated,
fas mediated and cytokine mediated.
 The major role of CD4+T cell mediated hypersensitivity is in
autoimmunity while CD8+T cell mediated hypersensitivity act
against viral infection, tumor cells and graft rejection.