Humoral & Celullar Immunity

Che Maraina Che Hussin

Immunology Department
USM
maraina@usm.my
 Many ways to protect our body from pathogens or foreign bodies
 First line of defense: mechanical barriers
 skin: prevent microorganisms from entering tissues
 lactic acid in sweat: prevent colonization by bacteria
 epithelia with layer of mucus: sweep away foreign substances
 Should any pathogen succeed in entering body, other additional
factors guard inner tissues:
 soluble proteins in blood and ECF (humoral)

 specialized cells: recognize, sequester and eliminate harmful

substances (cellular)
 Immunity

Innate Acquired
Celullar Macrophages, T-lymphocytes
Neutrophils,
Natural killer

Humoral Complement, Antibodies by B-

Cytokines, cells
Lysozyme, Acute
phase proteins
 Innate/natural immunity:
 present since birth
 response present at first time when a pathogen is encountered

 does not require prior exposure

 not modified by repeated exposures to pathogen in life

 Acquired/specific immunity:
 resistance that is weak or absent on first exposure
 increases response with subsequent exposures to same

specific pathogen
  Two types:
 active

 Passive

 Active:
 the host undergoes an immunological response and produces the
cells and factors responsible for the immunity, i.e., the host
produces its own antibodies and/or immuno-reactive
lymphocytes
 Active immunity can persist a long time in the host, up to many
years in humans
 Passive
 acquisition by a host of immune factors which were produced in
another animal, i.e., the host receives antibodies and/or immuno-
reactive lymphocytes originally produced during an active
response in another animal
 Passive immunity is typically short-lived and usually persists
only a few weeks or months
Both innate and acquired immunity work in
concert and dependent on each other
 Immune system
 Comprised of
 Lymphoid tissues: concentrated in bone marrow, lymph nodes,
spleen, liver, thymus, and Peyer's patches scattered in linings
of the GI tract

 Cells of the immune system: lymphocytes (T & B ),

macrophages, plasma cells, NK cells etc
Cells of the Immune System
 Three important features of the immunological system
 Specificity: An antibody or reactive T cell will react specifically with the
antigen that induced its formation. However, cross-reactivity is possible

 Memory: Once the immunological response has reacted to produce a

specific type of antibody or reactive T cell, it is capable of producing
more of the antibody or activated T cell more rapidly and in larger
amounts

 Tolerance: an immune response to "self" antigens (called an

autoimmune response) does not occur
 If tolerance is"broken", which may result in an autoimmune disease
Major phases of immune response:
Recognition of the antigen
A reaction to eradicate it
 Immune response: can divided into
 Antibody-mediated immunity (AMI): mediated by soluble host
proteins called antibodies or immunoglobulins
 AMI response involves interaction of B lymphocytes with

antigen and their differentiation into antibody-secreting plasma

cells
 The secreted antibody binds to the antigen and in some way

leads to its neutralization or elimination from the body

 Indication:
 Extracellular bacteria infection
Antibody-mediated immunity
 Cell-mediated immunity (CMI): mediated by specific
subpopulations of T-lymphocytes called effector T cells
 CMI response involves several subpopulations of T

lymphocytes that recognize antigens on the surfaces of cells

 T-helper (Th) cells respond to antigen with the production of

lymphokines
 The distinction between Th1 and Th2 is based on their
lymphokine profiles
 TH1 CD4+ cells secrete IL-2, gamma IFN and lymphotoxin

that
 activate macrophages

 activate TC (CD8+) cells to their full cytotoxic capacity

 mediate delayed type hypersensitivity responses (type IV)

 TH2 CD4+ cells secrete IL-4, IL-5, IL-6, IL-10 and IL-13 that
 that stimulate B cell development to differentiate into

plasma cells and production of antibodies

 T cell recognition of Ag only occurs when the Ag is associated
with proteins of the MHC complex
 T cells have receptors (TCR) complementary to the complexed
MHC determinant and the antigenic determinant
 Tc cells or cytotoxic T lymphocytes: able to kill cells that
are showing a new or foreign antigen on their surface (as
virus-infected cells, or tumor cells, or transplanted tissue
cells)

 Indication:
 Virus infected cells
 Tumor infected cells
 Intracellular bacteria infection
Cell-mediated immunity
Antigen presenting process
Immune response
Immune response
 Primary and secondary immune responses.
 Following the first exposure to an antigen the immune response
develops gradually over a period of days, reaches a low plateau
within 2-3 weeks, and usually begins to decline in a relatively
short period of time
 When the antigen is encountered a second time, a secondary
(memory) response causes a rapid rise in the concentration of
antibody level in the serum, which may persist for a relatively long
period of time
Immune response
 Antibody-mediated Immunity
 Antibodies are proteins produced by lymphocytes that can
specifically bind a wide variety of protein and polysaccharide
antigens and elicit a response
 Antibodies are the mediators of humoral (circulating) immunity,
 The classes of antibodies
 IgG, IgM, IgA, IgE, and IgD
 IgG and IgA are further divided into subclasses
Immunoglobulin structure
 IgG
 Immunoglobulin G is the predominant Ig in the serum; it makes
up about 80% of the total antibody
 IgG that crosses the placental barrier, and thereby provides
passive immunity to the fetus and infant for the first six months of
life
 Enhances phagocytosis, effective at the neutralization of bacterial
extracellular toxins and viruses
 IgM
 is the first immunoglobulin to be synthesized by infants and the
first to appear in the blood stream during the course of an
infection
 Mainly, it is confined to the bloodstream giving the host protection
against blood-borne pathogen
 It fixes complement
 IgM makes up about 5% serum immunoglobulins
 IgM is arranged to resemble a pentamer of five immunoglobulin
molecules
 IgA
 Accounts for 15% in normal serum.
 There are two subclasses based on different heavy chains, IgA1
and IgA2
 IgA1 is produced in bone marrow and makes up most of the
serum IgA
 Both IgA1 and IgA2 are synthesized in GALT (gut associated
lymphoid tissues) to be secreted onto the mucosal surfaces
 Secretion of dimeric IgA is mediated by a 100kd glycoprotein
called the secretory component
 Since IgA may be synthesized locally and secreted in the
seromucous secretions of the body, it is sometimes referred to as
secretory antibody or sIgA
 Secretory IgA
 is the predominant immunoglobulin present in gastrointestinal
fluids, nasal secretions, saliva, tears and other mucous
secretions of the body
 Secretory IgA is also transferred via the milk, i.e., the colostrum,
from a nursing mother to a newborn, which provides passive
immunity to many pathogens, especially those that enter by way
of the GI tract
 IgE 
 accounts for 0.002% of the total serum immunoglobulins
(traceble)
 The majority of IgE is bound to tissue cells, especially mast cells
 IgE is bound very firmly to the Fc receptors (specifically for IgE)
on mast cells
 Ig D
 Makes up about 0.2% of total serum immunoglobulins
 In B cells, IgD's function is to signal the B cells to be activated
 IgD starts to be expressed when the B-cell exits the bone marrow
to populate peripheral lymphoid tissues
 When a B-cell reaches its mature state, it co-expresses both IgM
and IgD
 Activates basophils and mast cells to produce anti-microbial
factors
 Functions of antibodies in host defense
 Opsonization: enhance phagocytic engulfment of microbial
antigens
 Steric hindrance: Antibodies combine with the surfaces of
microorganisms and may block or prevent their attachment to
susceptible cells or mucosal surfaces
 Toxin neutralization: block the interaction of the toxin
 Agglutination and precipitation: enhanced the microorganisms to
be phagocytosed
 Activation of complement: lysis of microorganism
 Antibody-dependent cell cytotoxicity (ADCC):
 IgG can enable certain cells (natural killer cells) to recognize

and kill opsonized target cells

 Cell Mediated Immunity
 During the cell-mediated immune response, various subsets of T
lymphocytes activated and develop into effector T cells
 These include
 T-helper cells (Th/CD4+)(Th1 and Th2 subsets)
 Cytotoxic-T cells(Tc/CD8+)cells
 T-helper cells
 T-helper cells are composed of distinct subsets that can be
distinguished on the basis of their patterns of lymphokine production

 Th1 cells "see" foreign Ag on the surface of APC's in the context of

MHC II
 Th1 cells produce IL-2, gamma IFN and lymphotoxin. This results

in macrophage activation and the delayed-type hypersensitivity

(DTH) reaction
 Th2 cells also see foreign Ag on the surface of APC's in the context
of MHC II
 Their response is to secrete IL-4, IL-5, IL-6, IL-10,IL-13 and TNF

alpha that help activate B cells

 T cell recognition of Ag only occurs when the Ag is associated
with proteins of the MHC complex
 The T cells have receptors (TCR) complementary to the
complexed MHC determinant and the antigenic determinant
 Th1 cells and Th2 cells recognize Ag in association with MHC II
(as displayed by macrophages and other APCs)
 T-helper cells (CD4+) reacting with Ag may produce a variety of
lymphokines
 Interleukin-2 (IL-2) stimulates T cell activation and IL-4 stimulates
B cells
Antigen recognition & presentation
 Cytotoxic T cells
 Tc (cytotoxic) cells can destroy cells bearing new antigens on
their surfaces (as might result in a viral infection, a tumor cell, or
an infection by a bacterial intracellular parasite)
 Tc cells exert their cytotoxic activity when they are in physical
contact with cells bearing new antigen and MHC I protein
 Tc-cells recognize Ag on cells complexed with MHC I
 Contact between the Tc cell and the target cell is required for lysis
by release of perforin
 almost all host cells, including macrophages, display MHC I
 an effector Tc cell can destroy a macrophage which is otherwise
carrying out a useful function by presenting Ag to TH lymphocytes
Antigen recognition & presentation
 Delayed type hypersensitivity
 Th1-cells (CD4+) are a subset of T-lymphocytes that recognize Ag
in association with Class MHC proteins
 When Th1-cells are presented Ag in association with MHC II by a
macrophage, their development is stimulated by macrophage
interleukin-1 (IL-1), and autostimulated by IL-2
 They respond by differentiating and producing a variety
lymphokines that induce a local inflammatory response, and
attract, trap, and activate phagocytes
 One aspect of this response is a state of delayed-type
hypersensitivity (DTH) in the host
 This is usually evident in chronic infections wherein CMI is largely
involved (e.g. tuberculosis)
 usually present themselves as allergic reactions.
 Such allergic reactions generally require about 24 hours to
develop following a secondary exposure to Ag
 circulating TH cells (actually memory cells) to encounter the Ag
and to begin producing lymphokines, and to attract macrophages
and TC cells to the site, for these cells are the real mediators of
the allergic reaction
 The phagocytic and cytolytic activities of these cells are
responsible for the localized tissue destruction which occurs
 Examples: tuberculosis, leprosy and brucellosis, and in some
fungal and protozoal infections
 best known examples of the delayed-type hypersensitivity
reaction is the Mantoux (tuberculin) test which is utilized to
determine current or previous infection by the tubercle bacillus
(Mycobacterium tuberculosis)
  A small amount of Ag called the purified protein derivative (PPD),
derived from the cell wall of the bacterium, is injected
subcutaneously usually just under the skin of the forearm
 The test is evaluated after 24-48 hours.
 A positive test is an allergic response (an "urticarial weal") at the
site of the injection, which might look like a swollen reddened
area about the size of a quarter
 A negative test is no reaction
 A positive test does not mean that the individual has an active
case of tuberculosis, but that the individual has at least been
exposed to the tubercle bacillus or one of its products sufficiently
to have undergone a primary immune response
 Macrophages
 found in tissues
 are important as Ag-presenting cells that initiate T-cell
interactions, development and proliferation
 Macrophages are also involved in expression of CMI since they
become activated by γIFN produced in a CMI response
 Activated macrophages have increased phagocytic potential and
release soluble substances that cause inflammation and destroy
many bacteria and other cells
Macrophage
 Natural killer (NK) cells
 Cytotoxic cells that lyse cells bearing new antigen regardless of
their MHC type and even lyse some cells that bear no MHC
proteins
 Natural Killer cells are defined by their ability to kill cells
displaying a foreign Ag (e.g. tumor cells) regardless of MHC type
and regardless of previous sensitization (exposure) to the Ag
 Some NK cells are probably derived from TC cells (CTLs), but
they do not display T cell markers. NK cells can be activated by
IL-2 and γ IFN
 Natural Killers lyse cells in the same manner as CTLs
 Some NK cells have receptors for the Fc domain of IgG and so
are able to bind to the Fc portion of IgG antibody on the surface
of a target cell and release cytolytic components that kill the
target cell
 This mechanism of killing is referred to as antibody-dependent
cell-mediated cytotoxicity (ADCC)
 Cytokines
 Extracellular factors that affect cell proliferation and differentiation
 IL-1 (Interleukin-1): Mainly a product of macrophages
 It acts as a growth regulator of T-cells and B-cells
 IL-1 forms a chemotactic gradient for neutrophils and serves as

an endogenous pyrogen which produces fever.

 IL-2 (Interleukin-2): stimulates the proliferation of T-cells and
activates NK (natural killer) cells
 IL-3 (Interleukin-3): regulates the proliferation of stem cells and the
differentiation of mast cells
 IL-4 (Interleukin-4): causes B cell proliferation and enhanced
antibody synthesis
 IL-6 (Interleukin-6): (same as beta Interferon) has effects on B cell
differentiation and on antibody production and on T cell activation,
growth, and differentiation
 IL-8 (Interleukin-8): chemotactic attractant for neutrophils
 IL-13 (Interleukin-13): shares many of the properties of IL-4, and is a
potent regulator of inflammatory and immune responses
 Interferons:  γ IFN is produced by T cells
 alpha-Interferon
 beta-Interferon
 gamma-interferon:
 antiviral effects
 activates macrophages and NK cells

 stimulates IL-1, IL-2, and antibody production

 Lymphotoxins: (TNF-β):
 TNF-beta is produced by T cells
 TNF-alpha is produced by T cells, as well as other types of cells.
 TNF kills cells, including tumor cells (at a distance)

 Colony Stimulating Factor (CSF): several, including GMCSF, cause
phagocytic white cells of all types to differentiate and divide
Immune response
Thank you