Download basicprinciplesofimmunesystem

BASIC PRINCIPLES OF
IMMUNE SYSTEM
Purnomo Soeharso
Department of Medical Biology
FMUI
Immunity : Defence capacity of the body to combat
diseases  counter infection.
The cells and molecules responsible for immunity
constitute the immune system.
Their collective and coordinative response to
introduction of foreign substance represent the immune
response.
Specific definition :
Immunity is a reaction to foreign substances including
microbes, as well as macromolecules (proteins,
polysacharides). The reactions include cellular and
molecular types (events).
Benefit of immunology for health/medicine
1. The immune system is potentially manipulated in
order the system to be under controlled condition to
combat diseases.
The manipulation of immune system may be applied by :
- manipulation of antigen potentially enter the body 
vaccination.
- manipulation of antigen recognition/interaction with
cells or molecules of immune system immunotherapy
History of vaccination :
Discovered by Edward Jenner, based on the observation
that milkmaids who had recovered from smallpox, never
suffer from smallpox infection again in the future.
Jenner’s experiment :
- take materials (exudates) from cowpox pustule and
injected to the arm of 8 year-old boy.
- After several weeks the boy was intentionally
inoculated with smallpox  the disease did not develop
 the boy become immune to smallpox infection.
Jenner’s method was considered later as vaccination.
It led to the widespread acceptance of this method for
inducing immunity to infectious diseases.
2. Immune reactions in vivo or in vitro are useful for
diagnosis and therapy of infectious diseases, toxin
poisoning or venom exposure.
Examples :
The level of antibody to virus or bacteria in serum is
considered to be adequate indicator for disease
progression.
Anti-toxin or anti-venom antibodies are useful to treat
one who are suffering from toxin or venom exposure.
 Anti-venom antibodies should be given (injected) to
one who suffered snake bite immedietly.
Components of immune system :
1. Innate / natural immunity
- defense mechanisms present prior to exposure to
infectious microbes or foreign molecules.
- exist since fetal development period and persist
permanently throughout life.
- create nonspecific response  nonspecific immunity
- represent the first line of defense mechanisms
against foreign invasion into the body.
2. Acquired / adaptive immunity
- defense mechanisms acquired in a certain period of
life.
- create specific response  specific immunity.
- develop due to induction / stimulation of foreign
substance that successfully invade the body.
- foreign substances capable of inducing immune
response are called antigen.
The major elements of the innate and adaptive immunity
Resistance
Soluble
Factors
Cells
Innate immune
system
Adaptive immune
system
Resistance is not
improved by repeated
infection
Lysozyme, complement,
interferon
Resistance is
improved by repeated
infection
antibody
Phagocytes,
Natural Killer (NK) cells
T lymphocytes
When pathogens (infectious agents) invade the body,
they are firstly facing elements of natural (innate)
immunity.
They eventually meet the adaptive immune system
provided they successfully break the natural immunity 
the adaptive immune system react specifically to
eliminate & destroy pathogens.
Adaptive immune system create immune memory 
give similar & better reaction in the secondary future
infection.
Elements constitute defense mechanisms in innate
immunity :
1. External (epithelial) surface of the body.
- epidermal skin is an effective barrier to prevent
microbial invasion.
- mucous epithelia of nasopharynx, gut, respiratory
tract, genitourinary tract are equipped with physical
(cilia) and chemical (enzymes) barriers to prevent /
inhibit microbial entry.
2. Phagocytes
cells which engulf microorganisms/particles capable
of crossing surface epithelia  reticuloendothelial
system  produced by stem cells in bone marrow :
tissue macrophages & blood monocytes.
3. NK cells  leucocytes which are able to recognize
membrane surface changes on virus infected cells 
NK cells bind and kill the infected cells.
4. Soluble factors
- interferon  proteins that are produced by virus
infected cells & lymphocytes  activate NK cells &
induce resistance to neighboring infected cells.
- complements  serum proteins
activated complement is coating bacteria & bring the
bacteria ready for phagocytosis  opsonisation.
Leads to lysis of bacterial membrane 
lytic pathway.
Inflammation
Body reaction to injury, caused by microorganisms/
particle invasion or scratched. Inflammatory reaction
leads elements of immune system to be mobilized
toward the site of infection.
Inflammatory reactions include :
1. vasodilatation  increase in the diameter of blood
vessels  increase blood supply to site of infection.
2. increase capillary permeability due to endothelial
retraction  lead macromolecules (serum proteins)
drip out the capillary & infiltrate the site of infection.
3. Influx of phagocytic cells  neutrophyls, monocytes
& lymphocytes penetrate away from capillary &
migrate to the site of infection.
Signs of inflammation :
rubor  redness
tumor  eudema (swelling)
kalor  heat
dolor  painful
 functio laesa (loss of function) of infected tissue
Specific/acquired immunity
Acquired as a result of induction & exposure to foreign
substances (antigen).
Fundamental characteristics of specific immunity :
- create immune memory  provide more effective
response in further secondary infection  basic
principle of vaccination.
- create focus response to certain/fixed antigen that
invades body & eliminate/destroy it  increase
protective capacity of innate immunity.
Specific Immunity involves 2 types of immunity :
1. Humoral immunity : is mediated by molecules (serum
proteins) which recognize and eliminate free antigens
(do not attach the cell or are not cell component) 
called antibody  bind and react specifically to
antigen.
2. Cellular immunity (cell mediated immunity) : is
mediated by cells  T lymphocytes  recognize and
bind antigen on the cell surface or nonself antigen 
produce immune mediator or lyse/destroy such cell
expressing antigen.
Antibodies and specific T lymphocytes are potentially
transferred to naive individuals  passive immunisation.
Humoral and cellular response to antigen stimulation
indicate fundamental characteristics :
1. Specificity
The immune response is specific to a particular antigen.
The antibody or lymphocyte are able to recognize part of
protein complex or any other macromolecules. Part of
molecules recognized by specific antibody or
lymphocyte is called determinant or epitope.
2. Diversity
The total number of antigenic specificities of the
lymphocytes in an individual  lymphocyte repertoire 
estimated the capacity to discriminate 109 determinants.
When a lymphocyte is stimulated by antigen  the
lymphocyte is going to proliferate yielding a specific
clone  “clonal selection theory”.
3. Memory
The effectiveness of immune response to a particular
antigen is increasing in secondary exposure to this
antigen and so on  called “immunological memory” &
mediated by “memory cells”.
4. Self limitation
Normal immune response is declining & disappearing
after a period of destimulation (stimulation is sunpended)
5. Discrimination of self from nonself
Able to discriminate foreign antigen from self
components. Lymphocytes react to foreign antigen
stimulation otherwise give no response to self molecules
or self components  immune tolerance.
Failure of immune tolerance to self components 
autoimmune diseases  create pathological
consequences for the sufferer.
Organs involved in immune system
Organs of immune system are classified into two groups
based on their function in immune system :
- primary (central) lymphoid organs.
- secondary (peripheral) lymphoid organs.
Immature lymphocytes are undergoing maturation to
become mature lymphocytes in primary lymphoid organs
 becoming immunocompetent cells.
The primary lymphoid organs in mammals are :
- bone marrow  B lymphocyte maturation
- thymus
 T lymphocyte maturation
Secondary lymphoid organs  collect antigens from
tissues or circulation & provide sites for immunocompetent cells to interact effectively with antigens.
Lymph nodes  collect antigens from intracellular fluid
of various tissues.
Lien (spleen)  filtered antigen from blood/circulation 
create response to systemic infection.
Mucous associated lymphoid tissue (MALT) in gut,
respiratory tract, genitourinary tract  (Peyer’s patch,
tonsils, adenoids) trapped antigens which enter via
mucous membrane.
Cells involved in specific immune system
The entire cells of specific immune system derive from
pluripotent “stem cells” in bone marrow & develop
through hematopoeisis process.
They differentiate into 2 lineages :
1. myeloid lineage  produce phagocytes and other
blood cells.
2. lymphoid lineage  produce lymphocytes.
Phagocytes are differentiated into two groups :
- monocytes  able to pass away from vascular system
& transform to tissue phagocytes 
macrophages.
- Polymorphonuclear cells  neutrophyls, basophyls,
eosinophyls.
Lymphocytes are produced in bone marrow, circulate in
blood and lymphoid system & occupy lymphoid organs.
Lymphocyte recognize & interact with antigen through its
receptor on the cell surface.
2 types of lymphocytes  discriminated based on their
membrane protein marker :
B lymphocytes  CD 11 marker on their surface.
T lymphocytes  CD 3 marker on their surface.
B lymphocytes
Produced and develop in bone marrow. Equipped with
Ab molecules as antigen receptor; the ab receptor is
fixed in cell membrane through its Ch terminal. When
naive B cell get in contact with specific antigen  it will
proliferate & differentiate to be B memory cells capable
of secreting specific antibody  plasma cells.
T lymphocytes
Develop from stem cells in bone marrow. They migrate
to the thymus & differentiate to become mature
T lymphocytes.
Mature T cells express “antigen binding protein” on their
surface, represent as T cell receptor (TCR)  compose
of 2 protein subunits  or , connected to each other
by disulphide bonds.
TCR recognize antigen on the cell surface in association
with (presented by) MHC (HLA) molecules.
When naive T cell contact to antigen  T cell proliferate
& differentiate to become memory and effector T cells.
Subpopulation of T cells :
Helper T cells (TH) & Cytotoxic T cells (TC) 
discriminated based on their protein marker on the cell
surface  CD4 marker for TH
CD8 marker for TC
After contact with antigen TH cells develop into effector
capable of cytokine (lymphokine) secretion  activate
B cells, TC cells, phagocytic cells etc.
 TC develop into effector which mediate cytotoxic
reactions  killing/ lysis cells expressing antigen :
- virus infected cells
- cells infected by intracellular microbes
- tumor cells
- allograft cells
Major Histocompatibility Complex (MHC)
Membrane proteins, expressed by gene cluster &
inherited in tight linkage modes.
MHC products play important roles in antigen (Ag)
recognition by immunocompetent cells & discrimination
between self and nonself  define tissue compatibility
among individuals of the same species  called
transplantation antigens.
MHC is also critical for the creation of humoral and cell
mediated immunity  TH & TC recognize Ag in
association with MHC molecules  establish antigen
repertoire which give response to TH & TC  implicate
in the susceptibility to disease & autoimmunity.
HLA code for 3 kind of molecules : HLA class I, class II &
class III.
HLA class I is coded by regio A, B and C
HLA class II is coded by regio DP, DQ and DR
each regio constitute alleles which are multiple  create
huge variation of individuals, despite of brothers or
sisters.
HLA class I molecules present Ag recognized by TC 
carried by almost all nuclear cells.
HLA class II molecules present Ag recognized by TH 
carried by antigen presenting cells (APC) 
macrophages, dendritic cells, B lymphocytes, etc.
Humoral immunity
Mediated by antibodies, proteins that are presence in
serum & body liquid of mammals  belong to protein
serum fraction,  globulin  immunoglobulin (Ig).
Produced and secreted by B lymphocytes that has been
stimulated by specific antigen  becoming committed
cells (sensitized B lymphocytes) and develop to plasma
cells.
Function as effector that mediate binding to free antigen
(no attachment or not part of cell components),
neutralize and eliminate such antigen away from the
body.
Ig molecules
Protein of 150.000. mw, compose of 4 subunits :
2 heavy (H) chains, each make pairing with light (L)
chain. Each subunit is connected to its complement by
disulphide bond.
The molecule is divided into two domains :
V (variable) domain  aminoterminal part, varies among
molecules & define the specificity
of Ig to Ag. The aminoterminal
end undergo modification to
become “antigen binding site”
C (constant) domain  constant & identical in similar Ig
type.
Immunoglobulin molecule variations
1. Isotype variation  defined by determinant present in
Ch and Cl which discriminate Ig of the same species.
2. Allotype variation  defined by the variation of amino
acids in either H or L chain, coded by different alleles
 expressed by individuals of the same species.
3. Idiotype variation  defined by variation of Vh and Vl
constructing Ag binding site  define the specificity of
Ig to Ag.
5 Ig classes available in all species, defined by Ig H
chain.
IgG – the predominant Ig in normal serum, constitute
70 – 75% of total Ig. Distribute intra and extra
vascular; represent dominant antibodies
accumulate during secondary immune response,
especially function as anti-toxin.
IgM – include 10% of total Ig. Present as pentamer
molecules, distribute intravascular. Represent
the predominant Ab in early response to
microbial infection.
IgA – include 15 – 20% of total Ig. Present in dimeric
conformation, equipped with “secretory
component”, recognized as sIgA. Predominant in
mucous secret i.e. saliva, tracheobronchial secret
genitourinary mucous, etc.
IgD – less than 1% of total Ig, fixed in cell membrane of
B lymphocytes. Function as antigen receptor &
necessary for B cell stimulation to become
plasma cells.
IgE – available in small proportion, attach to basophyl
and mast cell membrane. Involved in developing
immunity to parasites (helminthes) and
hypersensitivity disease i.e. asthma.
Phases of immune response :
1. Cognitive phase – antigen recognition through antigen
binding to specific receptor on lymphocyte surface.
B lymphocyte – bind Ag to surface Ig.
T lymphocyte – bind Ag fragment – MHC (HLA) to
TCR.
2. Activation phase
- lymphocyte proliferation – clonal expansion of
specific lymphocyte to certain antigen.
- lymphocyte differentiation
B lymphocyte  secreting cells (plasma cells) 
Ab bind to free Ag (soluble Ag).
T lymphocyte  mediated killing
 activate macrophages to kill
intracellular microbes.
 lysis of cells expressing foreign Ag or
viral Ag.
3. Effector phase – elimination and neutralisation of Ag.
Require participation of nonlymphoid cells 
collectively recognized as effector cells.
Ag-Ab complex are phagocyted by polymorpho
nuclear & mononuclear cells (in circulation).
Ag-Ab complex activate complement system to
mediate lysis & phagocytosis of microorganisms.
Sensitized T lymphocytes secrete cytokine 
activate cytolysis & phagocytosis.
Thank You & Good Luck