CMI and HMI pdf - أ.م.د.وئام سعد عبد الحمزة

Course: Immunology

Lecturer: Dr. Weam Saad

Lecture: Specific Immunity (HMI and CMI), Primary and Secondary Immune Response.

B and T cells Biology, Activation, Immunological role in

HMI and CMI.

Cells involved in specific immune responses:

1) Antigen Presenting Cell (APC): These cells are the messengers

between  innate  (non-specific)  immunity  and  the  adaptive  (specific).
Specialized  APC  are  macrophage  (MØ),  B-cells  and  Dendric  cells
(DC).

Roles of Antigen Presenting Cell (APC):
1. Engulfment of foreign Ag, processing it and presenting it (or a polypeptide

from it) on the surface near the Major Histocompatibility Complex MHC class
I or II.

2. Communication during the immune response between immune cells especially

T- cells to induce the proper immune response cellular or humolar.

3. Secretion of cytokines which are substances (glycoproteins) that regulate the

immune response.

2) Lymphocytes:

The immune system depends on the Lymphocytes:
 B-cells or B-lymphocytes.
 T-cells or T-lymphocytes.
 Natural killer cells (NK).
B-cells are responsible for Antibody mediated immunity (Humoral immunity

HMI). And T-cells are responsible for cell mediated immunity (cellular
immunity CMI).

In addition to MHC classes, each T-lymphocyte has surface molecules to give the

cell identity:
1- Clusters of Differentiation (CD): They are major surface markers (Ag) of T-

cells, T-cells are classified according to the presence of these CD marker:

T helper cells: CD3

CD4

CD8

T cytotoxic cells: CD3

CD4

CD8

Note: NK cells have no CD markers on the surface so they are usually called null

cells.

2- T-cell Receptors (TCR): they are proteins on the T-cells surface represent

the places (or regions) of binding to the presented Ag on the APC surface.
TCR is the accessory (help) of CD4

(T-helper) and CD8

(T-cytotoxic) cells

during recognizing foreign Ag presented near MHC and increase the storage
of binding. TCR and CD3 is usually called TCR- complex.

NOTE: B-cells are able to be APC by internalization of Ag inside the cell and do
the processing and presenting, which will be discussed later.

Dendric cells: cells found only in mammalian immune system; their function is to
engulf and process Ag then presents it on the surface to other immune cells. Found
in tissues that in contact with external environment such as skin, lung stomach and
intestine. Their name comes from their branches projects.

Differences between B and T cells

Properties

B-lymphocyte

T-lymphocyte

Site of maturation Bone marrow (bursa in

chickens)

Thymus

Surface markers

Immunoglobulins

CD markers(clusters of

differentiation)

Product after Ag
stimulation

Plasma cells which

secrets Abs

Sensitized T-cells

General function

Abs production and

APC

Regulating (Helping or suppressing)
immune response and CMI

Types

No types

T-helper, T-cytotoxic and T-

suppressor

Types of Lymphocytes and their functions

Lymphocytes

Surface

Markers

Function

T helper cells (Th)

CD3, CD4 Help other cells T and B in their function

Cytotoxic T cells (Tc) CD3, CD8 Kill and lyse target cells that express foreign

Ag (cell contain intracellular pathogen or
tumor cells).

T suppressor cells (Ts) CD3, CD8 Inhibit the immune function of other

lymphocytes

T memory cells

---------

Long live cells recognize Ag of first cellular

immune response.

B lymphocytes

Differentiate to plasma cells, which produce
Abs against Ag.

Plasma cells

Secrete Abs.

B memory cells

Long live cells recognize Ag of first

humoral immune response.

Natural killer cells(NK)

---------

Kill and lyse target cells that express foreign Ag.

NOTE: When Ag succeeds to inter the body; the results of the invasion can be
the followings:
 Dose of Ag is not enough or the Ag is hapten:

1. No response or Tolerance occurs, when the immune system do not

response to the Ag.

2. Phagocytosis and complement activation leading to non-specific

immune response against without memory.

 Enough Ag dose (complete Ag):

The Ag induces a specific immune response against it (either CMI or

HMI) and memory to remember the same Ag next time. Induction of the

immune response depends on: Ag dose, Ag type, Immune system health,
genetic factors and control.

Major Histocompatibility MHC

They are genes encoding for proteins found on the surface of all human

and animals cells. They have an important role in giving the identity of the cell
and in the communication with the immune system cells and regulation of
immune response:

MHC class I: found on the surface of all nucleated cells, have role in tissues
and organs transplantation.

MHC class II: found on the surface of all immune cells especially APC.

MHC class III: found on the surface of certain cells for some complement
components receptors.

Cytokines: proteins produced by many cells act as mediators between cells
and regulate other cells function. They include:

1. Monokines, cytokines produced by mononuclear phagocytic cells.
2. Lymphokines, cytokines produced by activated lymphocytes, especially

Th cells.

3. Interleukins (IL-), cytokines that act as mediators between leukocytes.
4. Interferons (IFN-), cytokines that play a major role in the innate

immunity.

NOTE: Interferones have many types α, β and γ.
IFN-γ: Is the immune interferone, it is antiviral protein, produced from T-
cells and MØ and activates monocytes and MØ.

Antibody mediated Immune Response

(Humeral Mediated Immunity, HMI)

1. The name Humoral came from the old Greek word (humor) mean

fluids.

2. The products of this specific immune response is specific Abs (able to

react with the same Ag started the immune response) and memory B-
cells.

3. HMI starts with B-cell activation:

B-cells have normal Ag receptors on the surface they are natural Igs,
these  Igs  are  able  to  form  Ag-Ab  complex  on  the  surface  of  B-cell.
This  complex  will  be  internalized  inside  B-cell,  then  the  foreign  Ag
will  be  processed  within  B-cell  and  presented  (or  polypeptides  from
it) on the surface of B-cell near MHC class II and now B-cell is APC.

T-helper  (Th)  cells  come  near  the  APC  B-cell  and  by  the  help  of
TCR  and  CD4;  Th  will  interact  and  communicate  with  APC  B-cell
and  Th  cell  will  be  activated  and  release  cytokines  or  lymphokines
(IL-2, IL-4, IL-5 and IFN-γ), these products will induce other B-cells
for dividing, proliferation and differentiation. IgM will be the first Ig
produced then B- cell will switch to make IgG. This response is called
T-dependent Ag immune response. The other type of response is T-
independent  Ag  immune  response,  this  type  of  Ag  stimulates  B-
cells without need for T-helper lymphocytes interfere.

4. After B-cells activation, series of events happen (proliferation, clonal

expansion, division and maturation), ending with Ab and memory B-
cells production. These series of events called B-cell Maturation.

5. During the second exposure to the same Ag that started the first

immune response (perhaps after year from first exposure), the B-
memory cells will remember the Ag and will be activated and divide
into a clone of plasma cells to start the Secondary immune response
(Memory response).

     Th      IL-1         Th (self activator)     HMI         plasma cells         Ab

                                                                                             B cells

Differences between T-dependent Ag and T-independent Ag

No.

T-dependent Ag

T-independent Ag

Strong response

less

need T-cell interaction

Stimulate and activate B-cells directly

protein mainly

Lipids ( LPS) or polysaccharides (capsules)

4 produce IgM then switch to IgG

produce IgM only

Produce B-memory cells

Do not produce B-memory because there is no

cytokines in this response

Interleukins involved in specific immune response:

IL-1 ------Source: (Monocytes, Macrophage, DC, NK, B-cells)
                   Action:
1. T-cells activation by induce IL-2 production.
2. Induce B-cells differentiation and maturation.
3. Induce NK cytotoxicity.
4. Inflammation and fever.
5. MØ activation.

IL-2 ------ Source: (T- helper cells)

              Action:
a. Induce proliferation of activated T and B- cells.
b. Induce Tc and NK cytotoxicity to kill tumor cell and bacteria.
c. Activation of monocytes and macrophage.

Cell mediated Immune Response

(Cellular Mediated Immunity, CMI)

This response occurs against cells, which are called Target cells. During

both HMI and CMI, T-helper cells recognize foreign Ag processed on the
surface of APC. If this Ag was processed and presented near MHC class II,
then Th cells will activate HMI by B- cells activation, but if the presented Ag
on APC was near MHC class I, then Th cells will activate CMI by activation
of Tc, NK and MØ. Th cells able to activate and regulate CMI and HMI by
many cytokines production.

In addition, in both CMI and HMI, when Th cells recognize the foreign

Ag, Th cells will start T-cells activation by series of events (expanding,
clonal proliferation and differentiation), then become mature to give specific
activated T-helper cells in HMI and give specific activated T-helper cells and
memory T-cells in CMI.

Types of CMI response:

1. Defense against Tumor cells or cancer cells. Target cell is the cancer cells.
2. Grafts Rejection: Immune response against foreign cells or tissues that

transplanted from other body even of the same species. Target cell is the
foreign cells.

3. Defense against Mutation affected cells: defense against modified body cells

or mutated cells with different surface Antigens due to radiation or chemical
agents exposure. Target cell is the mutation cell with new Ags.

4. Defense against Intracellular parasite infected cells: Cellular immune

response against infected cells with intracellular parasite (virus, bacteria,
fungi and protozoa), with foreign Ag presented near MHC class I. Target cell
is the infected cell with parasite.

5. Types 4 hypersensitivity (Delayed type of hypersensitivity

by the action of

DTH

a type of cytotoxic T-cells).

Target cell is the same body cells with

immunocomplex precipitated on the surface.

Cells involved in this response:

1. Antigen Presenting Cell (APC): The most common APC in CMI are

dendric cells DC, which act as APC. These cells process small parts of
intracellular parasite body if the DC Dendric cell was infected with it or if it
dies spontaneously and during clearing process in the site of infection.

2. T-cell types:

A. T-helper cells (Th):

1) Have central role in activation of this system by recognizing foreign or

abnormal cells (have abnormal, modified, or intracellular parasite Ag).

2) Responsible for the production of cytokines to induce other cells and

regulates the immune response.
B. Cytotoxic T- cells (Tc): These cells are responsible for killing and lysing
target cells, hence sometimes they are called killer cells.
C. Natural Killer (NK) cells: These cells are responsible for killing and
lysing target cells. These cells are called natural killer because they have non-
specific receptors for Ags.

3. Macrophages: Have role in killing target cells, killing intracellular
parasite inside MØ and production of cytokines (monokines) for other cells
activation and regulation of functions.

Activation of CMI cells:

When T-helper cells recognize foreign Ag on the surface of target cell in

association with (or near) MHC class I. The TCR and CD4

play role in

recognition. Then Th cell will be activated and produce cytokines (especially
IL-2 and IFN- γ). These cytokines will activate Tc CD8

cells, MØ and NK

cells. This activation will increase these cells ability for killing and became
more effecter.

Mode of action for killing target cells:

After T-cytotoxic cells and NK cells activation by Th cells, T-cytotoxic

cells come into close contact with target cell; they will bind to the Ag by
their specific Ag receptors. While NK cells will attach to Ag (on Target
cell surface) by their non-specific receptors for Ag.

T-cytotoxic cells and Nk cells will kill target cells by the following

mechanisms:

a. Direct contact killing: Production of perforin, which is a protein able to

form pores in target cell membrane at the point of contact between Tc cell
and target cell, lead to osmotic lysis of target cell.

b. Indirect killing: By secretion of a toxin protein in the space between the

two cells, which causes fragmentation of target cell nuclear DNA, then the
death of target cell by Apoptosis: the programmed cell death.

c. Antibody-dependent cellular cytotoxicity (ADCC) killing: it is specific

mode of killing occurs when the parasites Ags have ability to induce both
HMI and CMI , target cells will be coated with specific Abs formed after
HMI against some parts of intracellular parasite like virus. These Abs will
bring Tc and NK cells very close to the target cell by acting like a bridge
because Tc and NK have receptors to the constant region of Ab. Then Tc
and NK cells will be activated and kill the target cell by extracellular
products (toxins and enzymes).

This type of CMI occurs when the foreign Ag persist for long time (e.g

Mycobacterium tuberculosis infection is long standing intracellular
infection), also, against some kinds of cancer cells.

       Th       IL-2           CMI                         Tc
                                                                        NK
                                                                         MØ

Primary immune response

It is the first exposure to the Ag resulting of forming specific Abs and
memory B-cells for HMI or T-cells and memory T-cells for CMI, the phases
are:

1. Latent Phase: start after first time exposure to an Immunogen or after

induction, include the followings:

  No Ab level increase (titer).
  Recognizing Ag as foreign after processing the Ag inside APC.
  Cellular proliferation and differentiation.
  Duration  of  this  phase  (period)  is  variable  depending  on  many  factors

(Ag immunogenicity, Ag dose, Ag solubility, Ag route of immunization
or exposure).

2. Logarithmic phase: starts when Ab titer begin to increase (active

biosynthesis of Ab), last for 10-14 days till reach peak.

3. Steady phase: starts when the rates of both formation (synthesis) and

catabolism of are equal, then serum concentration of Ab is constant.

4. Decline phase: starts when the Ab titer starts to fall down due to increase

Ab catabolism rate than synthesis.

Note: during early primary response, IgM class antibodies is predominant
and first rise than IgG appears later.

Secondary immune response

It is the second exposure to the same immunogen that induced the first

immune response (after booster dose of vaccination) may be after weeks,
months, or even years later, includes:

1.  Accelerated or fast appearance of Abs.
2.  Shorter latent period.
3.  Rapid rate of Ab synthesis.
4.  Higher peak titer of Ab.
5.  More presence of memory cells.
6.  Dose of immunogen needed is lower than primary.
7.  Predominant Ab Class is IgG.
8.  Long standing steady phase, whereas Ab titer will stay high longer time.

Negative phase: occur between primary and secondary Immune response

when immunogen second dose is small and/or there is pre-existing antibodies
from the first immune response (primary), then immunogen will be all
consumed in Ag-Ab complex formation and phagocytozed then removed
with no induction to secondary immune response.

(Primary and Secondary immune response)

Time

Primary Im. Re.

Secondary Im. Re.

b C

ncentr

Laten
t

Steady

Decline

Negative phase