m_overview_immune_response

Document Sample
m_overview_immune_response Powered By Docstoc
					 Overview of the Immune
        Response
  The Immune System Seen in the
Context of the Response to Infectious
               Agents
Extracellular Bacteria

 Bacteria that replicate outside of host cells

Circulation
Connective tissue
Tissues spaces such as airways and intestinal lumen
Extracellular Bacteria

 Bacteria that replicate outside of host cells

Examples:
Streptococcus pneumoniae
E. coli
Staphylococcus aureus
   Extracellular Bacteria
        Induce Inflammation
        Produce toxins

Endotoxins- products of bacterial cell walls such as LPS
Exotoxins which are actively secreted
     cytotoxic
     interfere with cell function without death
     induce cytokine production
             Extracellular Bacteria


Upon exposure to the infectious agent the innate immune system is
                      activated
             Extracellular Bacteria
Upon exposure to the infectious agent the innate immune system is
                      activated

    Complement can be directly activated
         C1q binds directly to bacteria
    Mannan binding lectin binds the pathogen
             Alternative pathway
Cleavage products of complement function
          as opsonins
C3a , C4a and C5a are anaphylatoxins
Small peptides that causes smooth muscle contraction,
increases vascular permeability and mast cell and
basophil degranulation.

C5a is also a chemoattractant and activator of WBC
Also amplify the inflammatory response by inducing
the synthesis of pro-inflammatory cytokines.
Their receptors are present on many cell types
including leukocytes, mast cells, macrophages,
endothelial cells, astrocytes and microglial cells
Form membrane attack complex: only Gram negative lyse
 Phagocytes have receptors that directly recognize bacteria and
 lead to phagocytosis, activation, microbicidal activity and cytokine
                       secretion
Macrophage Has Many                            Activation
Receptors
                                                 Engulfment
                              Mannose
                              receptor
LPS
receptor
  (CD14)



Scavenger                            CD11b/
receptos                             CD18
                                                TLR
    TLR
                        Fc receptors
                                                     Cytokine Secretion
  TNF and IL-1: inflammation and leukocyte recruitment
                                                         Antigen presentation
       IL-12: TH1 differentiation and IFN-g production
        ADAPTIVE IMMUNITY
Adaptive immunity is triggered when an infection eludes the
innate defense mechanism and generates a threshold of antigen.
It becomes effective only after several days , the time required
to have antigen-specific T and B cells proliferate
and differentiate into effector cells.
The first step is the activation of T
cells in the draining lymphoid organ.
T cells do not become sensitized
in peripheral tissue.

Antigens in tissues are trapped in
draining lymph nodes; antigens in the
blood are taken to the spleen where the
immune response in initiated in the
white pulp.
        Ag uptake by Langerhans' cells




Langerhans' cell leave skin, enter lymphatics and move to
      lymph nodes to become dendritic cells expressing B7   =APCs


                                 B7-positive dendritic cells
                                 stimulate T cells
 Naive T cells continually recirculate through
 the lymphoid organs




If a naive T cell recognizes it antigen, LFA-1
is activated causing the T cell to adhere
strongly to the APC and cease migration
During the initial response of naïve CD4+ T cells to Ag,
differentiation into TH1 or TH2 occurs and has a critical
impact on the outcome of an adaptive immune.

This differentiation is influenced by the cytokines that
are present.
CD4 T cells develop into TH2 cells if
activated in the presence of IL-4,
especially if IL-6 is present . IL-4 and IL-
10 inhibit the differentiation of TH1. IL-4
from the early response may be from
NK1.1+ CD4 cells.




CD4 T cells develop into TH1 cells if
activated in the presence of IL-12 and
IFN- g. INF- g inhibits differentiation of
TH2 cells . IL-12 and INF- g are
produced by macrophages and NK
cells.
Activation of B cells takes place in secondary lymphoid organs




B cells specific for protein Ags cannot be activated until they encounter an activated
helper T cell. B cells migrate through peripheral lymphoid organs like T cells. If
they encounter Ag-specific helper T cells, they are activated to proliferate and
differentiate
Humoral immunity provides the principal
  protective immune response against
             extracellular bacteria
 Humoral immunity provides the principal
   protective immune response against
              extracellular bacteria

Innate:
T independent response against polysaccharide Ags
 Humoral immunity provides the principal
   protective immune response against
              extracellular bacteria

Innate:
T independent response against polysaccharide Ags
Adaptive:
T dependent response against protein Ags
Neutralization of toxins by high affinity IgG andIgA
Opsonization through Fc receptors

Complement activation by IgM and some subclasses
               of IgG
Receptors for Fcs of IgG and for cleavage produces of complement are
    important for the clearance of extracellular bacteria
    Intracellular Bacteria


Eliminated by cell mediated immunity

        Examples:
        Mycobacterium tuberculosis
        Listeria monocytogenes
        Mycobacterium leprae
           Intracellular Bacteria
      Eliminated by cell mediated immunity
Innate immune response consists mainly of phagocytes
                and NK cells

  NK cells activated either directly or by IL-12
              produced by macrophages
 The major protective immune response is
            cell mediated

         Macrophage activation by T cells (IFN- g)

              Lysis of infected cells by CTLs



If IL-12 and IFN-g are produced following the initial exposure to the
pathogens the response will be dominated by inflammatory T cells
Both IL-12 and IFN-g are critical for defense
 against an intracellular bacterial infection
The differential capacity of a pathogen to interact with dendritic cells,
macrophages, NK and NK1.1+ T cells influences the overall balance
of the cytokines present early in the immune response and thus
determines whether TH1 or TH2 cells develop preferentially
Since inflammatory T cell cytokines make more inflammatory cells and
       helper make more helper there tends to be amplification
TH1/TH2 decision can determine the
      outcome of infection
For example, most mice mount a TH1 response
to Leishmania major and clear the infection.
However BALB/c mice mount a TH2 response
and die of disseminated disease.

However, note as pointed out in class Leismania
is a protozoan parasite, not a bacterium.
Nevertheless, the immune issues remain the
same.
        Viruses
  Replicate within cells
Cytopathic - cause cell lysis

  Noncytopathic - latent
   Innate Immunity to Viruses
Inhibition of infection by type 1 IFNs

double stranded RNAs engage Toll-like
   receptors and trigger production
    NK cell-mediated killing
  Recognize stress-induced proteins

Viral infection frequently decreases class I
           MHC expression
     Adaptive Immunity to Viruses
            Antibodies

  block virus binding and entry into cell
                CTLs

eliminate the infection by killing infected cells
     Adaptive Immunity to Viruses
Antibodies- effective during extracellular stage
  neutralizing Abs prevent virus attachment
             and entry

opsonize viral particles and promote clearance
by phagocytes through Fc or C3b receptors
     Adaptive Immunity to Viruses
Antibodies- effective during extracellular stage
   effective in containing the spread of a virus
   during acute infection and in protecting
               against reinfection
 sIgA in mucosal secretions plays an important
 role by blocking viral attachment to mucosal
             epithelial cells
complement activation may promote direct lysis
      of viruses with lipid envelopes
     Adaptive Immunity to Viruses
Antibodies- effective during extracellular stage

While antibodies block viral infection of cells
and spread of viruses from cell to cell, once
the virus enters the cell it is inaccessible to
antibodies and infected cells must be eliminated
by CTLs
         Adaptive Immunity to Viruses
                                     CTLs




CD8+ T cells recognize cytosolic, usually
endogenously synthesized viral Ags in
        association with class I MHC
            Adaptive Immunity to Viruses
                                          CTLs




CTL activation requires co-stimulation.
If the virally infected cell is not a
professional APC, it may be
phagocytosed by one.




   CD8+ T cells recognize cytosolic, usually
   endogenously synthesized viral Ags in
           association with class I MHC
             Adaptive Immunity to Viruses
                                          CTLs



                                                 full differentiation of CTLs requires
                                                 cytokines produced by CD4+ helper
                                                 cells
CTL activation requires co-stimulation.
If the virally infected cell is not a
professional APC, it may be
phagocytosed by one




    CD8+ T cells recognize cytosolic, usually
    endogenously synthesized viral Ags in
            association with class I MHC
Activated CTLs differentiate
into effectors CTLs that can kill any infected
nucleated cell (Ag specific)
      Adaptive Immunity to Viruses

                    CTLs

  In some viral infections, especially with non-
  cytopathic viruses, CTLs may be responsible
              for tissue injury
T-cell deficient mice become chronic carriers of
                  LCMV
   Normal mice develop meningitis because
virus-specific CTLs kill infected meningeal cells
          Immunity to Parasites
 There is a wide range of animal parasites
including protozoa (which are small) and the
     helminths (large worms)
          Immunity to Parasites
Parasites currently account for greater morbidity
and mortality than any other class of infectious
organism, particularly in developing countries

  30% of the world’s population suffers from
            parasitic infection

 Malaria alone affects more than 100 million
     people, killing 1 million annually
          Innate Immunity to Parasites


Principal innate response is phagocytosis; however
many parasites are resistant to phagocytosis and
may even replicate within macrophages
           Innate Immunity to Parasites
Phagocytes attack helminthic parasites and secrete
microbicidal substances to kill organisms too large
          to be phagocytosed

Many helminths have thick teguments that make
them resistant to cytocidal mechanisms of
neutrophils and macrophages
Although some helminths activate the alternative
pathway of complement, many appear to have
developed resistance to complement-mediated lysis
       Adaptive Immunity to Parasites
Different parasites elicit distinct adaptive immune
responses

Pathogenic protozoa have evolved to live within
host cells.
The principal defense mechanism against
protozoa that survive within macrophages
is cell mediated immunity, particularly macrophage
activation by TH1-derived cytokines
Mice resistant to Leishmania produce large amounts of IFN-g.
BALB/c, which are susceptible, respond to Leishmania infection
with the production of IL-4.
Immunity to trypanosomes is mediated by antibodies.

Trypanosomes have developed the ability to change the expression
of their surface antigen, thereby evading the immune response
Protozoa such as malaria that replicate
within host cells and lyse these cells
stimulate specific antibody and CTL
              responses
The defense against many helminthic infections is mediated by the
activation of TH2 cells which results in the production of IL-4 and
IL-5 leading to IgE production and eosinophil activation
Eosinophils attached through Fce receptors are activated to secrete
      granule enzymes that destroy the parasites
  Protective Immunity
  Immunity to re-infection

Immune reactants such as Ab

   Armed effector T cells
      Protective Immunity
Immunity to polio requires pre-existing Ab to
  prevent neuron infection

 Specific IgA on epithelial surfaces can
neutralize a virus before it enters the body
Concentration (gml-1)
                                           Immunologic Memory
                                                             IgG




                                                            IgM
                         Affinity (M -1)




                                                             IgG



                                                            IgM

                                             Immunization
Are slightly increased in number relative to what is seen before
Immunization

Express markers characteristic of activated cells such as CD44

       The isoform of CD45 that is expressed changes
              CD45RA is on naïve T cells
              CD45RO is present on memory cells

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:1
posted:8/26/2012
language:English
pages:61