Overview of the Immune Response
The Immune System Seen in the Context of the Response to Infectious Agents/Bacteria Dr. A.Aziz Djamal MSc.DTM&H.SpMK(K)
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
LPS receptor (CD14) Mannose receptor
Scavenger receptos
CD11b/ CD18
TLR
Fc receptors
TLR
Cytokine Secretion TNF and IL-1: inflammation and leukocyte recruitment
IL-12: TH1 differentiation and IFN-g production
Antigen presentation
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 nave 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 IL10 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.
Thank you
Viruses
Replicate within cells Cytopathic - cause cell lysis
Noncytopathic - latent
Response immune against viral infection
Dr. A.Aziz Djamal MSc.DTM&H.SpMK(K)
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
CTL activation requires co-stimulation. If the virally infected cell is not a professional APC, it may be phagocytosed by one
full differentiation of CTLs requires cytokines produced by CD4+ helper cells
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 noncytopathic 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 worlds 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 nave T cells CD45RO is present on memory cells
