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Basic Concepts in Immunology

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  Basic Concepts In Immunology
This chapter introduces the cellular and molecular players of
the immune system (based mainly on our understanding of the
immune systems of mice and humans)
    • Components of the immune system (cells, organs, molecules)
    • Principles of innate and adaptive immunity
    • Recognition and effector mechanism

This chapter is a summary of immunology. It provides the
framework upon which the remainder of the course is built.
If you do not have a solid understanding of this chapter, you will
have significant difficulty following the subsequent chapters.
In 1796 Edward Jenner infects a boy with cow pox
to protect against small pox (before germ theory of
disease)
vacca=cow
Mid-late 1800s
Robert Koch showed that microorganism cause infectious
diseases and that different organisms cause different
diseases

Louis Pasteur first showed how vaccines could be made to
a variety of bacterial and viral pathogens.
    4 broad categories of pathogens (disease causing organisms): viruses,
    bacteria, fungi, and “parasites” (eukaryotes including protozoans and
    worms)

Emil Von Behring and Shibasaburo Kitasato found, in the
serum of immune individuals, a substance that bound to the
bacteria to which they were immune. Called the substance
ANTIBODY
Adaptive Immunity:
Specific Immune Response (e.g., antibody) against a particular
microorganism is an adaptive immune response. That is, it
occurs during one’s lifetime as an adaptation to the presence of
that particular organism. (usually, specific means the ability to
distinguish one organism from another)
An adaptive immune response might provide lifelong protective
immunity to a given pathogen.
These are central principles of adaptive immunity
Specific immunity can be induced by a variety of substances.
Things that are targets of adaptive immunity are called
ANTIGENS*
Antigen-specific responses are mediated by lymphocytes

 *Things that induce an adaptive immune response are immunogens
Innate immunity is the immunity that is immediately available
without having to adapt to the specific pathogen that is present.
It is not specific to a particular organism such that identical
responses can protect against several organisms. Innate
immunity is germline encode (evolved on an evolutionary time
scale).

Innate immunity is mediated by phagocytes (cell that ingest
bacteria or other particulate matter) such as macrophages and
neutrophils. It is also mediated by chemical compounds and
physical barriers that will be described later.
Together, innate and adaptive immunity prevent most
infectious diseases (no symptoms from exposure to the
microorganisms) or cure infections



This course mostly deals with adaptive immunity. However,
you must understand innate immunity and how adaptive
immunity works together with innate immunity to prevent or
cure infections.
 Cellular components of the immune system


Adaptive immunity is        Innate immunity
mediated primarily by       largely involves
lymphocytes                 granulocytes and
                            macrophages


              lymphocytes

  .. . .. .
  . . …

 natural
  killer
(NK) cell



                                               Figure 1-3 (5th ed;
                                               modified)
Most cellular components of the immune system
  originate in the bone marrow and circulate
  through
blood
tissues
lymphoid organs
lymphatic system [lymphoid organs and specialized
   vessels (lymphatics) used primarily by the
   immune system]
                                       progenitors


                                         Innate immunity
                                      largely involves
                                        granulocytes and
                                        macrophages (although
                                        macrophages can
                                        influence adaptive
                                 immunity)


                                        Adaptive immunity is
                                       mediated primarily by B
                                and T lymphocytes




                          other cells are regulatory or
                              involved with both adaptive and
                              innate immunity
Cells of the myeloid
       lineage




                       or PMN
B cell

T Cell cells and T
    B
    cells look alike
    but have
    important
    differences

T cell
 B Cell

 Mature lymphocytes
 have antigen-specific
 receptors
B cells have antibody on their surface as an antigen receptor
Plasma cells (effector B cells) secrete antibody

 antibody (ab) = immunoglobulin (Ig)
 immunoglobulin = antibody
 B cell antigen receptor (BCR) =
 B cell receptor =
 B cell surface antibody =
 Membrane immunoglobulin (mIg) (a transmembrane protein)

Soluble antibody is sIg (not BCR because it is not on a B cell)
Generally, if one does not specify BCR, they probably mean soluble antibody
All BCRs are antibodies but not all antibodies are BCRs
      T lymphocytes
            Cytotoxic T lymphocyte (CTL)
            kill infected host cells
               (a.k.a.* cytotoxic T cells or killer T cell)
            TH1 cells activate macrophages
              (a.k.a. inflammatory T cells)

            TH2 cells activate B cells
               (a.k.a. T helpers or helper T cells)
Although T cells are key players in adaptive immunity and
have antigen-specific receptors, T cell do not secrete their
antigen-specific receptor and do not directly kill or damage
pathogens. In fact, T cell’s antigen receptor does not bind to
pathogenic organisms (so, how can they have antigen-
specific receptors that protect against specific pathogens?).
   *a.k.a.; also known as
The T cell antigen-binding molecule is called the T cell
antigen receptor or the T Cell Receptor (TCR). It is found
only on T cells (no soluble form)


Antibodies bind native antigens (antigens as they are found
in nature). The TCR does not bind native antigen. The
TCR binds antigens taken-up, processed* and presented to
it on the surface of other cells (always cell-cell contact
between the T lymphocyte and the host antigen presenting
cell)

*processing is the degradation of the antigen; details of this process should become clear
later
  TCR  BCR
  TCR  Ig

Ig=Ab
All BCRs are Igs but not all Igs are BCRs
Natural killer (NK) cells are
lymphocytes that can kill host cells
(e.g., virus infected cells) without
making their own antigen-specific
receptor (do not require ab or TCR
and are part of innate immunity)



Once referred to as large grauular
lymphocytes or LGLs
The distribution of lymphoid tissues   Lymphoid organs
                                       contain lymphocytes
                                       and non-lymphoid
                                       cells such as
                                       macrophages and
                                       dendritic cells (and
                                       epithelial cells)
                                       Lymphoid organs are
                                       important for the
                                       generation and
                                       maturation of
                                       lymphocytes, the
                                       initiation of immune
                                       responses and the
                                       perpetuation of
                                       immune responses
           Central (primary)
 Central
lymphoid   lymphoid organs are
           the sites for generation
  organs
           and early maturation of
           lymphocytes (B and T
           cells)
           T cells mature in the
           thymus (T for thymus)

           B cells mature in the
           bone marrow
           B for bursa of Fabricius
           (a lymphoid organ in
           birds)
           [After Hieronymus Fabricius (1537-1619), Italian
           anatomist]
            Peripheral
            lymphoid organs

           and other stuff

                                      Peripheral lymphoid

                                         organs
                                    1. trap antigens
                  
                                    2. are the sites for
                                        initiation of most
                                        immune response
                  Blood
               circulation           3. provide signals for
                             Heart
                                        recirculation of
                                        lymphocytes


               capillaries           *other stuff
                                      (not peripheral
                                     lymphoid organs)
The flow of lymph through lymphatic vessels
To thoracic
duct
Gut associated lymphoid tissue (GALT)(tonsils,
adenoids, Peyer’s patches, appendix)
Immature B and T cells mature in the central lymphoid organs
(bone marrow for B cells and thymus for T cells). Then, they
circulate in the blood and through the peripheral lymphoid organs;
the circulating lymphocytes are mature naïve lymphocytes. As
long as they have not encountered the specific antigen that binds
their antigen receptors (BCR or TCR), they are referred to as naïve.
Note: by this logic, they must have made their antigen receptor in the absence of antigen.

When mature naïve lymphocytes encounter antigen (bind antigen in
 their antigen receptor), they
1. Stick in the lymph nodes (or other peripheral lymphoid
   organ)(they stop circulating, i.e., altered trafficking)
2. Proliferate (divide)
3. Differentiate into effector cells (or memory cells):
   B cell effectors are plasma cells;
   T cells effectors are effector CTLs, effector TH1 or effector TH2
Steps 2 and 3 are lymphocyte activation
Antigens in periphery may be taken up by macrophages and
dendritic cells and may be transported to the peripheral lymphoid
organs via the lymphatics (afferent lymph)
Antigens can also enter the lymphatics (afferent lymph) and move to
the draining lymphoid organ where they can be taken-up by
macrophages and dendritic cells
In the lymphoid organ, antigens can bind to the BCR of antigen-
specific B cells and/or be presented (shown) by dendritic cells where
they can bind to the TCR of antigen-specific T cell. This results in B
or T lymphocyte activation (proliferation and differentiation)
B cell activation requires help from activated T cells
Effector lymphocytes may stay in the lymphoid organ (TH2 and some
plasma cells) or leave via the efferent lymph to go to the site of
infection (plasma cell and TH1) or, for plasma cells, go to the bone
marrow to make antibody (altered trafficking)
      Principles of innate and adaptive immunity
                     (text page 12)

Innate immunity (e.g., macrophages, neutrophils, certain
molecules) is the first line of defense. It is fast (usually
good-to-go) and usually effective.
Adaptive immunity (mediated by B and T cells) can be
slow to respond (several days). It is highly effective when
the innate immune system cannot fully deal with the
threat.
             Bacteria trigger an inflammatory response




                  macrophage                                                      (1st)


bacteria
                                RBC

                               neutrophil

                               lymphocyte
                               monocyte
                                                           Monocyte       macrophage (2nd)
                      Endothelial cells
 Macrophages phagocytize                cytokines and chemokines can cause an
 bacteria and release                   inflammatory response
 cytokines and/or
 chemokines (hormones
 of the immune system)        Complement can also initiate inflammation
                              and act as an opsonin
The Cardinal Signs of Inflammation

     Redness    Caused by vasodilatation   Ultimately
     Swelling   and movement of cells      controlled by
                and/or fluid into the      endothelial
     Heat       interstitial spaces        cells
     Pain
                Caused by cytokines and
                other chemical mediators
          Adaptive immune response begins with the uptake of
                 antigens by immature dendritic cells                         Figure 1.13




                                                                *



                                                          mature dendritic cells are
   Macropinocytosis by dendritic cells
                                                          (professional) antigen
   (receptor-mediated and random)
                                                          presenting cells (APC)
Dendritic cells take up antigen to present to T cell. Dendritic cells do not constitute an
effective mechanism against pathogens as do macrophages and neutrophils.
*High endothelial venule (HEV)(i.e., specialized post capillary blood vessel)
Innate immunity relies on receptors that recognize common
bacterial (and other) molecules. The information on the
structure of these receptors is germline encode. Thus, the
number of different receptors is limited (<20 known) and
these receptors cannot evolve as fast as most pathogens.
Pathogens sometimes modify or mask molecule recognized
by the germline encoded receptors or inactivate the cells of
innate immunity. Virus are generally not recognized by
these receptors.
Dendritic cells can pick-up stuff randomly (e.g., viruses) and
present it to T cells (via a process that “unmasks” hidden
antigens: antigen processing)
Lymphocytes have overcome the problem of a limited
number of germline encoded receptors. Lymphocytes can
somatically create 109 to 1016 different antigen receptors (ab
or TCR).
However, you cannot simultaneously maintain 109-1016
different antibodies at functional levels.

This problem is solved by clonal selection
(perhaps the most important concept in immunology)




As an aside, for now, human have less than 25,000 genes. So, how can you make
1,000,000,000+ different antibodies and TCRs
                                       Bone marrow
                                       for B cells
Clonal                                 Thymus for T
                                       cells
Selection
                                    Antigen binding in the
The somatic                         bone marrow leads to B
evolution of              XX   XX   cell deletion (death). Strong
B and T cells                       antigen binding in the
                                    thymus leads to T cell
populations                         deletion



                                       periphery

       clonal expansion
                                    Antigen binding in the
                                    periphery can lead to
                                    activation (other signals
                                    are required, too)
1*

         Mature lymphocytes
3


4


         Immature lymphocytes
2

     The self/nonself discrimination (or tolerance) is “learned” in the soma

*Numbers represent the 4 panels in the previous slide
Clonal selection solves the problem of a repertoire that is too
large to be fully functional all the times.
Clonal selection is the basis of immunological memory (to
be dealt with later).
Clonal selection (deletion) deals with the problem of a
“complete” repertoire (enough specificities in the
individual to recognize everything) having the capacity to
recognize and destroy self.
Immunoglobulins (i.e., antibodies)

                              Antigen binding site




                            Constant regions
                            Variable regions
H
L




        Immunoglobulin and TCR
        variable region genes are
        made from gene segments
        by gene rearrangements.
        This contributes to the
        building of the antigen-
        recognition repertoire of B
        and T cells. Other
        mechanisms also contribute
    H
        to the generation of
    L
        diversity in the antigen-
        binding receptors
  The generation of diversity
  (i.e., the generation of a diverse antigen-binding
  repertoire for Ab and TCRs)
1. Gene rearrangements (combinatorial diversity)
2. Junctional diversity
3. Light chain-heavy chain pairing (L-H pairing)
      (combinatorial diversity)
4. For B cells only, somatic hypermutation
What is achieved by gene rearrangements and other
mechanisms for the generation of diversity?

1. Relatively few gene segments can combine to make
millions of different receptors (large repertoire) (i.e., 100s
of gene segments can be assembled to make millions of
variable regions for Igs and TCRs).
2. Different cells can have different antigen receptors.
3. Somatic progeny of a cell with a gene rearrangement
will inherit the gene rearrangement and thus inherit the
antigen recognition specificity of the parent cell.
Clonal selection solves the problem of a repertoire that is too
large to be fully functional all the time. It is also the basis of
immunological memory and tolerance (self/non-self
discrimination).
The down-side is that it is slower to respond than innate
immunity because lymphocytes must divide to produce enough
cells to mount an effective response and differentiate into
effector cells. Antigen-activated, dividing lymphocytes are
lymphoblasts.
Lymphoblasts divide every 6-8-12 hours. Eventually (usually 4-
7 days), lymphoblasts will differentiate into effectors and
memory cells.
              B cells  plasma cells
               T cells  active CTL (killers), or TH cells
               also B and T cells  memory B and T cells
Effector cells have limited life-spans (maybe 7 days) and
clonal expansion will continue only in the presence of
antigen.
Therefore, when antigen is gone
1. Activation (division and differentiation) ends.
2. Effectors die off and are not replaced, or lose effector
function
3. The response subsides

Adaptive immune responses are limited by the
concentration of antigens. As long as antigen is
present, the response continues. When antigen is
gone, the response subsides; however, memory cells
remain.
Primary response (primary immunization) is relatively:
       slow (4-7days)
       small amount of antibody (low concentration of antibody)
       low affinity antibody
       IgM first, IgG second (equal amounts of IgM and IgG)


Secondary response (secondary immunization or booster
immunization) is relatively:
      fast (2-4 day)
      large amounts of antibody
      high affinity antibody
      mostly IgG
Often, a secondary (memory) response is so fast and effective in
removing antigens (pathogens), there are few or no symptoms
detected by the infected individual (protective immunity).

Secondary responses are the reason we do not get certain
infectious diseases more than once.
Secondary responses also explain why vaccinations work. For
vaccinations, instead of immunizing with something that makes
you sick, a vaccine contains antigens that are expressed on the
pathogen but the vaccine is usually not pathogenic (e.g., live
organism that is not pathogenic, dead organism, purified protein,
others).
              The two signal model for lymphocyte activation
                       (antigen alone is insufficient)



                                                             Here, signal 2 is TCR-
                                                             mediated, antigen specific
                      Antigen     TCR                        recognition; not shown.
                                                             (see similar slide later)
                                         TH2 activation,
                                          for example
                                                                                              B cell
                                                                                            activation,
                                                                                           for example




                                                                                                  Memory B cell
(Mature dendritic cell)   (Mature naive T cell)      (Armed effector T cell)

 Proliferation and differentiation of               Proliferation and differentiation of
 the T cell to effector function                    the B cell to effector function

                                    Signal 1 comes from recognition of antigen
                                    Signal 2 comes from another (activated) cells
                           Professional antigen presenting cells
                      Professional antigen presenting cells (APC)


Usually to activate                                                 Usually the targets
certain T cells                                                     of certain armed
                                                                    effector T cells
Antigen recognitions and effector mechanisms of
              adaptive immunity
                                          Protection
                                          is generally
                                          provided by

                                          Antibody


                                          T cells

                                          T cells (antibody
                                          when extracellular)

                                          Antibody
Antibody-mediated effector mechanisms
                                        Humoral immunity:
                                        the immunity mediated by
                                        antibodies




                                        Different Ig isotypes
                                        (classes) provide for
                                        different functions.
                macrophage
                                        Also, different isotypes have
                                        different distributions
                                        [blood, secretions (mucus,
                                        saliva, tears, milk), cross the
                                        placenta].
TH2 cells control (activate) B cells (Humoral Immunity).


Cell-mediated Immunity (CMI)
Other T cells (TH1 and CTL) deal with intracellular (inside
a cell) pathogens. Intracellular pathogens (some bacteria
and all viruses) are found in vesicles or in the cytoplasm.
Vesicular and cytoplasmic pathogens are usually dealt with
differently.
Generally, TH1 for vesicular antigens and CTLs for
cytoplasmic antigens
 Effector CTL




CTLs have CD8 on
their surface and are
sometimes referred to
as CD8+ T cells.
             Effector TH1


            TH1 T cells are
            sometimes
            referred to as
            inflammatory T
cytokines   cells


            TH1 and TH2 T
            cells have CD4 on
            their surface and
            are sometimes
            referred to as
            CD4+ T cells.
    The two signal model for lymphocyte activation
             (antigen alone is insufficient)



                                                                        Clonal selection
                          Clonal selection         Effector TH2         for B cell
                          for TH2 cell

                                          activation                                               B cell
                                                            T H2                                 activation,
                                                                                                for example




                                                                                                       Memory B cell
 (Mature dendritic cell) (Mature naive TH2 cell)       (Armed effector TH2 cell)

Activation (proliferation and                      Activation (proliferation and
differentiation) of the T cell to effector         differentiation) of the B cell to effector
function                                           function
                                              TH2 cells are sometimes
                                              referred to as helper T cells
CTL deal with antigens in the cytoplasm by killing the cells
  that present the antigen.
TH1 deals mostly with antigen in macrophage that have
  phagocytized the antigens so that the antigens are in
  vesicles. TH1 cells activate these macrophages. Activated
  macrophages are more aggressive in killing phagocytized
  material and they release toxic compounds into the local
  environment.
TH2 deals with antigens that were bound to a B cell’s BCRs
  (extracellular antigens) and internalized (into vesicles).
  They activate B cells for antibody secretion.

For antigens to be recognized by T cells, the antigen must
get into a cell, be processed into peptides and presented in
association with MHC proteins (see next slide)
T cells recognize foreign antigen as peptides bound to proteins
encoded in the major histocompatibility complex (MHC)




               Outside of
                the cell



                Inside of
                 the cell                 MHC is polymorphic
                                          (lots of allelic variants)
CTL deal with antigens in the cytoplasm
TH1 deals mostly with antigen in macrophage vesicles
TH2 deals with antigens that were bound to BCRs and
interalized (in vesicles) the by B cells

 For antigens to be recognized by CTLs, they must be
presented in association with MHC class I (i.e.,
cytoplasmic antigens are associated with MHC class I).

 For antigens to be recognized by TH1 or TH2, they must
be presented in association with MHC class II (i.e.,
vesicular antigens are associated with MHC class II).
Antibodies bind native antigens (antigens in the configuration
they have in nature)
T cells bind to the combination of foreign peptide* and MHC.
T cells cannot bind foreign peptide alone nor MHC alone.


             T cell       T cell     T cell
                                                           peptide
    TCR

                                                           MHC



    TCR                                           *derived from foreign
  binding?   Yes          No          No          protein by antigen-
                                                  processing
                                                MHC class I gets
                                 peptides
                                                its peptides from
                                                the cytoplasm (i.e.,
                                                proteins
                                     Protein    synthesized in the
                                     ribosome   cell)
                                     mRNA



Some cytoplasmic
proteins are chopped
into peptides (frame 2)                         MHC class I
                           peptide
and transported into the
ER (frame 3)
                                                              peptide

All nucleated cells are
doing this all the time
 MHC class II gets its peptides from the proteins transported
 into the cellular vesicles from the outside (i.e., proteins
 synthesized outside of the cell)
                                                               = peptide




                                                        MHC class II
macrophage




                                                        This peptide was derived
                                                        from this antigen.
                                                        Thus, for B cells there is
                                                        a relationship between
                                                        the specificity of the B
                                                        cell’s BCR and the
   B cell                                               peptide presented by
                                                        MHC class II
For antigens to be recognized by CTLs, they must be
presented in association with MHC class I.

For antigens to be recognized by TH1 or TH2, they
must be presented in association with MHC class II.


Therefore, CTLs are interested in proteins synthesized
inside a cell whereas TH1 and TH2 are interested in
proteins that were synthesized outside of a cell but were
brought into the cell in vesicles

   Why is that important to the immune system?
CD8 is a transmembrane
protein found on CTLs
and is a co-receptor for
MHC I
Inflammatory T cell
                      CD4                               (Signal 2)
                                                         CD4




 cytokines



CD4 is a transmembrane protein found on TH1 and TH2 cells and
is a co-receptor (along with the TCR) for MHC II
Subacute sclerosing
panencephilitis
(SSPE)

				
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Description: introduces the cellular and molecular players of the immune system (based mainly on our understanding of the immune system of mice and humans