Pathology 5
HC 4+5
The Normal Immune Response
The immune system is subdivided into two types:
- innate immunity: mediated by cells and proteins always present which act
immediately in reaction to a pathogen through an inflammatory response. The major
players are epithelial barriers, the complement system, dendritic cells, phagocytic
cells and natural killer cells. Many of these have receptors that may sense the
presence of a pathogen by the substances they release (through dead cells). These
receptors hence recognize pathogen-associated molecular patterns (PAMPs) which
characterize specific microbes. These can range from (bacterial or viral) DNA and
RNA, to LPS to certain residues of bacterial proteins. Dead cells following pathogen
exposure release damage-associated molecular patterns (DAMPs), like DNA. Both
PAMPs and DAMPs are recognized by pattern recognition receptors of immune cells.
The pattern recognition receptors are on the plasma membrane, in endosomes and
in the cytosol, so everywhere a microbe may be detected. Examples include the Toll-
like receptor, which is located on the plasma membrane and in endosomes, where it
looks for PAMPs. If one is detected, inflammation is kick-started, and lymphocytes
are recruited. Another example is the NOD-like receptor, which is in the cytosol and
looks for DAMPs. If one is detected, it activates the inflammasome which activates
IL-1 which induces inflammation. There are more receptor types for each and any
pathogen, like the C-type lectin which recognize fungi.
Whenever the innate system is activated, inflammation follows with all its
characteristics. As does an anti-viral defense arise, involving type I interferons which
stimulate degradation of viral nucleic acids and inhibit viral replication. But more
importantly, it activates the adaptive response.
- adaptive immunity: responds to the presence of a pathogen by generating potent
mechanisms for neutralizing and eliminating the pathogen which work slow but on
the long term. The major players here are the lymphocytes with their products, like
the antibodies. This system confers immunity, of the humoral type – mediated by
antibodies from B-cells – or of the cellular type – mediated by T-cells. The former is
more active in extracellular pathogens on mucosal surfaces or in the blood, whereas
the latter is more oriented towards intracellular pathogens.
Cells of the Immune Response
- Lymphocytes: develop from precursors in lymphoid organs, maturing into two
distinct types later on. The total population can recognize billions of antigens thanks
to the variant DNA of their antigen receptors; antibodies in B-cells and TCRs in T-
cells. Activation of lymphocytes occurs in secondary lymphoid organs, where naïve
cells are turned into effector cells. The two types:
o T-cells: thymus-derived, these help B-cells to produce effective antibodies.
The TCR only recognizes antigens presented on MHC-complexes. T-cells have
distinct other receptors, like CD4 (react to MHC II on APCs) and CD8 (react to
MHC I on APCs).
, Expressing CD4, makes it a T-helper cell, as they secrete cytokines which help
B-cells. When activated, they become a T-helper cell or T-memory cell. Which
particular T-helper cell it becomes, depends on the cytokine environment the
cell resides in. Th1 activates macrophages and stimulates IgG production, Th1
stimulates IgE production, Th17 recruits neutrophils and monocytes. CD4 T-
cell activation requires co-stimulation of CD28.
Expressing CD8, makes it a cytotoxic T-lymphocyte that directly induces
apoptosis of virus-infected cells through granules and cytokines. Another
subset are the T-regulatory cells, which suppress the immune response.
MHC molecules are there to display antigens to CD4 and CD8 T-cells.
They are encoded by HLA genes on chromosome 6. There are two
classes:
MHC I: encoded by HLA-A, HLA-B and HLA-C and to which only
CD8 T-cells can bind. These are present on every nucleated
cell. Loading of intracellular antigens in the ER.
MHC II: encoded by HLA-D and which are only present on
APCs, macrophages and B-cells. Only CD4 T-cells can bind.
Loading o extracellular antigens in an
endosome/phagolysosome.
The HLA-genes which encode the MHC proteins are highly
polymorphic, whereby an infinite number of HLA molecules may exist
– one for every microbe. The MHC proteins themselves may also act
as antigens. There is a sort of microevolution of the HLA genes that
thus give rise to antibodies and TCRs that involves fusion of random
gene segments of the HLA gene, for both the light and heavy chain of
the molecule. Afterwards, there is selection of which receptor is
actually functioning and not autoreactive.
o B-cells: bone-marrow derived, these produce antibodies which mediate
humoral immunity. They recognize antigens by a membrane-bound antibody,
IgM that is connected to signaling molecules (BCR-complex). This can react to
may chemical structures, not only MHC-peptides. The antibody variation is
because of Ig gene rearrangements. B-cells are activated if their CD21
recognize a complement breakdown product deposited on microbes; EBV has
hijacked CD21 to infect it. When activated, B-cells often turn into plasma cells
which secrete large number of antibodies, ranging from one of five types of
immunoglobulins; each isotype has a certain specialty. IgA for mucosal
pathogens, IgE for allergies, IgD for sensitization of basophils, IgG activates
complement.
o Natural Killer cells: innate immune cells from the same progenitor as the
lymphocyte, but which are functional without prior activation and which do
not express highly variable receptors for antigens. They just have activating
(recognize overexpressed molecules and stressed cells) and inhibitory
receptors (recognize self-MHC I).
o Antigen-presenting cells: specialized to capture antigens and display them to
lymphocytes.
Dendritic cells: located under epithelia and in the interstitium, where
pathogens usually enter or reside. They have many pathogen-
