Introduction to immunology.
LESSON 5: ELEMENTS OF PATHOLOGY AND IMMUNOPATHOLOGY
Today we will get to know:
• How microbes evade the immune responses
• Immunodeficiencies and hypersensitivity
• Transplantation and tumor immunology
• Immunoprivileged sites
1
Introduction to immunology. Lesson 5
Microbial immunoevasion
Microbes are living organisms, subjected to natural selection. Hence, evolution positively
selects those microorganisms which are able to evade the immune response and
successfully replicate in the host. Extracellular microbes tend to decrease their antigenicity
and the possibility to be recognized and killed by humoral immunity, while intracellular
microbes tend to suppress killing mechanisms of phagocytes.
EXTRACELLULAR MICROBES
MECHANISMS
EXAMPLES
Inhibition of
phagolysosome formation
M. Tuberculosis, L.
Pneumophila
ROS neutralization
(phenolic glycolipids)
M. Leprae
Destruction of phagosome
membrane (Listeriolysin)
L. Monocytogenes
MECHANISMS
EXAMPLES
Antigen variation
N. Gonorrhoeae, E. Coli, S.
Typhimurium
Complement inhibition
(sialic acid)
Many extracellular bacteria
Resistance to phagocytosis
(bacterial capsule)
Pneumococcus
ROS neutralization
Catalase-positive
Staphylococci
INTRACELLULAR MICROBES
2
Introduction to immunology. Lesson 5
Microbial immunoevasion
VIRUSES
MECHANISMS
EXAMPLES
Antigenic variation (antigenic shift)
Ortho- and Paramyxoviridae,
Rhinoviridae, HIV
Inhibition of antigen-MHC complex
formation
Herpes simplex
Removal of MHC-I in the
endoplasmic reticulum
Cytomegalovirus
Production of cytokine/chemokine
receptors’ homologs
Poxviridae (IL-1, IL-18, TNF-a, IFN-g);
Cytomegalovirus (chemokines)
Production of immunosuppressive
cytokines
Epstein-Barr virus (IL-10)
Infection (and destruction) of
immunocompetent cells
HIV
3
Introduction to immunology. Lesson 5
Primary and secondary immunodeficiencies
The frequency of circulating leukocytes is quite stable, and increases can have a physiological
explanation. Conversely, decreases in WBC counts are never physiological. A deficit in WBC
counts (leukopenia) can be caused by primary or secondary immunodeficiencies.
PRIMARY
IMMUNODEFICIENCY
SECONDARY
IMMUNODEFICIENCY
Genetic defects in immune
cells
Malnutrition, tumors, drugs,
viral and bacterial infections
Increased susceptibility to
infections and cancer
4
Introduction to immunology. Lesson 5
Primary immunodeficiencies
Immunodeficiencies can affect cellular and humoral immunity mechanisms (depending on
the cells involved). When both humoral and cellular defenses are involved, together with a
severe defect of T-cells, they are defined as Severe Combined ImmunoDeficiencies (SCID).
Those defects can be in the numbers (developmental problems)..
Abbas et al.
5
Introduction to immunology. Lesson 5
Primary immunodeficiencies
… or in the functions, generally impairing T-cells and phagocytes
Abbas et al.
6
Introduction to immunology. Lesson 5
Primary immunodeficiencies
Abbas et al.
7
Introduction to immunology. Lesson 5
Secondary immunodeficiencies
Secondary (acquired) immunodeficiencies arise from problems other than genetic ones.
Infections, states of malnutrition, chemo-radiotherapy etc. can result in immunodeficiencies.
HIV is the etiological agent of
the acquired immunodeficiency
syndrome (AIDS) in humans. It
efficiently infects macrophages,
dendritic cells and T-cells.
Nevertheless, it is not the
primary infection that is really
detrimental for the host!
Abbas et al.
8
Introduction to immunology. Lesson 5
Secondary immunodeficiencies - AIDS
The primary (acute) infection follows more or less the
normal course of a viral infection. Rising of specific
immunity against HIV (anti-HIV antibodies, anti-HIV
CTLs) keeps the infection under control. But, since
HIV “hides into leukocytes”, it never gets eradicated
and becomes a latent, chronic infection that is
asymptomatic.
When a new infection occurs, HIV-infected leukocytes
activate normally. But, their activation will instead
trigger HIV replication. As viruses are produced, Tcells and APCs are destroyed and the host is unable to
defend from the pathogens.
Abbas et al.
9
Introduction to immunology. Lesson 5
Immune system neoplasms
Transient increase in leukocyte counts has generally a physiological base (leukocytosis). But,
when this increase is stable and in absence of external factors, then immune system
neoplasms must be suspected. In the old classification scheme, three ”levels” were
considered:
•
•
•
The course of proliferation: CHRONIC (slow and indolent) or ACUTE (fast and aggressive)
The site involved: the blood (LEUKEMIA) or the lymph nodes (LYMPHOMAS)
The cell type (franco-american-british [FAB] classification)
In 2001, the WHO has reorganized the classification with much emphasis on the cell type and
the presence of mutations as the basis for proliferation. Also, the category of
myeloproliferative-myelodysplastic (normal vs defective differentiation of myeloid cells) has
been introduced.
10
Introduction to immunology. Lesson 5
Immune system neoplasms – overview of WHO classification
11
Introduction to immunology. Lesson 5
Autoimmune disorders and hypersensitivity
The goal of the immune system is to discriminate self vs non self. To ensure protection of host
cells, self cells must be recognized as “friends” and left unharmed (TOLERANCE). But,
sometimes the immune system turns against self cells. This results in autoimmune disorders.
Also, sometimes the immune response is “too big” and damages the host. This results in
hypersensitivity.
Defects in self-tolerance
Excessive immune reactions
AUTOIMMUNE DISORDERS
HYPERSENSITIVITY
12
Introduction to immunology. Lesson 5
Tolerance and autoimmune disorders and hypersensitivity
Many mechanisms in the body check that T- and B-cells do not react against self markers.
T-cells (in the thymus) and Bcells in the bone marrow are
tested against self antigens
Autoreactive T- and B-cells in
peripheral tissues are under
the control of APCs and Treg
cells
If they react, their
development is stopped and
cells die by apoptosis
If they react in absence of
APCs, they become anergic
(non-responsive) and die by
apoptosis. Treg cells also
suppress them spontaneously
CENTRAL TOLERANCE
PERIPHERAL TOLERANCE
13
Introduction to immunology. Lesson 5
Autoimmune disorders
When tolerance is broken, immune cells can attack and destroy host cells. Generally, this
depends on genetic defects of immune cells, which might be clinically unnoticed until external
factors stimulate the immune response and problems arise.
Autoimmune disorder
Mutations
Mechanisms
Systemic lupus erythematosus
(SLE)
HLA-DR2 and DR3 haplotypes,
complement deficits, FcgRIIB
mutations, IFN-a and TLR
polymorphisms.
Autoreactive B- and T-cells attack
self cells, multi-organ problems,
circulating antibodies can form
immunocomplexes which cause
problems in the kidneys
Rheumatoid arthritis
Excessive production of proinflammatory cytokines (IL-1,
TNF-a, IL-17, IL-6, IFN-g),
excessive RANK production.
Over-activated T-cells stimulate
chronic inflammation of the joints
which results in tissue destruction.
Auto-antibodies are also present.
Multiple sclerosis
HLA-DR2 haplotype, viral proteins
similar to neuronal myelin, CD25
polymorphisms.
Th1 and Th-17 cells specific against
myelin of neurons. Extensive
destruction of nerves leads to
paralysis and death.
14
Introduction to immunology. Lesson 5
Autoimmune disorders
Autoimmune disorder
Mutations
Mechanisms
Type-I diabetes mellitus
HLA-DR3 and DR4 haplotypes, IL2 and CD25 polymorphisms,
Coxsackie B4 virus
Th cells and CTLs recognize antigens
from pancreatic b cells (including
insulin) and destroy them.
Crohn’s disease and ulcerative
colitis
Defects in defensins and NOD2
receptor
determining
overproliferation of the intestinal
flora,
defects in autophagy
genes, excessive Th17 responses
maybe due to defective Tsuppressor cells.
Excessive inflammatory reactions
occurring spontaneously in the
whole span of the intestinal mucosa
(Crohn’s disease) or in colon’s
mucosa
(ulcerative
colitis),
destroying the mucosal tissue.
15
Introduction to immunology. Lesson 5
Hypersensitivity
Hypersensitivity occurs when
uncontrolled,
excessive
reactions are directed against
foreign antigens, resulting in
host damage.
Hypersensitivity disorders are
classified according to the
principal
immunological
mechanism which determines
damages to the host.
16
Abbas et al.
Introduction to immunology. Lesson 5
Hypersensitivity – the example of Type I reactions
Type I hypersensitivity is also called immediate hypersensitivity, allergy or atopy. These
reactions only occur in some individuals in response to foreign antigens for whom the
individuals have been already exposed. Immediate hypersensitivity depends on Th2-induced
release of IgE by B-cells which, in turn, super-activate mast cells with consequent excessive
release of histamine and other vasoactive molecules.
In some individuals, the encounter with
some antigens (like the pollen) strongly
triggers a Th2 response in the mucosae.
Under Th2 influence, B-cells undergo
isotype switch and produce IgE, which bind
to FceRI on mast cells. Mast cells, thus,
acquire the ability to autonomously react
against the allergen.
Mast cells are ready to respond (still
they are not “firing”)
SENSITIZATION STEP
Abbas et al.
17
Introduction to immunology. Lesson 5
Hypersensitivity – the example of Type I reactions
When sensitized individuals encounter
again the allergen, their mast cells will
start producing high amounts of vasoactive
amines, prostanoids, lytic enzymes and
cytokines
Mucosae are affected by vessel
leakage and chronic inflammation
Abbas et al.
18
Introduction to immunology. Lesson 5
Hypersensitivity – the example of Type I reactions
The overall marker of Type I
hypersensitivity is that they are immediate,
meaning that the onset is extremely rapid.
In some cases, they can be lethal if
immunosuppressive drugs are not
administered immediately.
In 1989, Strachan proposed the “hygiene
hypothesis”. After several revisions, the
general idea is that with increasing
hygienic standard, children are no more
exposed to some pathogens, especially
parasitic helminthes. Thus, the Th2
response (developed to face helminthic
infections) becomes useless and “left
uncontrolled”.
This
re-directs
Th2
responses against non-harmful allergens.
Abbas et al.
19
Introduction to immunology. Lesson 5
Hypersensitivity – Type II reactions
Type II are autoimmune reactions determined by autoantibodies. These auto-IgM and autoIgG bind to self antigens of the extracellular matrix or on cell surface, triggering inflammation
and damage of host tissues. Sometimes, antibodies are against bacterial structures which
are very similar to self antigens (which thus get involuntarily involved).
Examples of Type II include Grave’s disease (autoimmune thyroiditis), myasthenia gravis,
insulin-resistant diabetes etc.
20
Introduction to immunology. Lesson 5
Hypersensitivity – Type III reactions
Type III are systemic diseases caused by antibodies bound to antigens (immunocomplexes)
which, being too many, are not efficiently cleared from our body. Thus, immunocomplexes
deposit in the vessels and in the kidney, determining occlusions and chronic inflammation
under the vessels and in organs’ parenchyma.
Examples of Type III include SLE, post-streptococcal glomerulonephritis, serum sickness
(immune reaction against animal antisera for toxins and venoms), etc.
21
Introduction to immunology. Lesson 5
Hypersensitivity – Type IV reactions
Type IV are autoimmune reactions determined by excessive T-cell sensitivity to certain
antigens. Almost all autoimmune reactions which we have already discussed involve, at least
partially, Type IV reactions. A particular case of Type IV reactions is Delayed-Type
Hypersensitivity (DTH), where hyper-sensitive T-cells get “activated” by a first encounter with
the antigen (this is not pathological yet) and super-respond when the antigen is met again (this
is pathological). Hyper-response generally takes 24-48 hours to establish (hence the name
delayed). A practical use of DTH is the tuberculin skin reaction.
22
Introduction to immunology. Lesson 5
The immunological problems of transplantation
Transplantation is the procedure by which cells, tissues and organs are excised from a donor
and integrated in a receiver. If the object of transplant is blood or plasma then is defined as
transfusion.
Transplantation of cells, tissues and
organs within the same individual
AUTOLOGOUS TRANSPLANTATION
Transplantation of cells, tissues and
organs within individuals of the same
species
HETEROLOGOUS TRANSPLANTATION
Syngeneic or Allogeneic
Transplantation of cells, tissues and
organs within individuals of different
species
XENOLOGOUS TRANSPLANTATION
23
Introduction to immunology. Lesson 5
The immunological problems of transplantation
When foreign cells are transplanted into a receiver, non-self (allogeneic) MHC molecules are
recognized by the receiver’s immune system. Activation of receiver’s immune system will lead
to rejection.
T-cells can recognize alloantigens
(non-self MHC molecules) either
on the surface of donor’s APCs or,
more widely, if self-APCs capture
non-self MHC by any type of cell
in the transplant.
Also humoral immunity can play a
big role in transplant recognition
and rejection.
Abbas et al.
24
Introduction to immunology. Lesson 5
The immunological problems of transplantation
When a transplant is recognized as “non self”, rejections occurs. From the hystopathological
point of view, three types of rejection can occur:
HYPERACUTE REJECTION
(minutes/hours after transplantation)
Pre-existing antibodies of the receiver
recognize MHC on donor’s endothelial
cells -> vascular thrombosis
ACUTE REJECTION
(1 week to 3 months after transplantation)
T-cells and B-cells recognize non-self
MHC and start to develop adaptive
immunity against the transplanted
tissue -> CTL kill non-self cells, Ig
induce thrombosis
CHRONIC REJECTION
(many months to years after
transplantation)
Mechanisms are not fully understood,
the clinical manifestation is similar to
atherosclerosis
25
Introduction to immunology. Lesson 5
The immunological problems of transplantation - GVHD
To ensure successful transplantation, compatibility must be checked: this means that donors
and receivers must have haplotypes as close as possible. Also, immunosuppressive drugs
must be given to the receiver to minimize rejection. Nowadays, most of the rejections are due
to chronic reactions. A particular form of rejection is Graft Versus Host Disease (GVHD).
GVHD can happen when sufficient amounts
of donor’s immune cells are present in the
transplanted tissue (as in the case of bone
marrow transplantation). In this case,
donor’s T-cells recognize recipient’s immune
cells (and other cells) by the so-called minor
histocompatibility antigens and attack them.
26
Introduction to immunology. Lesson 5
The immunological problems of transplantation - transfusions and the AB0 system
All RBC in the blood have a
particular carbohydrate (linked to
proteins and lipids) on their
surface called antigen H. In A
individuals, antigen H is modified
by an enzyme and a GalNac
residue is added (antigen A). In B
individuals, a Gal residue is added
instead (antigen B). In 0
individuals,
no
further
modifications of antigen H occur.
From the first year of life, natural
antibodies from B1 cells are
produced against blood antigens
different from the self. If the
wrong blood is transfused,
hemolytic anemia (a form of
hyperacute rejection) occur.
27
Introduction to immunology. Lesson 5
The immunological problems of transplantation – the Rh disease during pregnancy
Fetal blood passes to the
mother through placental
circulation
Mother gets sensitized with
fetal blood during birth
processes
Mother develops anti-Rh antibodies, able to
pass the placenta and lyse fetal RBCs
Anti Rh antibodies are already present during
the 1st pregnancy, but they generally do no
harm to the fetus (IMMUNOPRIVILEGE)
2nd
From the
pregnancy onwards, maternal
memory B-cells will immediately activate and
produce anti-Rh Ig, extremely dangerous for the
fetus.
All RBC also express another
series of antigens on their surface
collectively called Rh blood group
(including the Rh factor). An
individual can either have the Rh
factor or not (Rh+ or Rh-).
A woman who is Rh- must expect
immunological reactions against
a fetus which is Rh+ (paternal
allele). This is called Rh disease, it
generally occurs from the second
pregnancy onwards and ranges to
mild disease to very severe
(lethal for the fetus) conditions.
Intramuscular
injections
of
immunoglobulins
against
maternal
anti-Rh
antibodies
(Rho(D) immune globulin) solve
the problem.
28
Introduction to immunology. Lesson 5
The immune privilege
In animal models of transplantation, reject is never observed if tissues are
transplanted into the brain or in the anterior eye chamber. In 1940, Peter
Medawar defined this as immunological privilege. Currently the
definition of immunoprivileged sites applies to those anatomical
compartments where immune responses are always avoided, because
their result would always be detrimental for the host. Known
immunoprivileged sites are:
Peter Medawar
•
The brain
•
The anterior eye chamber
•
The testicle
•
The fetus
29
Introduction to immunology. Lesson 5
The immune privilege – the example of the fetus
A fetus expresses antigens which are of both maternal and paternal origin. But, those antigens
inherited from the father would be allogeneic for the mother and should be rejected. This
doesn’t happen because of many mechanisms suppressing the immune responses against the
fetus.
Trophoblast cells singularities
Lack of paternal MHC-II in mice;
expression of an invariant HLA (HLA-G)
in humans; lack of costimulatory
molecules in humans and mice.
Active T-cell suppression
Expansion of Th2 clones (which inhibit
pro-inflammatory Th1 clones) in mice,
Expansion of Treg cells and tolerogenic
DCs in both humans and mice.
Immunosuppressive enzymes
Elevated
presence
of
immunosuppressive Indoleamine 2,3dioxygenase (IDO) in humans and mice,
complement inhibitor (Crry) in mice
30
Introduction to immunology. Lesson 5
Cancer as an immunological problem
The immune system plays a big role in clearing transformed cells before they form cancerous
masses. CTLs, Th cells, B-cells and phagocytes are all involved in the anti-cancer defense.
Recognition of tumors is due the adaptive immunity, thanks to the fact that tumors express a
wide variety of antigens.
TUMOR-ASSOCIATED
ANTIGENS (TAS)
Products of mutated
genes
Oncofetal antigens
Oncoviral antigens
Normal proteins,
expressed in anomalous
ways
Tissue differentiation antigens
Altered glycolipidic and
glycoproteic antigens
31
Introduction to immunology. Lesson 5
Cancer as an immunological problem
Tumors evade immune recognition by passive and active mechanisms:
Reduction the antigenicity, either by loss of the antigens or
of the MHC molecules, can make the tumor “invisible” to
the immune system.
Tumors are strong cytokine producers. They can release
big amounts of immunosuppressive IL-10, TGF-b and also
low amounts of pro-inflammatory cytokines. As a result,
immune cells shut-down. But, they can also get EDITED:
the tumor induces changes in immune cells’ gene
expression so that those cells start to release factors
which aid tumor growth and further suppress immune
responses.
32