2.

IMMUNOLOGY AND THE RHEUMATIC DISEASES

GENERAL TERMS

Immune system is a coordinated system of cells, tissues, and soluble molecules

that constitute the body’s defense against invasion by non-self entities, including
infectious, inert agents and tumor cells.
The immune system plays 4 key roles:
1. Recognition: detect infection or harm
2. Effector: contain and eliminate infection
3. Regulation: control activity to avoid damage to the body

4. Memory: remember exposure; react immediately and strongly upon re-
exposure
Tolerance – the normal non-reactivity of the immune system towards harmless
antigens.
Self-non-self discrimination/ harmful-harmless discrimination – is the to
distinguish between harmless components of the body (self) and components
such as commensal bacteria, food, and the potential pathogens (foreign agents).
Autoimmunity – reactivity towards self.
Imunological tolerance – mechanism that keep auto-aggressive pathways in
check.
Immune complexes – antigen binding to antibodies and/or complement either
in circulation or specific tissues.
Molecular mimicry – the antigenically cross-reactivity of an antigen from a
microbe with a self antigen leading to a response from the immunity system
against the microbe and the self antigen, causing disease (eg. Guillain-Barré
syndrome).

INNATE IMMUNITY

Innate immunity is a system that can discriminate between molecules

expressed by the infectious agents and their hosts. Rarely causes direct damage
to the host.
Innate immunity
 Nonspecific
 All the time
 Immediate but general protection
 Activates adaptive immune response
 Does not improve with repeated exposure to pathogen

Components of innate immunity

Macrophage:
 antigen presentation
 activation of bactericidal activity
 phagocytosis
Dendritic cells:
 antigen presentation
 antigen uptake in the periphery
Neutrophil:
 activation of bactericidal activity
 phagocytosis
Myeloid cells (mast cells, basophils, eosinophils):
 release histamine granules and other pro-inflammatory mediators
 kill antibody-coated parasites
Natural Killer cells:
 kill virus-infected cells by releasing lytic granules
Complement:
 soluble proteins that form a complex to destroy microorganism.
Complement components have immunologic activity individually and in
activation cascade leading to a polymer formed by C5, C6, C7, C8, and C9
(the membrane attack complex or MAC) and thus in lysis of target cell
membranes. MAC is involved in host defence against Neisseria infection.
The complement is involved in opsonisation and phagocytosis (C3) and
also increases vascular permeability by a direct stimulation of mast cells
and basophils, releasing histamine. Deficiency of certain components (C1,
 C4, C2) is increased in autoimmune diseases secondary to impaired
clearance of immune complexes. It acts as “anaphylatoxin” and it is
chemotactic (C3a and C5a) for phagocytic neutrophils.
 Three pathways are involved in activation of the complement:
1. Classical – the binding of IgM and IgG to antigen forming immune
complexes activating C1 sequences. Other molecules can activate this
pathway such as: C reactive protein, C4 nephritic factor and serum
amyloid P.
2. Alternative – is characterized by the absence of antibody, being
activated by the lipopolysaccharide on microbial cell surfaces.
3. Lectin – mannan – binding lectin is secreted by the liver and binds to
microbial ligands. These activates the associated proteases and lead to
complement activation by the cleavage of C4.
Cytokines:
 proteins secreted by cells that affects the behavior of nearby cells bearing
appropiate receptors

ADAPTIVE IMMUNITY

Adaptive immunity can cause damage (by recruiting components and

augmenting the functions of innate immunity) and death to the host. This is due
to the fact that the antigens expressed by the pathogens recognised by the
adaptive immunity are not so different from the host’s own molecules. So, the
antigen receptors of the adaptive system cannot be preselected to recognize
only-pathogen expressed antigens.
Adaptive immunity
 Develops in response to an infection
 Protective against specific pathogens
 Leverages components of the innate response
 Develops memory, colide may provide lifelong immunity to reinfection
with the same pathogen

Components of adaptive immunity

T cells:
 according to their antigen specificity (function), T lymphocytes are
divided in 2 major classes CD4+ T cells and CD8+ T cells.
 CD4+ T cells – helper T cells – orchestrate and regulate immune
responses. There are 4 subsets of helper T cells: Th1, Th2, Th 17 and Treg
cells.
 Th1 cells: help for cytotoxic T cell, help for B cells (instruct B cells to
develop into plasma cells, opsonisation of antibodies), help for
macrophage activation
 Th2 cells: help for B cells (barrier antibodies), help for “alternative
macrophage activation”
 Th 17 cells: help for acute inflammation (recruitment of neutrophils)
 Treg cells: suppress the responses of other cells (eg. dendritic cells and/or
other lymphocites)
 CD8+ T cells – cytotoxic T cells – kill cells infected with viruses or other
intracellular pathogens
TCR – T cell receptor – antigen receptor conferring antigen specificity to
the T cell. T cells can’t recognize free soluble antigen. They need the T cell
receptor, only binding to antigen linked to MHC (major histocompatibility
complex) molecule on the surface of the antigen-presenting cell (APC).
 T cell activation requires 2 signals:
1. Implication of the T cell receptor by the antigen/MHC complex
2. Direct interaction between co stimulatory cell surface molecules on
the antigen presenting cell and T cell. Except for CTLA4-/B7 interactions,
all the other co stimulatory pairs are upregullating the T cells. Also, CTLA-
4 has a higher affinity than CD28 to B7. Biologic treatments have been
developed to interfere with these interactions in order to treat
autoimmune diseases.
Lacking one of the signals will lead to apoptosis.
MHC – is a group of genes located on human chromosome 6. 2 Types of
MHC are most encountered:
 Class I MHC – expressed on the surface of all nucleated cells.
 Class II MHC – expressed on antigen presenting cells.
B cells:
 antigen presentation
 produce antibodies in response to antigens
 cytokine secretion
Antibodies:
 bind the antigens to neutralize them or to facilitate destruction of
microorganisms. The antibodies are active participants in immune and
inflammatory responses by: coating and neutralising invading organism,
activating the complement (IgM, IgG) and improving the phagocytosis by
opsonisation.
 The major classes of antibodies are:
G – IgG – fixes the complement. It is found in serum and penetrates the
tissues.
A – IgA – it is involved in host defence at mucosal surfaces (sites of
antigen entry).
M – IgM - fixes the complement. It is the first antibodie as response to the
antigen. It is involved in host defence against blood – borne antigens.
E – IgE – binds to the surface of mast cells and basophils – releasing
histamine when cross-linked. It is involve din host defence against
parasites.
Cytokines:
 proteins secreted by cells that affects the behavior of nearby cells bearing
appropiate receptors. Cytokines regulate many biological processes,
including inflammatory and immune responses. The complex network of
cytokines balances pro-inflammatory and anti-inflammatory effects. An
imbalance between pro and anti-inflammatory cytokines or the
uncontrolled production of cytokines can result in inflammatory disease.
 Pro – inflammatory cytokines: Il-1, TNF, Il-6, IFN, Il-17, Il-18, TGF,
IL-8, GM-CSF and other chemokines.
 Anti – inflammatory cytokines: Il-4, Il-10, monoclonal antibody to TNF,
Il-1RA etc.
Autoimmune diseases can result from activation of adaptive immune responses
against intrinsic (harmless) components of the host itself or against extrinsic
(non-infectious, foreign) agents from the environment. The mechanisms causing
the damage are mediated by:
 antibodies
 large immune complexes
 T cells that abnormally activate macrophages
 cytotoxic T cells
In autoimmune diseases we are dealing with a defective mechanism of tolerance
induction. Others mechanisms are involved as well, such as:
 activation of autoreactive B cells
 secretion of antibodies against the normal components –
autoantibodies. So a cytotoxic effect is induced and the consequence
will be the tissue damage (mediated by the cells that interact with the
autoantibodies). Another way is to block the binding of molecules to their
receptors – the direct inhibition of the normal function of the cells of the
body (eg. myasthenia gravis: the autoantibody blocks the transmission of
the nerve impulses to muscles such leading to progressive paralysis)
 production of immune complexes (IC); the fail of removing the IC can
lead to inflammation preventing normal functioning of certain organs (eg.
kidney damage in systemic lupus erythematosus)
 induction of T cells – mediated responses against self antigens, such
activating the main mediators of damage – the cytotoxic T cells or
macrophages. This response is encountered in insulin-dependent (Type I)
diabetes.
So the previous paragraph outline the four main types of the immune responses
as described by Gell and Coombs. According to them we can classify the immune
related diseases as:
1. Diseases caused by IgE antibodies (Type I: allergic hypersensitivity)
IgE antibodies cause allergy and anaphylaxis by acting through mast
cells. Treatment of less severe reactions includes anti-histamines and
non-steroidal anti-inflammatory drugs.
2. Diseases caused by antibody-dependent modulation of function
(Type II: cytotoxic hypersensitivity)
IgG and IgM can modulate cell function directly, by killing the cell (eg.
haemolytic anaemia) or by blocking or stimulating receptors (eg.
myasthenia gravis).
3. Diseases mediated by immune complexes (Type III: hypersensitivity)
Immune complexes can cause acute inflammation locally or systemically
(eg. SLE or Farmer’s lung).
4. Diseases caused by cell-mediated immune responses (Type IV:
delayed – type hypersensitivity)
Cell – mediated (antibody - independent) immunopathology is usually
due to Th1 – biased responses involving cytotoxic CD8 T cells and/or
activated macrophages (eg. type I diabetes or contact sensitivity)

+ ANTIGEN

Sensitisation

Immediate hypersensitivity:
rapid (acute) inflammation
minutes to hours

Delayed hypersensitivity:
slow onset (chronic)
inflammation over days
 Fig. 2.1 Immediate and delayed – type hypersensitivity reactions (adapted
from MacPherson  Austyn)
Immediate hypersensitivity consists in a very rapidly inflammatory response
(minutes to hours) in a person that has been sensitized to a particular antigen
and is challenged with the same antigen (eg. allergy, Farmer’s lung). It only
occurs in cases with pre-formed antibody.
Delayed hypersensitivity takes 24 to 48 h to occur. The delayed response is
due to time taken to reactivate and expand memory cells, but the response in fact
is accelerated relative to the primary T cell response that occurs during
sensitization.

IMMUNE BASED THERAPIES

Antigen - based therapies

The most common antigen – based therapy is vaccination (eg. stimulate
protective immunity against an infectious disease). Antigens are used to
decrease or alter the immune response. How? By inducing tolerance antigen
unresponsiveness in trigerring suppressive mechanism mediated by regulatory
T (Treg) (eg. treatment of allergies). Antigens can be used to reduce specific
immune responses (desensitization).
Vaccination against cancer and infectious
disease
AG +

AG - Desensitization for allergies

Fig. 2.2 Antigen – based vaccines (adapted from MacPherson  Austyn)

Antibody – based therapies

Antibodies are used to block the activity of certain molecules such as cytokines
or to inhibit or deplete cell populations expressing specific molecules. (eg.
rheumatoid arthritis – anti TNF therapies). The depletion of antibodies that
cause damage (eg. plasmapheresis) is another therapeutically option (eg.
vasculitis).

Passive vaccination against autoimmune and infectious

Ab + diseases

Ab - Therapeutic antibodies for autoimmune diseases, cancer and

transplant

Fig. 2.3 Antibody – based therapies (adapted from MacPherson  Austyn)

Adoptive cell – based therapies
In chronic infections and tumours, antigen-specific lymphocytes or dendritic
cells (DCs) can be transferred to stimulate or modulate ongoing responses. Treg
have been used to suppress transplant rejection and experimentally used for the
treatment of autoimmune diseases.

Immunotherapy against cancer and chronic infectious diseases

T Cells
DC +++

Treg Immunotherapy for autoimmune diseases and prevention of

_______ transplant rejection
_

Fig. 2.4 Cell – based therapies (adapted from MacPherson  Austyn)

Immunosuppresive drugs
They were developed mainly for their anti-inflammatory effects in order to
control autoimmune diseases and to prevent transplant rejection. They can
interfere with key intracellular signalling pathways in cells such as T cells.

Cytokine therapy
The management is relying in the potency and selectivity of cytokines. Initially,
the drugs developed were aiming the cancer and chronic infections such as
hepatitis B and C (eg. type I interferons – IFNs, Il-2). Growth factors can be used
to mobilise cells (eg. neutrophils) from the bone marrow when their number is
reduced.

TAKE HOME MESSAGES

 Two signals are needed for the T cells to be activated.

 Autoimmune diseases are characterized by defective mechanisms of
tolerance induction.
 Four main immune responses are known: type I: allergic hypersensitivity,
type II: cytotoxic hypersensitivity, type III: hypersensitivity, type IV:
delayed – type hypersensitivity.
 Immune based therapies are used in order ameliorate the outcome of
autoimmune diseases and also to suppress their side effects.

References :

1. MacPherson G, Austyn J, Exploring Immunology – Concepts and

Evidence, ed. Wiley Black, 2012, 351: 259-298
2. West S, Rheumatology Secrets second edition, ed. Hanley  Belfus, 2002,
695: 12-22