Autoimmune Diseases

Dana M. Tofiq, MB ChB, FAAAAI

Assistant Professor – Department of Medical
Education
Learning Objectives

By the end of the session, students should be able to:

1. Define autoimmunity: Understand the concept of autoimmunity and

differentiate it from normal immune responses. Identify key features that
characterize autoimmune diseases.

2. Describe the mechanisms of autoimmunity: Explain the breakdown of self-

tolerance and the mechanisms that lead to the recognition of self-antigens as
foreign. Understand the role of genetic and environmental factors in the
development of autoimmune diseases.

3. Explore common autoimmune diseases: Discuss specific examples of

autoimmune diseases. Identify the target tissues or organs affected in each
autoimmune condition.
4. Examine immunological basis: Explore the immunological basis of
autoimmune diseases, including the involvement of autoantibodies and
autoreactive T cells. Understand the role of cytokines and inflammatory
mediators in autoimmune responses.

5. Describe the laboratory diagnostic approaches used in identifying

autoimmune diseases.
Autoimmune Disease

Autoimmunity is when the immune response turns against

self, i.e. recognizes ‘self’ antigens. The vast array of possible
TCRs and antibodies that can be generated by the host make
it highly probable that at least a small proportion can
recognize self (i.e. are autoreactive). Moreover, a degree of
autoreactivity is physiological: the TCR is designed to
interact both with the peptide epitope in the HLA molecule
binding groove and with the HLA molecule itself.
The critical event in the development of autoimmune disease is
when T and B lymphocytes bearing these receptors for ‘self’
become activated: this leads to loss of immunological tolerance.

The major checkpoints that the immune system has in place to

prevent this are:

1. Removal of TCRs with very strong affinity for ‘self’ in the

thymus.

2. The presence of naturally arising regulatory T lymphocytes

(Tregs).

3. The requirement for a danger signal to license dendritic cells to

activate CD4 T lymphocytes.
Failure of immune tolerance checkpoint 1: thymic
education

During thymic education, TCRs with a dangerously high affinity

for self are deleted. It has become apparent that this process relies
on the thymic expression of self antigens. Situations that
compromise the expression of a self protein would be expected to
favour the development of autoimmunity. Indeed, in a rare group of
patients who develop multiple autoimmune disorders affecting the
adrenal and parathyroid glands (autoimmune polyglandular
syndrome type 1), there is a defect in the autoimmune regulator
(AIRE) gene, which controls thymic expression of a host of self
genes. When the gene malfunctions, there is reduced expression of
self proteins in the thymus and autoimmune disease is a
consequence.
Failure of immune tolerance checkpoint 2: regulatory T lymphocytes

An example of Treg failure is the defect in the gene encoding FoxP3, a

critical transcription factor in Tregs, which leads to IPEX syndrome
(Immunodysregulation polyendocrinopathy enteropathy X-linked
syndrome). IPEX syndrome is very rare but it serves to indicate how Treg
defects can lead to autoimmune disease.

Laboratory studies in this area are revealing subtle Treg defects in several
autoimmune diseases (e.g. type 1 diabetes, multiple sclerosis, rheumatoid
arthritis). The role of FoxP3 in regulating peripheral immune responses
highlights the control of immune expansion and regulation of
immunological space. Another component of this process is the
contraction of an immune response once the infection has been dealt with.
Autoimmune lymphoproliferative syndrome (ALPS) is a
disorder with defects in either Fas, its ligand (FasL) or the
associated intracellular signaling pathway. Individuals
develop multiple cytopenias, organ-specific autoimmunity,
and lymphoproliferation that may mimic lymphoma. The
common problem is the inability to switch off activated T
cells. Treatment is with hematopoietic stem cell
transplantation (HSCT) if the disorder is severe.

Many patients with multiple cytopenias, including Evans

syndrome (autoimmune thrombocytopenia and hemolytic
anemia), are revealed to have ALPS defects when
appropriately tested.
Failure of immune tolerance checkpoint 3: CD4 T
lymphocyte activation against an autoantigen (or its
mimic)

For an autoimmune disease to develop, there must be presentation of

autoantigens to a naive, potentially autoreactive CD4 T lymphocyte by
activated conventional dendritic cells (cDCs). Several theories exist to
explain this:

1. Tissue damage due to infection leads to both the release of hidden self
antigens and the provision of sufficient danger signals to activate cDCs,
which in turn activate autoreactive CD4 T lymphocytes, as well as
pathogen-specific ones. This is often termed bystander activation.

2. A pathogen mimics a self antigen. In the process of mounting an

entirely appropriate immune response against the pathogen, T or B
lymphocytes are generated that also have the capacity to recognize self.
This is termed molecular mimicry.
3. Post-translational modification. Self proteins and peptides
are modified in such a way that they appear foreign. A good
example is an antibody found in patients with rheumatoid
arthritis, which recognizes citrulline-modified forms of self
peptides.

It is unlikely that, for the common autoimmune diseases,

there is a single tolerance checkpoint explanation. Rather, it is
likely that multiple subtle defects, at various checkpoints, are
at play.
Some Autoimmune Diseases and their Autoantigens
Mechanisms of Tissue Damage in
Autoimmune Disease
1. Tissue damage via chronic inflammation

In a number of autoimmune diseases (e.g. type 1 diabetes,

multiple sclerosis), autoreactive T lymphocytes are likely to
be the main drivers of disease and tissue damage. Th1 cells,
CTLs and Th17 cells induce chronic inflammation and release
cytokines that recruit other effector cells (macrophages) or are
directly toxic (e.g. insulin-producing β cells are susceptible to
the combined effects of IL-1β, IFN-γ and IL-17 in type 1
diabetes).
IgG4-related disease

IgG4-related disease is a fibro-inflammatory condition with the

formation of swellings at multiple sites infiltrated with IgG4-
producing plasma cells and a tendency to high circulating levels of
IgG4.
Unlike many autoimmune disorders, IgG4-related disease is driven
by Th2 T cells in association with high numbers of FoxP3+ T cells.

The first recognized form of this disorder was autoimmune

pancreatitis, but lesions in the biliary tree, salivary glands,
periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta,
breast, prostate, thyroid, pericardium and skin are recognized.
The current hypothesis is that Th2 cells drive the activation of
macrophages and myofibroblasts, leading to fibrosis and IgG4
plasma cell proliferation.
IgG4-related disease
2. Tissue Damage via Autoantibodies

Examples of damage through direct binding to a target cell or

structure, with recruitment of complement and other
destructive processes, include:

• myasthenia gravis (autoantibodies against the acetylcholine

receptor cause damage to the neuromuscular junction).

• autoimmune hemolytic anemia (autoantibody targets red

blood cell autoantigens, leading to lysis).

• Goodpasture’s syndrome (anti-glomerular basement

membrane autoantibodies damage glomerular integrity).
Autoantibodies can also bind their antigen in the circulation to
form immune complexes. When these are deposited in the tissues,
complement- and cell-mediated immune reactions are initiated.
Immune complexes preferentially deposit in sites such as the
kidney glomerulus, leading to chronic kidney disease. This is a
feature of systemic lupus erythematosus, in which the autoantigen
within the immune complexes is DNA.

Autoantibody binding may act by binding to surface receptors.

In Graves’ thyroiditis, for example, the anti-thyroid stimulating
hormone receptor antibody stimulates follicular cells to produce
thyroid hormones, leading to hyperthyroidism.
Potential Mechanisms of Immune Damage in Autoimmune
Disease
Common Autoimmune Diseases

Over 80 diseases are now classified as autoimmune. The

autoimmune origin of some of these diseases is very clear-cut but
that is not so for others, and both major and minor factors must be
defined.

Major Criteria

1. There is evidence of autoreactivity (e.g. activated or memory

autoreactive T lymphocytes or autoantibodies).

2. A clinical response to immune suppression can be demonstrated.

3. Passive transfer of the putative immune effector (e.g.

autoreactive T lymphocyte or autoantibody) causes the disease (this
is the hardest criterion to satisfy in humans but is the most
stringent).
Minor Criteria

1. An animal model exists that resembles the human

condition, and in which there is a similar loss of
immunological tolerance to self.

2. There is evidence that, in the animal model, passive

transfer of the putative immune effectors reproduces the
disease in a naive animal.

3. There is an HLA association (a frequent indicator that a

disease is autoimmune).