Pathology

2009 –
Immune System &
2010
Autoimmunity
Doctor: Raed Al Ani
 Autoimmunity
 The evidence is compelling that an immune
reaction to self-antigens (i.e., autoimmunity) is
the cause of certain human diseases; a
growing number of entities have been
attributed to this process .
 However, in many of these disorders the proof
is not definitive, and an important thing is that
the simple presence of auto-reactive
antibodies or T cells does not equate to
autoimmune disease only.
 Low-affinity antibodies and T cells reactive with
self-antigens can be readily demonstrated in
most otherwise healthy individuals;
presumably, these antibodies and T cells are
not pathogenic and are of little consequence.
 Moreover, similar innocuous autoantibodies to
self-antigens are frequently generated
following other forms of injury (e.g., ischemia)
and may even serve a physiologic role in the
removal of products of tissue breakdown.
Immunological tolerance
 Immunological tolerance is unresponsiveness
to an antigen that is induced by exposure of
specific lymphocytes to that antigen.
 Self-tolerance refers to a lack of immune
responsiveness to one's own tissue antigens.
During the generation of billions of antigen
receptors in developing T and B lymphocytes,
it is not surprising that receptors are produced
that can recognize self-antigens.
 Central tolerance
 This refers to deletion of self-reactive T
and B lymphocytes during their maturation
in central lymphoid organs (i.e., in the
thymus for T cells and in the bone marrow
for B cells).
 Any developing T cell that expresses a
receptor for such a self-antigen is
negatively selected (deleted by apoptosis),
and the resulting peripheral T-cell pool is
thereby depleted of self-reactive cells .
 Unfortunately, the process of deletion of self-
reactive lymphocytes is far from perfect. Many
self-antigens may not be present in the
thymus, and hence T cells bearing receptors
for such autoantigens escape into the
periphery.
 There is similar "slippage" in the B-cell system
as well, and B cells that bear receptors for a
variety of self-antigens, including
thyroglobulin, collagen, and DNA, can be found
in healthy individuals.
 Peripheral tolerance
 Self-reactive T cells that escape negative
selection in the thymus can potentially
wreak disturbances unless they are
deleted or effectively muzzled.
 Several mechanisms in the peripheral
tissues that silence such potentially auto-
reactive T cells have been identified:
 Anergy
 Anergy: This refers to functional inactivation (rather than
death) of lymphocytes induced by encounter with antigens
under certain conditions.

 Because costimulatory molecules are not strongly expressed

on most normal tissues, the encounter between autoreactive
T cells and self-antigens in tissues may result in anergy.

 B cells can also become anergic if they encounter antigen in

the absence of specific helper T cells.Suppression by
regulatory T cells.

 The responses of T lymphocytes to self-antigens may be

actively suppressed by regulatory T cells.
 Factors
Factors affecting
affecting tolerance:
tolerance: role
role
of
of antigen
antigen

Factors which Favor immune Favor tolerance

affect response response
Physical form Large, aggregated, soluble, aggregate-free,
of antigen complex molecules simple small molecules
Antigen processing properly processed improperly processed
Route of injection Subcutaneous or Oral or, sometimes,
intra-muscular intravenous

Dose of antigen Optimal dose Very large or very

small dose
 Factors
Factors affecting
affecting
tolerance:
tolerance:
role
role of
of antigen
antigen
Factors which Favor immune Favor tolerance
affect response response
Age of responding Adult, Newborn (mice)
animal immunologically Immunologically
mature immature

Differentiation Fully Undifferentiated B cell

state of cells differentiated, with only IgM, T cells in
Memory the thymic cortex
Theories & Hypothesis of
Autoimmunity
 Autoimmune diseases range from those
in which
1- Specific immune responses are
directed against one particular
organ or cell type and result in
localized tissue damage.
2- Multisystem diseases
characterized by lesions in many
organs and associated with
multiple autoantibodies or cell-
mediated reactions against
numerous self-antigens.

In the systemic diseases, the

lesions affect principally the
connective tissue and blood
vessels of the various organs
involved.
Autoimmune diseases (AIDs)
may be classified as organ-
specific or systemic (non-
organ-specific). There is a
spectrum of AIDs including
some that exhibit
intermediate
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 Theories:
 1. Cryptic Antigen
 2- By-pass Theory (a) .
 3- By-pass Theory (b)
 4- By-pass Theory (c)
 5. Genetic Defects.
 6- Regulatory T-cells (a)
 7- Danger Theory.

Hypothesis:
 Somatic Mutation Hypothesis
 Polyclonal Activation Hypothesis

15
 Mechanisms of
Autoimmunity
 Unfortunately, there are no simple answers
to this question, and we still do not
understand the underlying causes of most
human autoimmune diseases.
 We referred to gene mutations that
compromise one or another pathway of self-
tolerance and cause pathologic
autoimmunity.
 These single-gene mutations are extremely
informative, and they help to establish the
biologic significance of the various
pathways of self-tolerance.
 The breakdown of self-tolerance and the
development of autoimmunity are probably
related to the inheritance of various
susceptibility genes and changes in tissues,
often induced by infections or injury, that
alter the display and recognition of self-
antigens
 Role of Genetic Factors in
Autoimmunity
There is abundant evidence that genes play an important role
in the development of autoimmune diseases.
 Autoimmune diseases have a tendency to run in families,
and there is a greater incidence of the same disease in
monozygotic than in dizygotic twins.
 Several autoimmune diseases are linked with the HLA locus.
The frequency of a disease in an individual with a particular
HLA allele, compared to individuals who do not inherit that
allele, is called the relative risk
 Despite enormous interest in this area, so far most of the
associations are with chromosomal segments, and the
actual genes have not been identified with certainty.
Role of Infections and Tissue Injury
 Molecular Mimicry
 Viruses and other microbes, particularly certain
bacteria such as streptococci and Klebsiella
organisms, may share cross-reacting epitopes with
self-antigens, such that responses to the microbial
antigen may attack self-tissues.
 This phenomenon is called molecular mimicry. It is
the probable cause of a few diseases, the best
example being rheumatic heart disease, in which an
immune response against streptococci cross-reacts
with cardiac antigens. It is not known if more subtle
mimicry plays a role in other autoimmune diseases.
Cross-Reactivity
. The display of tissue antigens may be altered by
infections and other triggers. Local tissue injury
for any reason may lead to the release of self-
antigens and autoimmune responses.
 At present there is no evidence that clearly
implicates any microbe in the causation of
human autoimmune diseases.
 The activation of such autoreactive T cells is
called "epitope spreading" because the immune
response "spreads" to epitopes that were not
recognized initially.
Systemic Lupus Erythematosus
 Systemic lupus erythematosus (SLE) is a multisystem
autoimmune disease of protean manifestations and
variable behavior.
 Clinically, it is an unpredictable, remitting and
relapsing disease of acute or insidious onset that may
involve virtually any organ in the body; however, it
affects principally the skin, kidneys, serosal
membranes, joints, and heart.
 Immunologically, the disease is associated with an
enormous array of autoantibodies, classically including
antinuclear antibodies (ANAs).
 The clinical presentation of SLE is so
variable and it has so many overlaps with
other autoimmune diseases (rheumatoid
arthritis, polymyositis, and others) that it
has been necessary to develop diagnostic
criteria for SLE .
 The diagnosis is established if a patient
demonstrates four or more of the criteria
during any interval of observation.
 SLE is a systemic autoimmune disease
caused by autoantibodies produced against
numerous self-antigens and the formation
of immune complexes.

 The major autoantibodies, and the ones

responsible for the formation of circulating
immune complexes, are directed against
nuclear antigens.

 Other autoantibodies react with

erythrocytes, platelets, and various
complexes of phospholipids with proteins.

 Disease manifestations include nephritis,

skin lesions and arthritis (caused by the
deposition of immune complexes), and
hematologic and neurologic abnormalities.
 Rheumatoid Arthritis
 Rheumatoid arthritis (RA) is a systemic, chronic
inflammatory disease affecting many tissues but
principally attacking the joints to produce a
nonsuppurative proliferative synovitis that frequently
progresses to destroy articular cartilage and underlying
bone with resulting disabling arthritis.
 When extra-articular involvement develops-for example,
of the skin, heart, blood vessels, muscles, and lungs-RA
may resemble SLE or scleroderma.
 The peak incidence is in the second to fourth decades of
life, but no age is immune. Morphology will be
considered first, as a background to a discussion of
pathogenesis
 broad spectrum of morphologic alterations is
seen in RA; the most severe occur in the joints.
RA typically presents as symmetric arthritis,
principally affecting the small joints of the
hands and feet, ankles, knees, wrists, elbows,
and shoulders.
 Typically, the proximal interphalangeal and
metacarpophalangeal joints are affected, but
distal interphalangeal joints are spared. Axial
involvement, when it occurs, is limited to the
upper cervical spine; similarly, hip joint
involvement is extremely uncommon.
 The subarticular bone may also be attacked and
eroded. Eventually the pannus fills the joint space,
and subsequent fibrosis and calcification may
cause permanent ankylosis.
 The radiographic hallmarks are joint effusions and
juxta-articular osteopenia with erosions and
narrowing of the joint space and loss of articular
cartilage.
Destruction of tendons, ligaments, and joint capsules produces the characteristic deformities, including radial
deviation of the wrist, ulnar deviation of the fingers, and flexion-hyperextension abnormalities of the fingers.
 Sjögren Syndrome
 It is a clinicopathologic entity characterized by dry
eyes (keratoconjunctivitis sicca) and dry mouth
(xerostomia), resulting from immune-mediated
destruction of the lacrimal and salivary glands.
1- Primary form :It occurs as an isolated disorder ,
also known as the sicca syndrome.
2- Secondary form or more often in association with
another autoimmune disease . Among the
associated disorders, RA is the most common, but
some patients have SLE, polymyositis, systemic
sclerosis, vasculitis, or thyroiditis.
 Etiology and
Pathogenesis
 Several lines of evidence suggest that Sjögren
syndrome is an autoimmune disease in which the
ductal epithelial cells of the exocrine glands are the
primary target.
 Nevertheless, there is also systemic B-cell
hyperactivity, as evidenced by the presence of ANAs
and RF (even in the absence of associated RA.
 Most patients with primary Sjögren syndrome have
autoantibodies to the RNP antigens SS-A (Ro) and SS-B
( these antibodies are also present in some SLE
patients and are therefore not diagnostic for Sjögren
syndrome)
 Involved tissues show an intense lymphocyte
(primarily activated CD4+ T cells) and plasma-
cell infiltrate, occasionally forming lymphoid
follicles with germinal centers.
 There is associated destruction of the native
architecture
 Lacrimal gland destruction results in a lack of
tears, leading to drying of the corneal
epithelium, with subsequent inflammation,
erosion, and ulceration
(keratoconjunctivitis).
 Similar changes may occur in the oral mucosa as
a result of loss of salivary gland output, giving
rise to mucosal atrophy, with inflammatory
fissuring and ulceration (xerostomia).
 Dryness and crusting of the nose may lead to
ulcerations and even perforation of the nasal
septum.
 When the respiratory passages are involved,
secondary laryngitis, bronchitis, and pneumonitis
may appear. Approximately 25% of the patients
(especially those with anti-SS-A antibodies)
develop extraglandular disease affecting the CNS,
skin, kidneys, and muscles.
Example of an Autoimmune
Disease: Multiple Sclerosis

(MS)
Degenerative disease of the myelin sheath
 Myelin sheath damage is initiated by increased migration of
autoreactive T cells across the BBB, leading to
inflammation and formation of hardened scar tissue
(“sclerotic plaques”) in various areas of the CNS
 Demyelination along the axons disrupts nerve conduction

Saladin, 2005
 • Canadians have one of the highest
rates of multiple sclerosis in the world.
•MS is the most common neurological
disease affecting young adults in
Canada

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 Multiple Sclerosis:
Genes and Environment
Genetic predisposition:
 Familial recurrence rate of about 20%

 Mostly seen in patients of northern European

background

Environmental Factors:
 Reported links to infection with measles, mumps,
rubella, Epstein-Barr virus
 Molecular mimicry between Epstein-Barr virus and
myelin basic protein (MBP) provides basis for immune
response; cross-reaction between virus and myelin
results in demyelination
Multiple Sclerosis: Signs &
Symptoms
 Blindness

 Partial or complete paralysis

 Impaired speech, swallowing,
coordination
 Erectile dysfunction, incontinence

 Stiffness of muscles

 Short-term memory problems

 • not all MS patients will
experience these symptoms
•Different area(s) of CNS
affected - accounts for
symptom heterogeneity among
MS patients
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This remark on the previous slide