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AUTOIMMUNE DISEASES
Autoimmunity: Immune reactions to
self antigens
Autoimmune diseases
range from those in
which specific immune
responses are directed
against one particular
organ or cell type and
result in localized tissue
damage,
to multisystem diseases
characterized by lesions in
many organs and associated
with multiple autoantibodies
or T cell–mediated reactions
against numerous self
antigens.
In many of the systemic diseases that
are caused by immune complexes and
autoantibodies, the lesions affect
principally the connective tissue and
blood vessels of the various organs
involved.
Therefore, these diseases are often
referred to as “collagen vascular” or
“connective tissue” disorders, even
though the immunologic reactions are
not specifically directed against
constituents of connective tissue or
blood vessels.
Normal persons are unresponsive
(tolerant) to their own (self)
antigens, and autoimmunity results
from a failure of self-tolerance.
- Self tolerance:
refers to a lack of immune
responsiveness one’s own tissue
antigens.
Central Tolerance :
This refers to the process by which T
and B cells that recognize self
antigens are either killed (negative
selection) or rendered harmless
during their maturation in central
(generative) lymphoid organs (i.e., in
the thymus for T cells and in the bone
marrow for B cells).
Peripheral Tolerance
Self reactive cells that escape
central regulatory mechanisms can
be removed or inactivated in the
periphery through one of the
following pathways:
1.Anergy: This term refers to
functional inactivation (rather
than death) of lymphocytes induced
by encounter with
antigens under certain conditions.
2. suppression by regulatory T
lymphocytes,
3. Activation-induced cell death (
apoptosis).
combination of inherited
susceptibility genes, which
influence lymphocyte tolerance,
and environmental factors, such as
infections or tissue injury, that alter
the display of self antigens
Mechanisms of Autoimmunity:
It is believed that the breakdown of
self-tolerance and development of
autoimmunity result from a
-Autoimmune diseases have a
tendency to run in families.
-Several autoimmune diseases are
linked with the HLA locus, especially
class II alleles (HLA-DR, -DQ) e.g.
- Rheumatoid arthritis and HLA DRB1
-Ankylosing spondylitis and
HLA- B*27
-many genetic polymorphisms in (
non - HLA Genes) are associated
with different autoimmune diseases.
e.g. PTPN-22 gene and type I
diabetes and rheumatoid
arthritis.
Microbes may induce autoimmune
reactions by several mechanisms:
-Viruses and other microbes may share
cross-reacting epitopes with self
antigens,This phenomenon is called
molecular mimicry.
.
• Microbial infections with resultant
tissue necrosis and inflammation can
expose self-antigens and activate APCs and
lymphocytes in the tissues.

Autoimmune diseases are , more
common in women than in men.
-It is a multisystem autoimmune
disease caused by autoantibodies
produced against numerous selfantigens and the formation of immune
complexes.
-Clinically, it is an unpredictable, remitting
and relapsing disease of acute or insidious
onset that may involve virtually any organ
in the body; mainly the skin, kidneys,
serosal membranes, joints, and heart.
-SLE is more common and severe in black
Americans.
- Onset typically is in the second or third 
decade of life, but it may manifest at any
age, including early childhood.
-The pathogenesis of SLE involves a
combination of genetic and
environmental factors and immunologic
factors :
Familial association. Family members have
an increased risk for the development of
SLE.
 HLA association:
HLA-DR2 , HLA-DR3
 Other genes:
Genetic deficiencies of classical pathway
complement proteins, especially C1q, C2, or
C4, are seen in about 10% of patients with
SLE.

• Ultraviolet (UV) radiation (sun exposure)
exacerbates the lesions of SLE.
• Cigarette smoking
• Sex hormones : There is a strong female
preponderance (approximately 9 : 1)(female
:male)
It has been suggested that factors other than
hormones may account for the increased risk
of this disease in women.
• Drugs:
such as procainamide and
hydralazine can induce an SLE- like disease,
several components of the innate
and adaptive immune system are
involved in the pathogenesis of
SLE.
 Defective elimination of selfreactive B cells, and ineffective
peripheral tolerance mechanisms
are most important.

The fundamental defect in SLE is a
failure to maintain self tolerance.
Cell injury (e. g., UV and other
environmental insults) leads to
apoptosis and an increased burden of
nuclear antigens(due to defective
clearance of nuclear antigens) .

Defective B and T-cell tolerance
leads to autoantibodies directed
against the nuclear antigens, with
the resulting immune complexes
being ingested by B cells and
dendritic cells; then further cellular
activation, cytokine production, and
augmented autoantibody synthesis,
which causes more apoptosis in a
self amplifying loop.
A.Antinuclear antibodies(ANA):
ANAs are directed against several
nuclear antigens and can be grouped
into :
(1) antibodies to DNA, (2) antibodies to
histones,
(3) antibodies to nonhistone proteins
bound to RNA,
and (4) antibodies to nucleolar antigens.
-ANAs also occur in other
autoimmune disorders, and in 5-15%
of normal individuals .
- anti-double-stranded DNA and antiSmith antigen antibodies strongly
suggest SLE.
B.Other autoantibodies:
-Some directed against blood
elements (i.e., red blood cells,
platelets, leukocytes).
- Sometimes SLE patients have
(antiphospholipid antibodies).
-Some Abs bind to cardiolipin antigen,
giving rise to false-positive results for
syphilis.
- lupus anticoagulants :
1.type III hypersensitivity
Most organ damage in SLE is caused
by immune complex deposition.
2. type II hypersensitivity.
Autoantibodies against red cells,
white cells, and platelets opsonize
these cells and lead to their
phagocytosis, resulting in cytopenias
(autoimmune haemolytic anaemia,
immune thrombocytopenia)
3-Antiphospholipids antibodies
lead to increased thrombosis in
patients, with varied clinical
consequences, including recurrent
spontaneous abortion and thrombotic
episodes. These disorders are part of
the antiphospholipid syndrome
4- lupus anticoagulants.
Autoantibodies against clotting
factors such as thrombin, and these
may interfere with in vitro
coagulation assays; actually exert a
procoagulant effect in vivo, causing
recurrent vascular thromboses,
miscarriages, and cerebral ischemia
5- Autoantibodies against central
nervous system receptors for
various neurotransmitters have
been implicated in the
neuropsychiatric complications of
the disease.

Although any organ can be involved,
the most characteristic tissues
affected are skin, blood vessels,
kidneys, and connective tissue.
-Classically, there is a type III
hypersensitivity response with acute
necrotizing vasculitis and fibrinoid
deposits involving small arteries and
arterioles. Immune complexes can
be found in vessel walls.
1. Kidneys. Kidney involvement is
one of the most important clinical
features of SLE.
Mostly it is glomerular pathology
(lupus nephritis), although
interstitial and tubular lesions are
also seen in SLE.
2. Skin: Malar erythema is the classic
lesion (butterfly rash) , Exposure to
sunlight (UV light) exacerbates the
erythema
(so-called photosensitivity)
3. Joints: There is synovitis.
4. CNS. Central nervous system (CNS)
involvement
5. Spleen , Lungs , heart
-It typically presents insidiously as a
systemic, chronic, recurrent, febrile
illness with symptoms referable to
virtually any tissue but especially
joints, skin, kidneys, and serosal
membranes.
-Autoantibodies to hematologic
components may induce
thrombocytopenia, leukopenia,
anemia.
-neurologic abnormalities with focal
neurologic deficits and/or
neuropsychiatric symptoms
-
The most common causes of
death are renal failure,
intercurrent infections, and
cardiovascular disease.
Rheumatoid arthritis (RA)
is a chronic autoimmune inflammatory
disease that affects mainly the joints,
especially small joints ( (digits before
wrist, ankles, elbows, and knees) in a
bilaterally symmetric pattern), but can
affect multiple tissues (blood vessels,
skin, heart, lungs, and muscles)

RA is caused by an autoimmune
response
against
self-antigen(s),
which leads to T cell reactions in the
joint with production of cytokines that
activate phagocytes that damage
tissues and stimulate proliferation of
synovial cells (synovitis).
Antibodies may also contribute to the
disease. About 80% of patients have
serum immunoglobulin M (IgM) (and,
less frequently, IgA) autoantibodies
that bind to the Fc portions of their
own (self ) IgG..

These autoantibodies are called
rheumatoid factor. They may form
immune complexes with self-IgG that
deposit in joints and other tissues,
leading to inflammation and tissue
damage.
Sjogren syndrome
It is characterized by dry eyes
(keratoconjunctivitis sicca) and dry
mouth (xerostomia), resulting from
immune-mediated destruction
of the lacrimal and salivary glands.
It occurs as an isolated disorder
(primary form), also known as the
sicca syndrome,
or more often in association with
another autoimmune disease
(secondary form).
Most patients have rheumatoid factor
without having rheumatoid arthritis;
ANAs against ribonucleoproteins SS-A
(Ro) and SS-B (La) are especially
common
The disease is believed to be caused by an
autoimmune T cell reaction against one or
more unknown self antigens
expressed in these glands, or immune
reactions against the antigens of a virus
that infects the tissues.
Systemic Sclerosis
(Scleroderma) (SS)
It is is an immunologic disorder
characterized by excessive
fibrosis in multiple tissues,
obliterative vascular disease,
and evidence of autoimmunity,
mainly the production of multiple
autoantibodies.
The distinctive feature of SS is the striking
cutaneous involvement. Cutaneous
involvement is the usual presenting
manifestation and eventually appears in
approximately 95% of cases
The visceral involvement—of the
gastrointestinal tract, lungs, kidneys,
heart, and skeletal muscles—is
responsible for most of the related
morbidity and mortality.
scleroderma
Almost all patients exhibit Raynaud
phenomenon, a vascular disorder
characterized by reversible vasospasm
of the arteries. Typically the hands turn
white on exposure to cold, reflecting
vasospasm, followed by change to blue
as ischemia and cyanosis develop.
Finally, the color changes to red as
reactive vasodilation occurs
Raynaud phenomenon
-
SS affects women three times more
often than men, with a peak incidence
in the 50- to 60-year age group.
SS can be classified into two groups
on the basis of its clinical course:
-1-Diffuse scleroderma, characterized by
initial widespread skin involvement, with rapid
progression and early visceral involvement
2- Limited scleroderma, with relatively mild
skin involvement, often confined to the
fingers and face. Involvement of the viscera
occurs late.
This clinical presentation is also
called the CREST syndrome because
of its frequent features of calcinosis,
Raynaud phenomenon, esophageal
dysmotility, sclerodactyly, and
telangiectasia.
IMMUNE DEFICIENCY DISEASES:
1.Primary immunodeficiencies
are usually hereditary and manifest between 6
months and 2 years of life .
2. Secondary immunodeficiencies
result from altered immune function due to
infections e.g. Acquired Immunodeficiency
Syndrome (AIDS), malnutrition, aging,
immunosuppression, irradiation, chemotherapy,
or autoimmunity.
 -Clinically,
patients with immune
deficiency present with increased
susceptibility to infections as well
as to certain forms of cancer.

 The
type of infections in a
given patient depends largely
on the component of the
immune system that is
affected:
-
Patients with defects in
immunoglobulin, complement, or
phagocytic cells typically suffer
from recurrent infections with
pyogenic bacteria.

-Those with defects in cellmediated immunity are prone to
infections caused by viruses, fungi,
and intracellular Bacteria
Primary immunodeficiencies
(Congenital) Caused by mutations in
genes involved in lymphocyte
maturation or function, or in innate
immunity
• Some of these disorders are :
1.X-Linked Agammaglobulinemia(XLA)
Bruton Disease
 is
characterized by the failure of pre-B
cells to differentiate into B cells and, there
is a resultant absent or markedly
decreased numbers of B cells in the
circulation, with depressed serum levels of
all classes of immunoglobulins.
 Normal
T cell–mediated responses
-XLA does not become apparent until
the affected infant reach the age of
approximately 6 months.
In most cases, recurrent bacterial
infections such as acute and chronic
pharyngitis, sinusitis, otitis media,
bronchitis.
2.Common Variable Immunodeficiency
 -Is
a heterogeneous group of disorders
characterized by
hypogammaglobulinemia, impaired
antibody responses to infection (or
vaccination), and increased
susceptibility to infections.
 The
clinical manifestations are
superficially similar to those of XLA, but
in common variable immunodeficiency,
males and females are affected equally
and the onset of symptoms is much later,
in the second or third decade of life

3.Isolated IgA Deficiency
The most common of all the primary immune
deficiency diseases
-Absent serum and secretory IgA
- IgA is the major immunoglobulin in mucosal
secretions and is thus involved in defending
the airways and the gastrointestinal tract.
 Although
most people with this condition
are asymptomatic, weakened mucosal
defenses predispose patients to
recurrent sinopulmonary infections and
diarrhea.
 -There is also a significant (but
unexplained) association with
autoimmune diseases.
Hyper-IgM Syndrome
Patients with the hyper-IgM syndrome
produce normal (or even supranormal)
levels of IgM antibodies to antigens but
lack the ability to produce the IgG, IgA, and
IgE isotypes; the underlying defect is an
inability of T cells to induce B cell isotype
switching.
In 70% of patients, the disease is X-linked
Other primary immunodeficiency
diseases include:
-Severe Combined Immunodeficiency
-Thymic Hypoplasia: DiGeorge Syndrome
- Wiskott-Aldrich Syndrome :Immune
Deficiency with thrombocytopenia and
Eczema.
-Genetic Deficiencies of Complement Protein
-Defects in Lymphocyte Activation
-Defect in phagocyte