AUTOIMMUNITY

Dr. Vignesh Ram

Learning Objectives

• To describe the tolerance and autoimmunity

• To understand the factors associated with the autoimmune diseases

• To understand the pathogenesis and clinical features of autoimmune diseases

• To advice the laboratory diagnostic tests for the detection of autoimmune diseases

• To understand the general management of autoimmune diseases

 Tolerance
Tolerance is specific immunologic unresponsiveness,
i.e., an immune response to a certain antigen does not
occur, although the immune system is otherwise
functioning normally.
 Self reactive T cell
In general, antigens that are present during embryonic
life are considered "self" and do not stimulate an
immunologic response, i.e., we are tolerant to those
antigens.
The lack of an immune response is caused by the
deletion of self-reactive T-cell precursors in the foetal
thymus.
 T cell tolerance
The main process by which T lymphocytes acquire the
ability to distinguish “self” from “nonself” occurs in the
foetal thymus. This process, called clonal deletion
involves the killing of T cells ("negative selection") that
react against antigens (primarily self MHC proteins)
present in the foetus at that time.
The self-reactive cells die by a process of programmed
cell death called apoptosis.
 T cell tolerance
Tolerance to self acquired within the thymus is called
central tolerance, whereas tolerance acquired outside
the thymus is called peripheral tolerance.
T cell tolerance
 Autoimmune diseases
• Theadult host usually exhibits tolerance to tissue antigens
present during foetal life that are recognized as "self“.
However, in certain circumstances tolerance may be lost and
immune reactions to host antigens may develop, resulting in
autoimmune diseases.
• The most important step in the production of autoimmune
disease is the activation of self-reactive helper (CD4) T
cells.
• Theseself-reactive Th-1 or Th-2 cells can induce either cell-
mediated or antibody-mediated autoimmune reactions,
respectively.
 Autoimmune diseases
Factors responsible for triggering of autoimmune diseases
• Genetic

• Hormonal

• Environmental
 Genetic Factors
• Many autoimmune diseases exhibit a marked familial
incidence, which suggests a genetic predisposition to these
disorders.
• There is a strong association of some diseases with certain
human leukocyte antigen (HLA) specificities, especially the
class II genes. For example, rheumatoid arthritis occurs
predominantly in individuals carrying the HLA-DR4 gene.
• Ankylosing spondylitis is 100 times more likely to occur in
people who carry HLA-B27, a class I gene, than in those who
do not carry that gene.
 Hormonal Factors
• Approximately 90% of all autoimmune diseases occur in
women. Although the explanation for this markedly unequal
gender ratio is unclear, there is some evidence from animal
models that oestrogen can alter the B-cell repertoire and
enhance the formation of antibody to DNA.
• Clinically,
the observation that systemic lupus erythematosus
either appears or exacerbates during pregnancy (or
immediately postpartum) supports the idea that hormones
play an important role in predisposing women to
autoimmune diseases.
 Environmental Factors
• There are several environmental agents that trigger
autoimmune diseases, most of which are either bacteria or
viruses.
• Forexample, pharyngitis caused by Streptococcus pyogenes
predisposes to rheumatic fever.
• Though it is speculative at this time, but members of the
normal flora of the bowel are thought to play a role in the
genesis of inflammatory bowel diseases, such as Crohn's
disease and ulcerative colitis.
 Mechanisms
• Molecular mimicry

• Alteration of normal proteins

• Release of sequestered antigens

• Failure of regulatory T cells

 Mechanisms – Molecular mimicry
• Various bacteria and viruses are implicated as the source of cross-
reacting antigens that trigger the activation of autoreactive T cells
or B cells.

• The concept of molecular mimicry is used to explain these

phenomena, i.e., the environmental trigger resembles (mimics) a
component of the body sufficiently that an immune attack is
directed against the cross-reacting body component.
 Mechanisms – Molecular mimicry
• One of the best-characterized examples of molecular mimicry is
the relationship between the M protein of S. pyogenes and the
myosin of cardiac muscle. Antibodies against certain M proteins
cross-react with cardiac myosin, leading to rheumatic fever.
Mechanisms – Alteration of normal proteins
Drugs can bind to normal proteins and make them immunogenic.
Procainamide-induced systemic lupus erythematosus is an
example of this mechanism.
Mechanisms – Release of sequestered antigens
• Certaintissues, e.g., sperm, central nervous system, and the
lens and uveal tract of the eye, are sequestered so that their
antigens are not exposed to the immune system.
• These are known as immunologically privileged sites.
• When such antigens enter the circulation accidentally, e.g., after
damage, they elicit both humoral and cellular responses,
producing aspermatogenesis, encephalitis, or endophthalmitis,
respectively.
Mechanisms – Release of sequestered antigens
 Mechanisms – Failure of Regulatory T cells
• Regulatory T cells (Tregs) suppress the
proinflammatory effects of other T cells.
• An important function of Treg cells is to
produce IL-10, which inhibits
proinflammatoryTh-1 cells.
• If
Treg cells fail, then autoimmune diseases
characterized by inflammation such as
systemic lupus erythematous, can occur.
 Multiple Sclerosis
• It is an inflammatory, T-cell–mediated
autoimmune disease characterized by the
demyelination or destruction of the myelin
sheaths surrounding central nervous
system nerve axons.
• It is caused by the release of sequestered
myelin antigens following trauma to the
CNS, or molecular mimicry to a
neuroepitope following a viral infection.
EBV is one of many viruses that have been
implicated in MS.
 Multiple Sclerosis
• The clinical findings in multiple sclerosis typically wax and
wane and affect both sensory and motor functions. MRI of
the brain reveals plaques in the white matter.
• Immunosuppressive drugs, e.g., prednisone, methotrexate, or
beta interferon, are effective in reducing the severity of some
of the symptoms.
 Hashimoto’s Thyroiditis
• Thisdisease, most commonly found in
middle-aged women, is characterized
by the production of antibodies to
two major thyroid proteins, thyroid
peroxidase and the hormone
thyroglobulin.
• These autoantibodies play a major
role in the destruction of the thyroid
gland, eventually causing a decline
in the output of thyroid hormones
resulting in hypothyroidism.
 Autoimmune Haemolytic Anaemia
• Inautoimmune hemolytic anemia, antibodies specific for blood
group antigens (including Rh) expressed on the surface of RBCs
are responsible for destroying these RBCs. This results in anaemia,
a reduced number of RBCs or decreased haemoglobin level in the
circulation.
• Mechanisms include
• activationof complement cascade and eventual lysis of RBC
• opsonization of RBC facilitated by antibodies and C3b, leading to
engulfment by macrophages
• Destruction of RBCs by antibody-dependent cellular cytotoxicity
(ADCC)
 Idiopathic Thrombocytopenic Pupura
Idiopathic thrombocytopenic purpura(ITP) is caused by
antibodies directed against platelets. Platelets coated with
antibody are either destroyed in the spleen or lysed by the
membrane attack complex of complement.
 Myasthenia Gravis
• Thetarget self-antigen in this disease is the acetylcholine
receptor at neuromuscular junctions.
• The autoantibody acts as an antagonist that blocks the
binding of acetylcholine (ACh) to the receptor.
• This
inhibits the nerve impulse from being transmitted across
the neuromuscular junction, resulting in severe muscle
weakness, manifested by difficulty in chewing, swallowing,
and breathing and eventually death from respiratory failure.
 Myasthenia Gravis
Myasthenia gravis may affect individuals of any age, but the
peak incidence occurs in women in their late-20s and men in
their 50s and 60s.
 Insulin Dependent Diabetes Mellitus (IDDM)
• Inthis disease, autoreactive T cells destroy the islet cells
of the pancreas. The main antigen against which the T-cell
attack is directed is the islet cell enzyme, glutamic acid
decarboxylase. Infection with Coxsackie virus B4 has been
shown to be a trigger of IDDM in mice, but it is yet to be
established as a cause in human diabetes.
• There is a six–amino acid sequence in common between a
Coxsackie virus protein and glutamic acid decarboxylase.
Antibodies against various antigens of the beta islet cells
also are produced, but the major damage is T-cell mediated.
 Grave’s Disease
• Patientswith this disease develop autoantibodies against
receptors for thyroid-stimulating hormone (TSH) that
are expressed on the surface of thyroid cells.
• The interaction of autoantibodies with the TSH receptor
activates the cell in a manner similar to TSH activation,
thereby stimulating excess production of thyroid hormone
leading to hyperthyroidism.
 Grave’s Disease
• It
most commonly affects women in their 30s and 40s; the
female to male ratio is about 8:1.
 Guillain-Barre Syndrome (GBS)
• This disease is the most common cause of acute paralysis.
• It follows a variety of infectious diseases such as viral
illnesses (e.g., upper respiratory tract infections, HIV
infection, and mononucleosis caused by Epstein-Barr virus
,cytomegalovirus and zika virus) and diarrhoea caused by
Campylobacter jejuni.
 Guillain-Barre Syndrome (GBS)
• Antibodies against myelin protein are formed and result
in a demyelinating polyneuropathy.
• The main symptoms are those of a rapidly progressing
ascending paralysis.
• The treatment involves either intravenous immunoglobulins
or plasmapheresis.
 Systemic Lupus Erythematosus (SLE)
• Inthis disease, autoantibodies are formed against DNA,
histones, nucleolar proteins, and other components of the
cell nucleus. Antibodies against double-stranded DNA are
the hallmark of systemic lupus erythematosus.
• Thedisease affects primarily women between the ages of 20
and 60 years.
• Individualswith HLA-DR2 or -DR3 genes are predisposed
to SLE. The agent that induces these autoantibodies in most
patients is unknown. However, two drugs, procainamide
and hydralazine, are known to cause SLE.
Systemic Lupus Erythematosus (SLE)
 Rheumatoid Arthritis
• Inthis disease, autoantibodies are formed against IgG. These
autoantibodies are called rheumatoid factors and are of the IgM
class.
• Rheumatoid arthritis affects primarily women between the ages of 30
and 50 years.
• People with HLA-DR4 genes are predisposed to rheumatoid arthritis.
• The agent that induces these autoantibodies is unknown.
• Within the inflamed joints, the synovial membrane is infiltrated with
T cells, plasma cells, and macrophages, and the synovial fluid
contains high levels of macrophage-produced inflammatory
cytokines such as tumor necrosis factor (TNF), IL-1, and IL-8.
Rheumatoid Arthritis
 Rheumatic Fever
• Group A streptococcal infections
regularly precede the
development of rheumatic fever.
• Antibodies against the M
protein of group A streptococci
that cross-react with myosin in
cardiac muscle and proteins in
joint and brain tissue are involved
in the pathogenesis of rheumatic
fever.
 Goodpasture’s Syndrome
• In this syndrome, autoantibodies are formed against the
collagen in basement membranes of the kidneys and
lungs.
• Goodpasture's syndrome affects primarily young men, and
those with HLA-DR2 genes are at risk for this disease.
• The agent that induces these autoantibodies is unknown,
but GS often follows a viral infection.
 Laboratory Diagnosis of autoimmune diseases
• Routineinvestigations – Urine examination – renal pathology,
proteinuria, haematuria, urine sediments

• Haematological investigations – Hb, RBC, WBC counts,

Platelet counts, ESR (inflammatory process)

• Biochemical tests – Renal function tests, liver enzymes

• Serological
tests - CRP, Rheumatoid factor, Antinuclear
antibody, ASO titre, Immunofluorescence

• Study of HLA association

 Treatment of autoimmune diseases
• Theconceptual basis for the treatment of autoimmune diseases
is to reduce the patient's immune response sufficiently to
eliminate the symptoms.
• Corticosteroids, such as prednisone, are the mainstay of
treatment, to which antimetabolites, such as azathioprine and
methotrexate, can be added.
• Immunosuppressive therapy must be given cautiously because
of the risk of opportunistic infections.
• Anticytokine therapies have proven very successful against
several autoimmune diseases. Blockade of TNF-α by
monoclonal antibody or soluble receptor is an important
therapeutic option in RA and inflammatory bowel disease.
 In a nutshell…
Autoimmune diseases Targeted autoantigens
Multiple Sclerosis Myelin basic protein
Hashimoto’s Thyroiditis Thyroid proteins
Autoimmune Haemolytic Anaemia Blood group antigens
Insulin-Dependent Diabetes Mellitus Pancreatic -islet cell antigen
Grave’s Disease TSH receptor
Guillain-Barre Syndrome Myelin protein
SLE DNA, nuclear protein
Rheumatoid arthritis IgG
Goodpasture’s Syndrome Renal and lung basement membrane