Autoimmunity &

Autoimmune Disorders
INJAMAM UL HOSSAIN
MSc Medical Biochemistry
Final Year

20/06/2023 1
Contents:
Autoimmunity

Types of autoimmune disorders

Organ Specific autoimmune diseases

System Specific autoimmune diseases

Laboratory diagnosis of autoimmune diseases

Treatment and management

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Autoimmunity:
• Autoimmunity is defined as an immune response against self
(autologous) antigens

• The principal factors in the development of autoimmunity are

the inheritance of susceptibility genes and environmental
triggers, such as infections

Reference: Basic Immunology Functions and disorders of immune system; Abul.K Abbas,
Andrew H. Lichtman; 3rd ed.

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Mechanism of
Autoimmunity:

Reference: Basic Immunology

Functions and disorders of immune
system; Abul.K Abbas, Andrew H.
Lichtman; 3rd ed.
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Environmental Factors Favoring the
Development of Autoimmune Disease:
• Some autoimmune syndromes are more common in certain
geographic locations or in particular climates

• Infections may also influence the induction of autoimmunity

• Environmental exposures (some of which may be microbial) or

lifestyle factors, such as diet, in the development of
autoimmune disease

20/06/2023 Reference: Kuby Immunology; 7th Edition 5

Common pro-
inflammatory
environmental factors
in autoimmune
diseases:

Reference: Kuby
Immunology; 7th
Edition
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Mechanisms by
which
microbes
promote
autoimmunity

Reference: Basic Immunology

Functions and disorders of immune
system; Abul.K Abbas, Andrew H.
Lichtman; 3rd ed.
20/06/2023 7
Autoimmunity due to self reactive B and T cells:

As a result of random V(D)J recombination, over half of all antigen-

specific receptors recognize self proteins

Not all of these are deleted during negative selection

Potentially self-reactive T and B cells found in the periphery are

normally held in check by anergic or regulatory mechanisms, such
as TREG cells

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 Exposure to carcinogens or infectious agents that favor DNA
damage or polyclonal activation can potentially interfere with
this regulation and/or lead to the expansion and survival of rare
T- or B-cell clones with autoimmune potential

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The Role of Genes in Susceptibility to Autoimmunity:
• Certain alleles within the MHC have been linked to several
different autoimmune disorders

• Example:

Ankylosing spondylitis,

• Individuals who express HLA-B27 are 90 times more likely to

develop this disease compare to others

20/06/2023 Reference: Kuby Immunology; 7th Edition 10

Non-MHC inherited genetic mutations leads to
autoimmunity:
• Inactivating mutations in two immune-related genes, aire and
FoxP3, result in forms of immune deficiency that impact central
and peripheral tolerance

• Mutation of aire gene leads to Autoimmune

Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy
(APECED)
Reference: Kuby Immunology; 7th Edition
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• Mutation of FoxP3 gene leads to immune dysregulation,
polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX)

• Genes for cytokines and their receptors, antigen processing

and presentation, c-type lectin receptors, signaling pathways,
adhesion molecules, and costimulatory or inhibitory receptors
have all been linked to specific autoimmune diseases

Reference: Kuby Immunology; 7th Edition

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 Tyrosine
Phosphtase

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Autoimmunity due to release of
sequestered antigens:
• Tissue antigens that are not expressed in the thymus will not
engage with developing T cells and will thus not induce self-
tolerance

• Trauma to tissues following either an accident or an infection

can release these sequestered antigens into the circulation

Reference: Kuby Immunology; 7th Edition

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Autoimmunity due to release of
sequestered antigens:
• For example, the release of heart muscle antigens following
myocardial infarction (heart attack) can lead to the formation of
auto-antibodies that target healthy heart muscle cells

Reference: Kuby Immunology; 7th Edition

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Why Are Women More Susceptible
Than Men to Autoimmunity?
• In general, females tend to mount more vigorous humoral and
cellular immune responses

• Immune cell activation, cytokine secretion after infection,

numbers of circulating CD4 T cells and mitogenic responses
are all higher in women than men

Reference: Kuby Immunology; 7th Edition

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• Why this dichotomy between the sexes? One hypothesis posits that
this increased risk of autoimmunity in women is a by-product of the
evolutionary role of women as bearers of children

• Pregnancy may give us a clue as to how sex plays a role in

regulating immune response

• During pregnancy, it is critical that the mother tolerate the fetus,

which is a type of foreign semi-allograft, so that the female immune
system undergoes important modifications during pregnancy
Reference: Kuby Immunology; 7th Edition
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• Females normally tend to mount more TH1-like responses than
TH2 responses

• During pregnancy, however, women mount more TH2-like

responses

• Diseases enhanced by TH2- like responses, such as SLE,

which has a strong antibody-mediated component, can be
exacerbated during pregnancy
Reference: Kuby Immunology; 7th Edition
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• Another effect of pregnancy is the presence of fetal cells in the
maternal circulation, creating a state called microchimerism

• Fetal cells can persist in the maternal circulation for decades.

These long-lived fetal cells may play a role in the development
of autoimmune disease

Reference: Kuby Immunology; 7th Edition

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 Autoimmune
Disease

Organ
Systemic
Specific
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Organ specific autoimmune diseases:
Hashimoto’s Thyroiditis

Grave’s Disease

Type 1 Diabetes Mellitus (T1DM)

Myasthenia Gravis

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Hashimoto’s Thyroiditis:
• In this disease individuals produce autoantibodies against various
proteins such as, thyroglobulin and thyroid peroxidase

• These proteins are involved in iodine uptake

• Binding of the auto-antibodies to these proteins interferes with

iodine uptake, leading to decreased thyroid function leads to
hypothyroidism

20/06/2023 Reference: Kuby Immunology; 7th Edition 24

Hashimoto’s Thyroiditis:
• In this autoimmune disorder delayed type of hypersensitivity or
Type –IV hypersensitivity reaction involved

• This reaction involves an intense infiltration of the thyroid gland

by lymphocytes, macrophages, and plasma cells, which form
lymphocytic follicles and germinal centers

• Due to physiological response to hypothyroidism enlargement of

thyroid gland or goiter develop
20/06/2023 Reference: Kuby Immunology; 7th Edition 25
 Laboratory diagnosis of Hashimoto’s
Thyroiditis

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Type 1 Diabetes Mellitus (T1DM):
• Here autoantibody develops against β-cells of pancreas

• As a result absolute decrease in insulin synthesis leads to hyperglycemia

Mechanism of β-cells destruction:

• It mediated by type-IV or delayed type of hypersensitivity (DTH) reaction

• Followed by antibody-mediated complement lysis or antibody-dependent

cell-mediated cytotoxicity (ADCC)

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Reference: Kuby Immunology; 7th Edition 27
 Diagnosis:
Clinically:
 Age: <20years
 Polyuria
 Polyphagia
 Polydepsia
Laboratory diagnosis:
 FBS: ≥126mg/dl
 PPBS: ≥200mg/dl
 HBA1c: ≥6.5%
 Serum Insulin: Low
 Serum C-peptide: Low

Reference:
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Harrison’s Principles of Internal Medicine; 19th Edition 28
Myasthenia Gravis:
• Myasthenia gravis (MG) is an autoimmune disease caused by
antibodies against the acetylcholine receptor (AChR), muscle-
specific kinase (MuSK) or other AChR-related proteins such as
lipoprotein-receptor-related protein 4 (LRP4) in the postsynaptic
muscle membrane

Reference: Kuby Immunology; 7th Edition

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Myasthenia Gravis:
• This leads to blocking the normal binding of acetylcholine to its
receptor and inducing complement-mediated lysis of the cells

• Myasthenia gravis is the classic example of an autoimmune

disease mediated by blocking antibodies

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20/06/2023
Reference: Kuby Immunology; 7th Edition 31
Reference: Nils Erik Gilhus et al; Myasthenia gravis; NAture RevIews | DISEASE PrIMErS | Article citation I­D: (2019) 5:30
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Reference: Nils Erik Gilhus et al; Myasthenia gravis; NAture RevIews | DISEASE PrIMErS | Article citation I­D: (2019) 5:30
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Diagnosis of
Myasthenia
Gravis:

Reference: Nils Erik Gilhus et al; Myasthenia gravis; Nature reviews | DISEASE primers | Article citation I­D: (2019) 5:30
35
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Management
of Chronic
Myasthenia
gravis:

Reference: Nils Erik Gilhus et al; Myasthenia gravis; Nature reviews | DISEASE primers | Article citation I­D: (2019) 5:30
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 Management of Chronic
Myasthenia gravis:

Reference: Nils Erik Gilhus et al; Myasthenia gravis; Nature Review; Disease primer | Article citation I­D: (2019) 5:30
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Systemic autoimmune diseases:
Ankylosing spondylitis
Rheumatoid arthritis Scleroderma

Systemic lupus Immune dysregulation

polyendocrinopathy enteropathy X-
erythematosus (SLE)
linked (IPEX)
Multiple sclerosis Autoimmune polyendocrinopathy
candidiasis-ectodermal dystrophy
(APECED)
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Rheumatoid arthritis:
• Individuals with Rheumatoid arthritis produce a group of auto-
antibodies called rheumatoid factors (IgM and IgA) that are
reactive with determinants in the Fc region of IgG

• The classic rheumatoid factor is an IgM antibody that binds to

normal circulating IgG, forming IgM-IgG complexes that are
deposited in the joints

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Rheumatoid arthritis:
• These IgM-IgG complexes can activate the complement
cascade, resulting in a type III hypersensitivity reaction, which
leads to chronic inflammation of the joints

• In Rheumatoid arthritis autoantibody (anti-CCP) produced

against a peptide called Citrullinated peptides (CCPs)

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Pathophysiology of
Rheumatoid arthritis:

 IFN-γ from TH1 cells activates

macrophages and resident synovial
cells
 IL-17 from TH17 cells recruits
neutrophils and monocytes
 TNF and IL-1 from macrophages
stimulates resident synovial cells to
secrete proteases that destroy
hyaline cartilage
 RANKL expressed on activated T
cells stimulates bone resorption

Reference: Robbins and Cotran Pathologic basis of

disease; 9th Edition
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Symptoms of Rheumatoid arthritis:

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 Diagnosis of Rheumatoid arthritis:
Laboratory Investigations:
 C-reactive protein
 Erythrocyte Sedimentation rate (ESR)

 Rheumatoid arthritis factor(RA factor)

 Anti-cyclic citrullinated peptide

antibody (anti-CCP)

Reference:
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Harrison’s Principles of Internal Medicine; 19th Edition 43
 Diagnosis of Rheumatoid arthritis:
Synovial Fluid Analysis:
• White blood cell count (WBCs): 5000-50,000 WBC/μl
• Sterile, turbid synovial fluid with decreased viscosity, poor
mucin clot formation

Exclude the cause of non inflammatory condition such as

Osteoarthritis where WBC count <2000 WBC/μl

Reference:
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Harrison’s Principles of Internal Medicine; 19th Edition 44
 Diagnosis of Rheumatoid arthritis:
Imaging Techniques:

X-ray

MRI

PET Scan

CT Scan

DEXA Scan

Reference:
20/06/2023
Harrison’s Principles of Internal Medicine; 19th Edition 45
 Management of Rheumatoid arthritis:
• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Corticosteroids

• Antibody treatment to block TNF-α and IL-6

Reference: Harrison’s Principles of Internal Medicine; 19th Edition

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Multiple Sclerosis:
• Individuals with this disease produce autoreactive T cells that
participate in the formation of inflammatory lesions along the
myelin sheath of nerve fibers in the brain and spinal cord

• Since myelin functions to insulate the nerve fibers, a breakdown

in the myelin sheath leads to numerous neurologic
dysfunctions, ranging from numbness in the limbs to paralysis
or loss of vision
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Multiple Sclerosis:
• Epstein-Barr virus (EBV) infection leads to Multiple Sclerosis in
some persons

Reference: Kuby Immunology; 7th Edition

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Systemic Lupus Erythematosus (SLE):
• In this disease auto-antibodies forms against vast array of tissue
antigens, such as DNA, histones, RBCs, platelets, leukocytes, and
clotting factors

Pathophysiology:

• Auto-antibodies specific for RBCs and platelets can lead to

complement-mediated lysis, resulting in hemolytic anemia and
thrombocytopenia respectively
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Pathophysiology of SLE:
• These immune complex develop type III hypersensitivity
reaction

• The complexes activate the complement system and generate

membrane-attack complexes and complement fragments
(C3a and C5a) that damage the wall of the blood vessel,
resulting in vasculitis and glomerulonephrtis

Reference: Kuby Immunology; 7th Edition

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 Pathophysiology
of SLE:

Reference: Robbins and Cotran Pathologic basis

of disease; 9th Edition
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Reference:
20/06/2023 Harrison’s Principles of Internal Medicine; 19th Edition 53
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