AUTOIMMUNE DISEASES
Martin Liška
Autoimmune disease
 Results from a failure of self-tolerance
 Immunological tolerance is specific
unresponsiveness to an antigen
 All individuals are tolerant of their own
(self) antigens
Autoimmunity
 is defined as an immune response against self
antigens
 The principal factors in the development of
autoimmunity are the inheritance of
susceptibility genes and environmental
triggers, such as infections
 Most autoimmune diseases are polygenic and
are asssociated wih multiple gene loci, the
most important of which are the MHC genes
 Infections may activate self-reactive
lymphocytes, thereby triggering the
development of autoimmune diseases
AUTOIMMUNE PATOLOGICAL
RESPONSE- ETIOLOGY
 the diseases are chronic and usually irreversible
 incidence: 5%-7% of population, higher frequencies in
women, increases with age
 factors contributing to autoimmunity:
- internal (HLA association, polymorphism of cytokine
genes, defect in genes regulating apoptosis,
polymorphism in genes for TCR and H immunoglobulin
chains, association with immunodeficiency, hormonal
factors)
- external (infection, stress by activation of
neuroendocrinal axis and hormonal dysbalance, drug
and ionization through modification of autoantigens)
Type II hypersensitivity
reaction
 IgM and IgG Ab promote the phagocytosis of cells which
they bind, induce inflammation by complement – and Fc
receptor- mediated leukocyte recruitment , and may
interfere with the functions of cells by binding to
essential molecules and receptors.
 Graves‘ disease, Pernicious anemia, Myasthenia
gravis, Acute rheumatic fever, Goodpasture‘s
syndrome, Pemphigus vulgaris, Autoimmune
hemolytic anemia or thrombocytopenic purpura
Type III hypersensitivity
reaction
 Ab may bind to circulating antigens to
form immune complexes, which deposit
in vessels and cause tissue injury.
 Injury is due mainly to leukocyte
recruitment and inflammation.
 Systemic lupus erythematosus,
Polyarteritis nodosa,
Poststreptococcal glomerulonephritis
Type IV hypersensitivity
reaction
 T cell- mediated diseases are caused by
Th1-mediated delayed-type
hypersensitivity reactions or Th17mediated inflammatory reactions, or by
killing of host cells by CD8+ CTLs
(cytotoxic lymphocytes).
 Diabetes mellitus (insulin-dependent),
Rheumatoid arthritis, Multiple
sclerosis, Inflammatory bowel disease
CLINICAL CATEGORIES
 systemic
- affect many organs and tissue
 organoleptic
- affect predominantly one organ
accompanied by affection of other organs
(inflammatory bowel diseases, coeliac
disease, AI hepatitis, pulmonary fibrosis)
 organ specific
- affect one organ or group of organs
connected with development or function
EXAMPLES OF SYSTEMIC
AUTOIMMUNE DISEASES
 examples
 autoantibodies
SYSTEMIC AUTOIMMUNE DISEASES
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Systemic lupus erythematosus
Rheumathoid arthritis
Sjögren‘s syndrome
Dermatopolymyositis
Systemic sclerosis
Mixed connective tissue disease
Vasculitis
SYSTEMIC LUPUS
ERYTHEMATOSUS
 chronic, inflammatory, multiorgan disorder
 autoantibodies react with nuclear material and attack
cell function, immune complexes with dsDNA deposit
in the tissue
 general symptoms: include malaise, fever, weight
loss
 multiple tissue are involved including the skin,
mucosa, kidney, joints, brain and cardiovascular
system
 characteristic features: butterfly rash, renal
involvement, CNS manifestation, pulmonary fibrosis
DIAGNOSTIC TESTS
 a elevated ESR (erythrocyte sedimentation rate), low
CRP, trombocytopenia, leucopenia, hemolytic anemia,
decreased levels of complement compounds (C4, C3),
elevated serum Ig levels, immune complexes in serum
AUTOANTIBODIES
 Autoantibodies: ANA, dsDNA (doublestranded), ENA (SS-A/Ro, SS-B/La), Sm,
against histones, phospholipids
RHEUMATOID ARTHRITIS
 chronic, inflammatory disease with systemic involvement
 characterized by an inflammatory joint lesion in the synovial
membrane, destruction of the cartilage and bone, results in the joint
deformation
 clinical features: arthritis, fever, fatigue, weakness, weight loss
 systemic features: vasculitis, pericarditis, uveitis, nodules under skin,
intersticial pulmonary fibrosis
 diagnostic tests: elevated C- reactive protein
and ESR, elevated serum gammaglobulin levels
- autoantibodies against IgG = rheumatoid factor
(RF), a-CCP (cyclic citrulline peptid), ANA
- X-rays of hands and legs- show a periarticular
porosis, marginal erosion
SJÖGREN‘S SYNDROME
 chronic inflammatory disease affecting exocrine glands
 the primary targets are the lacrimal and salivary gland duct
epithelium
 general features: malaise, weakness, fever
 primary syndrome - features: dry eyes and dry mouth, swollen
salivary glands, dryness of the nose, larynx, bronchi and vaginal
mucosa, involvement kidney, central and periferal nervous
system, arthritis
 secondary syndrome – is associated with others AI diseases
(SLE, RA, sclerodermia, polymyositis, primary biliary cirhosis,AI
thyroiditis)
 autoantibodies against ENA (SS-A, SS-B),
ANA, RF
 The Schirmer test - measures the production
of tears
Dermatopolymyositis
• a connective-tissue disease related to polymyositis (PM) that is
characterized by inflammation of the muscles and the skin.
Gottron's sign is an
Heliotrope rash is a violaceous
erythematous, scaly eruption
eruption on the upper eyelids,
occurring in symmetric fashion often with swelling
over the MCP and
interphalangeal joints
Dermatopolymyositis
 Elevated creatine phosphokinase (CPK)
 muscle biopsy (a mixed B- and T-cell
perivascular inflammatory infiltrate,
perifascicular muscle fiber atrophy)
 EMG (electromyogram)
 autoantibodies - ENA (Jo-1)
Systemic sclerosis
 sclerosis in the skin or other organs
 Diffuse scleroderma (progressive systemic
sclerosis) is the most severe form,
involves skin, will generally cause internal
organ damage (specifically the lungs and
gastrointestinal tract)
 The limited form is much milder
 The limited form is often referred to as
CREST syndrome (CREST is an acronym
for the five main features: Calcinosis,
Raynaud's syndrome, Esophageal
dysmotility, Sclerodactyly, Telangiectasia
Immunological findings
 ANA, ENA - anti-Scl-70 (fluorescence of
nucleolus), anti-centromers
Mixed connective
tissue disease
 combines features of polymyositis, systemic
lupus erythematosus, scleroderma, and
dermatomyositis (overlap syndrome)
 Causes : joint pain/swelling, malaise,
Raynaud phenomenon, muscle inflammation
and sclerodactyly (thickening of the skin of
the pads of the fingers)
 Distinguishing laboratory characteristics:
a positive, speckled anti-nuclear antibody
(ANA) and anti-U1-RNP antibody (ENA)
Vasculitis
 characterized by inflammatory destruction
of vessels leading to thrombosis and
aneurysms
 proliferation of the intimal part of blood-vessel
wall and fibrinoid necrosis
 affect mostly lung, kidneys, skin
 diagnostic tests: elevated ESR, CRP,
leucocytosis, biopsy of affected organ
(necrosis, granulomas), angiography
Vasculitis
 p- ANCA (myeloperoxidase) positivity (Polyarteritis
nodosa, Churg- Strauss, Microscopic polyarteritis
nodosa)
 c- ANCA (serin proteinase) positive (Wegener
granulomatosis, Churg- Strauss syndrome)
Classification
 Large vessel vasculitis (Takayasu arteritis,
Giant cell (temporal) arteritis)
 Medium vessel vasculitis (Polyarteritis
nodosa, Wegener's granulomatosis, Kawasaki
disease)
 Small vessel vasculitis (Churg-Strauss
arteritis, Microscopic polyarteritis, HenochSchönlein purpura)
 Symptoms: fatigue, weakness, fever,
arthralgias, abdominal pain, hypertension,
renal insufficiency, and neurologic dysfunction
EXAMPLES OF ORGANOLEPTIC
AUTOIMMUNE DISEASES
 diseases
 autoantibodies
ORGANOLEPTIC AUTOIMMUNE
DISEASES
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Ulcerative colitis
Crohn‘s disease
Autoimmune hepatitis
Primary biliary cirhosis
Pulmonary fibrosis
Ulcerative colitis
 chronic inflammation of the large intestine
mucosa and submucosa
 features: diarrhea, bloody and mucus stools
 extraintestinal features (arthritis, uveitis)
 autoantibodies against pANCA, a- large
intestine
Crohn‘s disease
 the granulomatous inflammation of whole
intestinal wall with ulceration and scarring
that can result in abscess and fistula
formation
 the inflammation of Crohn's disease the most
commonly affects the terminal ileum, presents
with diarrhea and is accompanied by
extraintestinal features - iridocyclitis, uveitis,
artritis, spondylitis
 antibodies against Saccharomyces
cerevisiae (ASCA), a- pancreas
Primary biliary cirhosis
 autoimmune disease of the liver marked by the slow
progressive destruction of the small bile ducts; can lead to
cirrhosis
 AMA= antimitochondrial autoantibodies
AUTOIMMUNE HEPATITIS
 type I – association with autoantibodies against
smooth muscles SMA, ANA, ANCA, SLA
 type II – autoantibodies against microsomes LKM-1
= liver-kidney microsomes
 type III – autoantibodies against SLA (solubile liver
antigen)
 type IV – overlap syndrome with PBC –
antimitochondrial autoantibodies (AMA)
ORGAN SPECIFIC AUTOIMMUNE
DISEASES
 Autoimmune endocrinopathy
 Autoimmune neurological diseases
 Autoimmune cytopenia
AUTOIMMUNE ENDOCRINOPATHY
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Hashimoto‘s thyroiditis
Graves-Basedow disease
Diabetes mellitus I. type
Addison‘s disease
Autoimmune polyglandular syndrome
Pernicious anemia
Hashimoto‘s thyroiditis
 thyroid disease result to hypothyroidism on the
base of lymphocytes and plasma cells infiltrate
 autoantibodies against thyroidal peroxidase (aTPO) and/or against thyroglobulin (a-TG)
 infiltrate of plasma cells and lymphocytes with
germinal center formation is seen in this thyroid
Grave‘s disease
 thyrotoxicosis from overproduction of thyroid
hormone (patient exhibit fatigue, nervousness,
increased sweating, palpitations, weight loss,
exophtalmus)
 autoantibodies against thyrotropin receptor,
autoantibodies cause thyroid cells proliferation
Diabetes mellitus (insulindependent)
 characterized by an inability to process sugars in
the diet, due to a decrease in or total absence of
insulin production
 results from immunologic destruction of the
insuline- producing β-cells of the islets of
Langerhans in the pancreas
 autoantibodies against GAD- glutamic acid
decarboxylase = primary antigen),
autoantibodies anti- islet cell, anti- insulin
 islets are infiltrated with B and T cells
Polyglandular autoimmune
syndrome
 combination of several different AI
endocrinopathies
 autoantibodies appear in according with the
connected disorders
Pernicious anemia
 the deficiency of the intrinsic factor results in
inadequate and abnormal formation of
erythrocytes and failure to absorb vitamin B12
 clinical feature- atrophic gastritis, macrocytic
anemia
 autoantibodies against parietal cells of gastric
mucose, against intrinsic factor (transportation
of B12 vitamin)
AUTOIMMUNE NEUROPATHY
 Guillain-Barré syndrome (acute idiopathic
polyneuritis)
 Myasthenia gravis
 Multiple sclerosis
Guillain-Barré syndrome
 inflammation demyelinates peripheral neuropathy
that causes progressive muscle weakness and
paralysis
 the cause is the loss of myelin
 occurs often 1-3 weeks after infection
(Campylobacter jej.)
 features: progressive weakness and paresthesia of
the lower and later upper extremitas and respiratory
muscles, weakness can leads to paralysis and
respiratory failure
 immunologic findings: autoantibodies against
ganglioside membrane
Myasthenia gravis
 chronic disease with impaired neuromuscular
transmission
 characterized by muscle weakness and fatigue
 the muscle weakness and neuromuscular
dysfunction result from blockage and depletion
of acetylcholine receptors at the myoneural
junction
 immunological findings: autoantibodies against
Ach receptors
 ptosis of the eye
Multiple sclerosis
 chronic demyelinizing disease with abnormal reaction T
cells to myeline protein on the base of mimicry between a
virus and myeline protein
 features: weakness, ataxia, impaired vision, urinary
bladder dysfunction, paresthesias, mental abberations
 autoantibodies against MOG (myelin-oligodendrocyte
glycoprotein)
 Magnetic resonance imaging of the brain and spine
shows areas of demyelination
 The cerebrospinal fluid is tested for oligoclonal bands,
can provide evidence of chronic inflammation of the
central nervous system
AUTOIMMUNE CYTOPENIA
 AI hemolytic disease- autoantibodies
against membrane erythrocyte antigens
 AI trombocytopenia - autoantibodies against
trombocyte antigens (GPIIb/IIIa)
 AI neutropenia - autoantibodies against
membrane neutrofil antigens
IMMUNOSUPPRESSION
 non-specific treatment
examples of drugs
indication
risks
Immunosuppressants
 Drugs that inhibit or prevent activity of the immune
system
 They are used in immunosuppressive therapy to:
 Prevent the rejection of transplanted organs and
tissues (bone marrow, heart, kidney, liver)
 Treat autoimmune diseases or diseases that are
most likely of autoimmune origin (rheumatoid arthritis,
multiple sclerosis, myasthenia gravis, systemic lupus
erythematosus, Crohn's disease, pemphigus,
ulcerative colitis).
 Treat some other non-autoimmune inflammatory
diseases (allergic asthma, atopic eczema).
Glucocorticoids
 suppress the cell-mediated immunity- act by
inhibiting genes that code for various cytokines
(e.g.IL-2)
 decrease cytokine production reduces the T
cell proliferation.
 suppress the humoral immunity, causing B
cells to express smaller amounts of IL-2 and
IL-2 receptors- this diminishes both B cell clone
expansion and antibody synthesis.
Glucocorticoids
 leads to diminished eicosanoid production,
suppression of the cyclooxygenase expression
 Glucocorticoids also stimulate the lipocortin-1
escaping to the extracellular space, where it
binds to the leucocyte membrane receptors
and inhibits : epithelial adhesion, migration,
chemotaxis, phagocytosis, respiratory burst,
and the release of various inflammatory
mediators from neutrophils, macrophages, and
mastocytes.
 side-effects: hypertension, dyslipidemia,
hyperglycemia, peptic ulcers, osteoporosis,
disturbed growth in children
Drugs affecting the proliferation
of both T cells and B cells
 Cyclophosphamide -very efficient in the
therapy of systemic lupus erythematosus,
autoimmune hemolytic anemias
 high doses cause pancytopenia and
hemorrhagic cystitis
 Methotrexate is a folic acid antagonist, acts
during DNA and RNA synthesis, and thus it is
cytotoxic during the S-phase of the cell cycle;
used in the treatment of autoimmune diseases
(RA, Crohn's disease) and in transplantations.
Drugs affecting the proliferation
of both T cells and B cells
 Azathioprine is a purine synthesis inhibitor,
inhibiting the proliferation of cells, especially
leucocytes; SLE, RA, sclerosis multiplex,
transplantation
 Mycophenolate mofetil – affects the enzyme
that controls the purine synthesis
 Used in transplantation of solid organ
Drugs blocking the activation
of lymphocytes
 Tacrolimus - prevents the cell from transitioning from
the G0 into G1 phase of the cell cycle
 Used to prevent rejection reactions, atopic eczema
 Cyclosporin A- inhibits calcineurin, which is
responsible for activating the transcription of
interleukin-2; inhibits cytokines production and
interleukin release
 Used to prevent rejection reactions
 Side effects: nephrotoxicity, neurotoxicity,
hypertension, dyslipidemia, hyperglycemia
Monoclonal antibodies
 Monoclonal antibodies are directed towards
exactly defined antigens
 Daclizumab - acts by binding the IL-2a
receptor's α chain, preventing the IL-2 induced
clonal expansion of activated lymphocytes and
shortening their survival
 used in the prophylaxis of the acute organ
rejection after the bilateral kidney
transplantation