Download Autoimmune disease

74. AUTOIMMUNE DISEASES
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
Central and peripheral
tolerance
 Central tolerance is induced by the death
of or other changes in immature
lymphocytes that encounter antigens in
the generative lymphoid organs
 Peripheral tolerance results from the
recognition of antigens by mature
lymphocytes in peripheral tissues
Central tolerance in T
cells
 Central tolerance of T cells is the result of highaffinity recognition of antigens in the thymus
 Some of these self-reactive T cells die
(negative selection), thus eliminating the
potentially most dangerous T cells, which
express high-affinity receptors for self antigens.
 Other Tcells of the CD4+ lineage develop into
regulatory T cell that supress self reactivity in
the periphery
Peripheral tolerance in T
cells
 Peripheral tolerance in T cells is induced by
multiple mechanisms
 Anergy results from the recognition of antigens
without innate immunity and costimulators
 The mechanisms of anergy include a block in
TCR signaling and engagement of inhibitory
receptors
 Self reactive regulatory T cells supress
potentially pathogenic T cell
 Deletion may occure when T cell encounter self
antigens
Central tolerance in B
cells
 central tolerance in B lymphocytes
occurs when immature cells recognize
self antigens in the bone marrow – some
of the cells change their receptors and
others die by apoptosis (negative
selection)
Peripheral tolerance in B
cells
 Is induced when mature B cells
recognize self antigens without T cell
help - this results in anergy and death of
the B cells
Autoimmunity
 is defined as an immune respons against self
antigens
 The principial 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
 disorders are characterized by chronicity and usually
are irreversible
 incidence: 5%-7% of population, higher frequencies in
women, increases with age
 factors contribute to autoimmunity:
- internal (HLA association, polymorfism in genes for
cytokines, defect in genes regulating apoptosis,
polymorphism in genes for TCR a H immunoglobulin
chains, association with immunodeficiencies, hormonal
factors)
- external (infection, stress by activation of
neuroendocrine‘s line and hormonal disbalance, drug
and ionization through modification of autoantigens)
Type II hypersensitivity
reaction
 Ab against cell and tissue antigens may cause tissue
injury and disease
 autoantibodies characterized by a high afinity to
antigens, present in a high level in serum,
predominantly in the IgG class
 autoantibodies against intracelular proteins and nuclear
acid, cytoplasmatic molecules participating in protein
synthesis and expression and regulation of genes
 IgM and IgG Ab promote the phagocytosis of cells which
they bind, induce inflamation 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, Myastenia
gravis, Acute rheumatic fever, Goodpasture‘s
syndrome, Pemphigus vulgaris, Autoimmune
hemolytic anemia or trombocytopenic 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
 organ localised
- affect predominantly one organ
accompained by affection of other organs
(nonspecific bowel diseases, celiatic disease,
AI hepatitis, pulmonary fibrosis)
 organ specific
- affect one organ or group of organs
connected with development or function
75. 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
Antiphospholipid syndrome
Vasculitis
Sarcoidosis
SYSTEMIC LUPUS
ERYTHEMATOSUS
 chronic, inflammatory, multiorgan disorder
 predominantly affects young women
 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, leukopenia, hemolytic anemia,
depresed levels of complement (C4, C3), elevated
serum gamma globulin levels, immune complexes in
serum
AUTOANTIBODIES
 Autoantibodies: ANA, dsDNA (doublestranged), ENA (SS-A/Ro, SS-A/La), Sm,
against histones, phospholipids
RHEUMATOID ARTHRITIS
 chronic, inflammatory joint disease with systemic involvement
 predominantly affects women
 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
Rtg: symmetrical destruction
of proximal joints, erosion of
carpal bones, distal
radioulnar
joints
SJÖGREN‘S SYNDROME
 chronic inflammatory disease that affects the exocrine glands
 the primary targetsare 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,
artritis
 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
Systemic sclerosis
 sclerosis in the skin or other organs
 Diffuse scleroderma (progressive systemic
sclerosis)
is the most severe form - it has a rapid onset,
involves more widespread skin hardening, will
generally cause much internal organ damage
(specifically the lungs and gastrointestinal tract
 The limited form is much milder
 The scleroderma may be limited to the fingers known as sclerodactyly.
 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, Sclerodactyy, 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, and is thus considered an
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 an anti-U1-RNP antibody (ENA)
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)
Antiphospholipid
syndrome
 autoimmune disease characterized by vein and
arterial thrombosis, repeated abortions
 accompanied by anti-phospholipid
autoantibodies (APA) and antibodies against
β2-glykoprotein I
Vasculitis
 characterized by inflammatory destruction
of the bloodstream leads into thrombosis and
aneurysma
 proliferation of the intimal part of blood-vessel
wall and fibrinoid necrosis
 affect mostly lung, kidneys, skin
 diagnostic tests: elevated ESR, CRP,
leukocytosis, biopsy of affected organnecrosis, granulomas, angiography
Vasculitis
 p- ANCA (myeloperoxidase) positivity (Polyarteritis
nodosa, Churg- Strauss, Microscopic polyartheritis
nodosa, Good- Pasture‘s syndrome, Kawasaki
syndrome)
 c- ANCA (serin. proteinase) positivity (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, HenochSchonlein purpura)
 Complaints include fatigue, weakness, fever,
arthralgias, abdominal pain, hypertension,
renal insufficiency, and neurologic dysfunction
•Giant cell (temporal) arteritis
• Temporal artery tenderness or
decreased pulsation
Angiography of a.temporalis
Biopsy showing vasculitis with mononuclear
cell infiltrate, usually with multinucleated
giant cells
Sarcoidosis
 multisystem disorder characterized by noncaseating granulomas
 granulomas most often appear in the lungs or
the lymph nodes
 cause of sarcoidosis is not known
 fatigue, weight loss, arthralgia, shortness of
breath, a dry cough, skin lesions, bilateral
hilar lymphadenopathy
 Hypercalcemia, high level of ACE
(angiotensin converting enzyme)
76. EXAMPLES OF ORGANSPECIFIC AUTOIMMUNE
DISEASES
 diseases
 autoantibodies
ORGANOLEPTIC AUTOIMMUNE
DISEASES
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Ulcerative colitis
Crohn‘s disease
Coeliac disease
Autoimmune hepatitis
Primary biliary cirhosis
Primary sclerotic cholangoitis
Pulmonary fibrosis
Ulcerative colitis
 chronic inflammation of the large intestine
mucose and submucose
 features: diarrhea mixed with blood and mucus
 extraintestinal features (artritis, uveitis)
 autoantibodies against pANCA, a- large
intestine
Crohn‘s disease
 the granulomatous inflammation of all
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
Coeliac disease
 a malabsorption syndrome characterized by marked
atrophy and loss of function of the villi of the jejunum
 inflammatory bowell disease arise from gliadin
exposition
 autoantibodies against endomysium, the most
specific = tissue transglutaminaze; antibodies
against gliadin are nonspecific
 biopsy of the jejunum with findings of the villi atrophy
 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
 Primary sclerotic cholangoitis
 a chronic disorder of the liver in which the bile ducts become
inflamed, thickened, scarred (sclerotic), and obstructed
 process can in time destroy the bile ducts and lead to
cirrhosis
 pANCA
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 –
autoantibodies against mitochondries AMA
Pulmonary fibrosis
 is associated with SLE, RA, systemic
sclerosis, polymyositis
 autoantibodies nonspecific- RF, ANA, others
autoantibodies in according with associate
disease
 biopsy, spirometry, X-ray
ORGAN SPECIFIC AUTOIMMUNE
DISEASES
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Autoimmune endocrinopathy
Autoimmune neurological diseases
Autoimmune cytopenia
Autoimmune cutaneous diseases
Autoimmune eye diseases
AUTOIMMUNE ENDOCRINOPATHY
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Hashimoto‘s thyroiditis
Graves-Basedow disease
Postpartum thyroiditis
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 thyroglobulinu (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,
exophtalmos)
 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
Addison‘s disease
 a disorder involving disrupted functioning of the
adrenal cortex, this resullt in decreased
production of cortisol and aldosterone
 features malaise, pain of muscle and joint,
hyperpigmentation
 autoantibodies against adrenal cortex and/or
21-hydroxylase, autoantibodies against 17hydroxylase
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 intristic factor (transport vit.
B12)
AUTOIMMUNE NEUROPATHY
 Guillain-Barré syndrome (acute idiopathic
polyneuritis)
 Myasthenia gravis
 Multiple sclerosis
Guillain-Barre syndrome
 inflammatory demyelinate 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 (cross-react with
Campylobacter jejuni lipopolysacharids)
Myasthenia gravis
 chronic disease resulting from faulty
neuromuscular transmission
 characterized by muscle weakness and fatigue
 the muscle weakness and neuromuscular
dysfunction result from blockage and depletion
of acetylcholin receptors at the myoneural
junction
 immunological findings: autoantibodies against
Ach receptors
 ptosis of the eye
Multiple sclerosis
 chronic demyeline 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 DISORDERS OF
REPRODUCTIVE ORGANS
 Autoimmune men‘s infertility = autoimmune
orchitis
- autoantibodies against sperms
 Premature Ovarian Failure
= lymphocytic oophoritis
- autoantibodies against enzymes participate in
steroidogenesis
- autoantibodies against 17-hydroxylase,
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
EYE DISEASE
 Uveitis
- the autoreactive T cells react with retinal S
autoantigen
Bullous pemphigoid
 an autoimmune bullous disease of the skin
and mucosa
 the blisters form beneath the epidermis at the
dermal- epidermal junction
 lesions demonstrate deposition of antibody
and complement along skin basement
membrane
 circulating antibasement membrane
antibodies also can be detected
Pemphigus vulgaris
 an erosive disease of the skin and mucous
membranes characterized by intraepidermal
blisters
 skin lesions show antibody (mainly IgG)
deposition and complement components in
squamous intercellular spaces (when
examined by imunofluorescence)
Dermatitis herpetiformis (Duhring)
 autoimmune disease affect skin, associate with
coeliac disease
 autoantibodies against endomysium, more
specific against tissue transglutaminaze
 biopsy of skin: IgA deposition on the dermal
papilles
 biopsy of jejunum/duodenum:
atrophy of the intestine villi
Psoriasis
 Disorder which affects the skin and joints,
commonly causes red scaly patches to appear
on the skin
 T cells become active, migrate to the dermis
and trigger the release of cytokines which
cause inflammation and the rapid production of
skin cells
 It is not known what initiates the activation of
the T cells
77. IMMUNOSUPRESSION
 non-specific treatment
examples of drugs
indication
risks
Immunosuppressants
 are 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 the cytokines IL1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-γ,
the most important of which is the IL-2
 Smaller 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,
supression of the cyclooxygenase expression
 Glucocorticoids also stimulate the lipocortin-1
escaping to the extracellular space, where it
binds to the leukocyte 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, Wegener's
granulomatosis
 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, psoriasis) 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
leukocytes; 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
 Sirolimus - affects the signal transduction of T cells
and their clonal proliferation
 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
Immunosuppressionkidney transplantation
 Prevent the acute kidney rejection, tend to
eliminate side effects
 Induction by daclizumab
 Therapy: Glucocorticoids + mycophenolate mofetil
+ tacrolimus (or cyclosporin A)