Transcript Immunodeficiencies and autoimmune diseases

Immunodeficiencies
and
autoimmune diseases
Martin Liška
Immunodeficiencies
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Humoral – innate immunity - complement, MBL
acquired immunity – immunoglobulins (B lymphocytes)
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Cell mediated immunity – innate immunity – phagocytes
- acquired immunity – T lymphocytes
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Primary – congenital, genetically defined, symptoms predominantly
at an early age
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Secondary – the onset of symptoms at any age
chronic diseases
the effects of irradiation
immunosuppression
surgery, injuries
stress
Immunodeficiencies – critical life periods in respect to symptoms
onset
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Newborn age - severe primary disorders of cell mediated immunity
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6 mth. – 2 yrs. – severe humoral immunodeficiencies
cong./transient
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3 - 5 yrs. – transient and selective humoral immunodeficiencies,
secondary immunodeficiencies
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15 – 20 yrs. – hormonal instability, thymus involution, life-style changes,
some typical infections
first symptoms of CVID
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Middleage – often excessive workload, stress
first symptoms of autoimmune disorders (also immunodeficiency)
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Advanced and old age – rather symptoms of severe secondary immunodeficiencies,
repercussion of functional disorders
Immunodeficiencies – major clinical features
• Antibodies - microbial infections (encapsulated bacterias)
respiratory - pneumonia, sinusitis, otitis
GIT – diarrhea
• Complement – microbial infections (pyogenic), sepsis
various systems affection
edema (HAE) – C1-INH deficiency
• T lymphocytes - bacterial, fungal, viral
GIT – diarrhoea
respiratory – pneumonia, sinusitis
• Phagocytes - abscesses, recurrent purulent skin infections
granulomatous inflammations
I. Primary immunodeficiencies – phagocytic cell
defects
1/ Quantitative – decreased numbers of granulocytes –
neutrophil elastase mutation
Congenital chronic agranulocytosis
Cyclic agranulocytosis (neutropenia)
I. Primary immunodeficiencies – phagocytic cell
defects
2/ Qualitative – phagocytes functional disorders, various enzyme deficits,
inability of phagocytes to degrade the ingested material
a/ Chronic Granulomatous Disease (CGD)
• Approximately in 60% X-linked
• Enzymatic inability to generate toxic oxygen metabolites (H2O2) during
oxygen consumption) - result of defect in neutrophilic cytochrome b (part of
complex containing NADPH oxidase)
• Inability to kill bacteria such as Staph.aureus, Pseud.aeruginosa that
produce the enzyme catalase
• Clinical features: granulomas in many organs
• Treatment: long-term ATB administration
I. Primary immunodeficiencies – phagocytic cell
defects
b/Myeloperoxidase deficiency
• Susceptible to Staph.aureus or C.albicans infections
c/Chédiak-Higashi syndrome
• Clinical features: recurrent, severe, pyogenic infections
(streptococcal, staphylococcal)
• Defective intracellular killing of bacteria (neutrophils contain
abnormal giant lysosomes
d/HyperIgE (Job’s) syndrome
• Recurrent “cold” staphylococcal abscesses, chronic eczema,
otitis media
• Extremely high serum IgE levels
II. Primary immunodeficiencies –
B cell disorders
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Bruton’s X-linked hypogamaglobulinemia
Blockage in the maturation of pre-B lymphocytes into B lymphocytes (tyrosine
kinase defect)
Undetectable or very low serum levels of Ig
Pneumonia, pyogenic otitis, complicated sinusitis, increased occurrence of
pulmonary fibrosis
Treatment: life-long IVIG substitution
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CVID – Common Variable ImmunoDeficiency
B cell functional disorder, mostly low levels of IgG and IgA
Symptoms’ onset between 2nd and 3rd decade
Recurrent respiratory tract infections (pneumonia)
Treatment: IVIG substitution
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II. Primary immunodeficiencies –
B cell disorders
Selective IgA deficiency
• Disorder of B cell function
• Recurrent mild/moderate infections (respiratory, GIT, urinary tract) or
asymptomatic
• Risk of reaction to live attenuated vaccines or generation of anti-IgA
antibodies after a blood transfusion
Selective IgG subclasses or specific IgG deficiency
• B cell function disorder
• Onset of symptoms in childhood, mostly respiratory tract infections
caused by encapsulated bacteria (H.influenzae, Pneumococci)
Transient hypogammaglobulinemia of infancy
III. Primary immunodeficiencies –
T cell disorders
diGeorge syndrome
• Disorder of prethymocytes maturation due to absence of thymus (disorder
of development of 3rd and 4th branchial pouch)
• Congenital heart diseases
• The onset of symptoms after the birth – hypocalcemic spasms and
manifestations of cong.heart disease
• Immunodeficiency could be only mild, the numbers of T lymphocytes later
usually become normal
• Treatment symptomatic
IV. Primary immunodeficiencies –
combined defects of T and B cells
SCID – Severe Combined ImmunoDeficiency
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X-linked recessive or AR disease, combined disorder of humoral and cell mediated
immunity
• Severe disorder (patients often die during first 2 years of life), symptoms’ onset
soon after the birth (severe diarrhoea, pneumonia, meningitis, BCGitis)
• Immunological features: typically lymphopenia and thymus hypoplasia
• Forms: AR form – often enzymatic deficiency (ADA, PNP) that leads to accumulation
of metabolites toxic to DNA synthesis (lymphocytes)
X-linked form – disorder of stem-cell
Treatment: ATB, IVIG
BMT is of critical significance
Wiskott-Aldrich syndrome
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trombocytopenia, eczema, recurrent infections (encapsulated microbes), decreased
IgM levels
V. Primary immunodeficiencies –
complement system disorders
Hereditary angioedema (HAE)
• Absence or functional deficiency of C1-inhibitor
• Anaphylactoid reactions with skin and/or mucosal (oral, laryngeal, gut)
edemas caused by C3a a C5a
• Injuries or surgical/stomatological operations are mostly the triggering
factor
• Laryngeal edemas could be life-threatening, immediate treatment is
necessary !
• Treatment: preventive – androgens, EACA
immediate – C1-INH concentrate or fresh frozen plasma
administration
• Secondary forms also exist !
Secondary immunodeficiencies
• Acute and chronic viral infections – infectious mononucleosis, influenza
• Metabolic disorders – diabetes mellitus, uremia
• Autoimmune diseases – autoantibodies against immunocompetent cells
(neutrophils, lymphocytes); autoimmune phenomena also after
administration of certain drugs (e.g. oxacilin, quinidine)
• Chronic GIT diseases
• Malignant diseases (leukemia)
• Hypersplenism/asplenia
• Burn, postoperative status, injuries
• Severe nutritional disorders
• Chronic infections
• Ionizing radiation
• Drug induced immunodeficiencies (chemotherapy)
• Immunosupressive therapy
• Chronic stress
• Chronic exposure to harmful chemical substances
Secondary immunodeficiencies
Chronic fatigue syndrome
• First, it is necessary to exclude all chronic diseases which can lead to
fatigue:
• autoimunity
• malignancy
• focal infection
• neurological disorders
• metabolic disorders
• depression
Secondary immunodeficiencies - A.I.D.S.
• Caused by retrovirus HIV 1 or HIV 2
• Virus has a tropism for cells bearing CD4 surface marker (Th CD4+
lymphocytes); also affects macrophages and CNS cells
• Viral genome transcribes into human DNA and infected cell provides viral
replication
• Transmission: sexual intercourse
contact with blood
endouterine (mother – fetus, breast milk)
• Phases: acute (flu-like sy)
asymptomatic – several years, viral replication
symptomatic – infections, autoimmune disorders, malignancy,
allergy
final – systemic breakdown, opportune infections
A.I.D.S. - Treatment
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Reverse transcriptase inhibitors (e.g.zidovudine)
Protease inhibitors - block the viral protease enzyme
Combined drug therapy
Antimicrobial agents
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
AUTOIMMUNE PATOLOGICAL RESPONSEETIOLOGY
• the diseases are chronic and usually irreversible
• incidence: 5%-7% of population, higher frequencies in
women, increases with age
• factors contribute to autoimmunity:
- internal (HLA association, polymorphism of cytokine genes,
defect in genes regulating apoptosis, polymorphism in genes
for TCR a H immunoglobulin chains, association with
immunodeficiency, hormonal factors)
- external (infection, stress by activation of neuroendocrine
axis and hormonal dysbalance, drug and ionization through
modification of autoantigens)
CLINICAL CATEGORIES
• systemic
- affect many organs and tissue
• organoleptic
- affect predominantly one organ accompanied
by affection of other organs (inflammatory bowel
diseases, celiac disease, AI hepatitis, pulmonary
fibrosis)
• organ specific
- affect one organ or group of organs connected
with development or function
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 (double-stranded),
ENA (SS-A/Ro, SS-A/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
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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, Henoch-Schönlein purpura)
• Symptoms: fatigue, weakness, fever, arthralgias,
abdominal pain, hypertension, renal insufficiency,
and neurologic dysfunction
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
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
AUTOIMMUNE ENDOCRINOPATHY
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Hashimoto‘s thyroiditis
Graves-Basedow disease
Diabetes mellitus I. type
Addison‘s disease
Autoimmune polyglandular syndrome
Hashimoto‘s thyroiditis
• thyroid disease result to hypothyroidism on the base
of lymphocytes and plasma cells infiltrate
• autoantibodies against thyroidal peroxidase (a-TPO)
and/or against thyroglobulinu (a-TG)
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 (insulin- dependent)
• 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 insulineproducing 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
AUTOIMMUNE NEUROPATHY
• Guillain-Barré syndrome (acute idiopathic
polyneuritis)
• Myasthenia gravis
• Multiple sclerosis
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
Immunosuppressive drugs
• 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
• 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
Drugs blocking the activation of
lymphocytes
• 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