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Immunodeficiencies and autoimmune diseases

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Title: Immunodeficiencies and autoimmune diseases


1
Immunodeficiencies andautoimmune diseases
  • Martin Liška

2
Immunodeficiencies
  • Humoral innate immunity - complement, MBL
  • acquired immunity
    immunoglobulins (B lymphocytes)
  • Cell mediated immunity innate immunity
    phagocytes
  • -
    acquired immunity T lymphocytes
  • Primary congenital, genetically defined,
    symptoms predominantly
  • at an early age
  • Secondary the onset of symptoms at any age
  • chronic diseases
  • the effects of
    irradiation
  • immunosuppression
  • surgery, injuries
  • stress

3
Immunodeficiencies critical life periods in
respect to symptoms onset
  • Newborn age - severe primary disorders of cell
    mediated immunity
  • 6 mth. 2 yrs. severe humoral
    immunodeficiencies
  • cong./transient
  • 3 - 5 yrs. transient and selective humoral
    immunodeficiencies,
  • secondary
    immunodeficiencies
  • 15 20 yrs. hormonal instability, thymus
    involution, life-style changes,
  • some typical
    infections
  • first symptoms of
    CVID
  • Middleage often excessive workload, stress
  • first symptoms of
    autoimmune disorders (also immunodeficiency)
  • Advanced and old age rather symptoms of severe
    secondary immunodeficiencies,

  • repercussion of functional disorders

4
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

5
I. Primary immunodeficiencies phagocytic cell
defects
  • 1/ Quantitative decreased numbers of
    granulocytes neutrophil elastase mutation
  • Congenital chronic agranulocytosis
  • Cyclic agranulocytosis (neutropenia)

6
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

7
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 (Jobs) syndrome
  • Recurrent cold staphylococcal abscesses,
    chronic eczema, otitis media
  • Extremely high serum IgE levels

8
II. Primary immunodeficiencies B cell disorders
  • Brutons 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
  • 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

9
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

10
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

11
IV. Primary immunodeficiencies combined
defects of T and B cells
  • SCID Severe Combined ImmunoDeficiency
  • 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
  • trombocytopenia, eczema, recurrent infections
    (encapsulated microbes), decreased IgM levels

12
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 !

13
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

14
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

15
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

16
A.I.D.S. - Treatment
  • Reverse transcriptase inhibitors (e.g.zidovudine)
  • Protease inhibitors - block the viral protease
    enzyme
  • Combined drug therapy
  • Antimicrobial agents

17
AUTOIMMUNE DISEASES
18
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

19
AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY
  • 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)

20
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

21
SYSTEMIC AUTOIMMUNE DISEASES
  • Systemic lupus erythematosus
  • Rheumathoid arthritis
  • Sjögrens syndrome
  • Dermatopolymyositis
  • Systemic sclerosis
  • Mixed connective tissue disease
  • Vasculitis

22
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

23
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

24
AUTOANTIBODIES
  • Autoantibodies ANA, dsDNA (double-stranded), ENA
    (SS-A/Ro, SS-A/La), Sm, against histones,
    phospholipids

25
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

26
SJÖGRENS 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

27
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 erythematous, scaly eruption
occurring in symmetric fashion over the MCP and
interphalangeal joints
Heliotrope rash is a violaceous eruption on the
upper eyelids, often with swelling
28
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)

29
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

30
Immunological findings
  • ANA, ENA - anti-Scl-70 (fluorescence of
    nucleolus), anti-centromers

31
Mixed connective tissue disease
  • combines features of polymyositis, systemic lupus
    erythematosus, scleroderma, and dermatomyositis
    (overlap syndrome)
  • Symptoms 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)

32
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

33
Vasculitis
  • p- ANCA (myeloperoxidase) positivity
    (Polyarteritis nodosa, Churg- Strauss,
    Microscopic polyarteritis nodosa)
  • c- ANCA (serin proteinase) positive (Wegener
  • granulomatosis, Churg- Strauss syndrome)

34
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

35
ORGANOLEPTIC AUTOIMMUNE DISEASES
  • Ulcerative colitis
  • Crohns disease
  • Autoimmune hepatitis
  • Primary biliary cirhosis
  • Pulmonary fibrosis

36
Ulcerative colitis
  • chronic inflammation of the large intestine
    mucosa and submucosa
  • features diarrhea, bloody and mucus stools
  • extraintestinal features (arthritis, uveitis)
  • Autoantibodies pANCA, a- large intestine

37
Crohns 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

38
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

39
AUTOIMMUNE ENDOCRINOPATHY
  • Hashimotos thyroiditis
  • Graves-Basedow disease
  • Diabetes mellitus I. type
  • Addisons disease
  • Autoimmune polyglandular syndrome

40
Hashimotos 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)

41
Graves 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

42
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
    insuline- producing ß-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

43
Polyglandular autoimmune syndrome
  • combination of several different AI
    endocrinopathies
  • autoantibodies appear in according with the
    connected disorders

44
AUTOIMMUNE NEUROPATHY
  • Guillain-Barré syndrome (acute idiopathic
    polyneuritis)
  • Myasthenia gravis
  • Multiple sclerosis

45
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-oligodendrocyt
    e 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

46
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

47
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).

48
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

49
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.

50
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

51
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

52
Monoclonal antibodies
  • Monoclonal antibodies are directed towards
    exactly defined antigens
  • Daclizumab - acts by binding the IL-2a receptor's
    a 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
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