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IgG and IgM based immunopathological reaction (reaction of hypersensitivity type II).

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Title: IgG and IgM based immunopathological reaction (reaction of hypersensitivity type II).


1
IgG and IgM based immunopathological reaction
(reaction of hypersensitivity type II).
  • antibody-dependent
  • antibodies produced by the immune response bind
    to antigens on the patient's own cell surfaces
  • intrinsic ("self" antigen, innately part of the
    patient's cells)
  • extrinsic (absorbed onto the cells during
    exposure to some foreign antigen, possibly as
    part of infection with a pathogen)
  • These cells are recognized by macrophages or
    dendritic cells which act as antigen presenting
    cells, this causes a B cell response where
    antibodies are produced against the foreign
    antigen.

2
IgG and IgM based immunopathological reaction
(reaction of hypersensitivity type II)
  • Autoimmune hemolytic anemia
  • Goodpasture's syndrome
  • Autoimmune pernicious anemia
  • Immune thrombocytopenia
  • Transfusion reactions
  • Myasthenia gravis
  • Rheumatic fever
  • Acute transplant rejection

3
Immune complex based immunopathological reaction
(reaction of hypersensitivity type III)
  • occurs when antigens and antibodies are present
    in roughly equal amounts, causing extensive
    cross-linking
  • large immune complexes that cannot be cleared are
    deposited in vessel walls and induce an
    inflammatory response
  • the reaction can take hours, days, or even weeks
    to develop

4
Immune complex based immunopathological reaction
(reaction of hypersensitivity type III)
  • Some clinical examples
  • Rheumatoid arthritis
  • Immune complex glomerulonephritis
  • Serum sickness
  • Subacute bacterial endocarditis
  • Systemic lupus erythematosus
  • Farmer's lung (Arthus-type reaction)
  • Polyarteritis nodosa

5
PRIMARY IMMUNODEFICIENCY
  • clinical manifestactions
  • examples

6
IMMUNODEFICIENCY
  • Primary immunodeficiencies
  • - congenital, genetically defined disorders
  • - onset of symptoms - predominantly at an
    early
  • age
  • Secondary immunodeficiencies
  • - caused by chronic infections, irradiation,
  • injuries, immunosupression therapy,
    surgery,
  • stress
  • - disorders appear at any age

7
IMMUNIDEFICIENCY
  • Humoral deficiency disorders
  • the B cell deficiency disorders the
    qualitative or quantitative defects of the B
    cells, present 70 of IDs
  • T cell deficiency disorders and the combined
    B-cell and T-cell deficiency disorders (20)
    group of the qualitative or quantitative defects
    of the T and B cells
  • Phagocytic cell disorders group of the
    qualitative or quantitative defects of the
    fagocytic cells (10)
  • Complement disorders caused by the deficiency
    of the complement components or functions (lt1)

8
MAJOR CLINICAL FEATURES
  • Humoral deficiency disorders - manifest as the
    recurrent bacterial sinopulmonary and
    gastrointestinal infections
  • - caused by streptococcus, staphylococcus,
    haemophilus, begin when infants are 5-9 months of
    age
  • T cell disorders - manifest as the recurrent
    bacterial, fungal and viral respiratory and
    gastrointestinal infection
  • Complement disorders are associated with
    increased incidence of the infections and
    autoimmune diseases and with edema in the case of
    hereditary angioedema
  • Phagocytic cell disorders characterized by
    recurrent infections caused by various organisms
    incluging abscesses, purulent skin infections,
    granulomatous inflammations

9
HUMORAL DEFICIENCY DISORDERS
  • Brutons X-linked hypogamaglobulinemia
  • CVID - Common Variable ImmunoDeficiency
  • Selective immunoglobulin A deficiency lt0,07 g/l

10
Brutons X-linked hypogamaglobulinemia
  • the genetic defect on the X chromosome leads to
    the defective function of a tyrosine kinase in
    the B cells
  • This defect result in a block of the pre-B cells
    maturation into the B cells with surface IgM
  • the immunologic findings lt 2 circulating B
    cells
  • - low serum levels of all
    classes of immunoglobulins
  • - number and function of T
    cells are intact
  • - pre-B cells are in the bone
    marrow
  • features begining from 5-9 months of age
  • - manifests as recurrent bacterial
    sinopulmonary and gastrointestinal infection
    caused by streptococcus, staphylococcus,
    haemophilus, meningococcus, salmonella,
    campylobacter, giardia
  • Treatment consists of life-long intravenous
    pooled human gammaglobulin replacement and
    antibiotics.

11
Common Variable ImmunoDeficiency
  • the B cell functional disorder characterized by
    the normal number
  • of the B cells, low levels of IgG and IgA, a
    poor response to all
  • vaccines and decrease of the T cells (CD4)
    number and function
  • the symptoms onset between 2nd and 3rd decade
  • the clinical features
  • - recurrent respiratory tract infections
    (pneumonia), cutaneous and
  • gastrointestinal infection
  • - disease is accompanied by occurrence of
    the granulomas,
  • lymphadenopathy, splenomegaly
  • Treatment consist of the intramuscular or
    intravenous
  • gammaglobulin replacement.

12
Selective deficiency of IgA
  • level of IgA up to 0,05 g/l, age gt 4 years
  • the most frequent primary ID
  • - stem cell defect
  • - repeated infections of respiratory tract
  • - susceptibility to autoimmune disorders,
    malignant disorders, allergy
  • - contra-indication of administration of drug
    with IgA

13
T cell deficiency disorders
  • DiGeorge syndrome
  • - the genetic defect on the chromosome 22
    leads to disorder of
  • development of 3rd and 4th branchial
    pouch with congenital
  • hypoplasia of both the thymus and
    parathyroid glands
  • - patients suffer from disorder of
    pre-thymocytes maturation due to
  • absence/hypoplasia of thymus
  • - syndrome CATCH 22 cardiac defects,
    abnormal facies, thymic
  • hypo/aplasia, cleft palate, hypocalcemia,
    deletion 22q11.2
  • - the symptoms onset soon after the birth
    hypocalcemic spasms
  • and manifestations of congenital heart
    disease
  • - treatment symptomatic, transplantation
    of a thymus

14
PRIMARY FAGOCYTIC CELL DEFECTS
  • Chronic granulomatous disease
  • - X- linked recesive disorder - leads to
    defect in neutrophilic cytochrome b with
    suppresion of intracellular killing of ingested
    microorganisms
  • - normal number of leucocytes
  • - infection of catalase-positive bacterias
  • - symptoms appear in the first year of age
    pyogenic cutaneous
  • infections, abscesses, granulomas in many
    organs, pyogenic
  • lymphadenitis
  • - treatment long-term ATB administration,
    interferon gamma,
  • corticosteroids

15
COMPLEMENT DEFICIENCY
  • C2, C3, C4 complement components deficiencies
  • - lead to an impaired opsonization,
    susceptibility to infections,
  • autoimune diseases
  • C6, C7, C8, C9 complement components deficiencies
  • - lead to the autoimmune diseases SLE,
    RA, sclerodermia and to
  • the neisserial infection
  • MBL deficiencies
  • - lead to the respiratory infections and
    susceptibility to the
  • autoimune and allergy diseases
  • Treatment vaccination, ATB

16
HEREDITARY ANGIOEDEMA
  • pathophysiology
  • clinical manifestations
  • treatment

17
HEREDITARY ANGIOEDEMA
  • the congenital AD complement disorder cased by
    the defect on the chromosome 11
  • leads to absence or functional deficiency of
    C1-inhibitor
  • C4 a C2 complement components show a low level
  • during atack
  • Type I - occurs in 85
  • - an absence of C1-inhibitor
  • Type II - occurs in 15
  • - a functional deficiency of
    C1-inhibitor
  • Secondary - SLE, lymfoma

18
HEREDITARY ANGIOEDEMA
  • C1 esterase inhibitor deficiency leads to
    uncontrolled C1 activity and resultant production
    of a kinin that increases capillary permeability
  • Clinical feature transient recurrent localized
    edema
  • the triggering factors injuries or
    surgical/stomatological operations
  • more offen occures in pregnancy
  • laryngeal edema could be life-threatening,
    immediate treatment is necessary !

19
TREATMENT
  • Preventive consist of an administration of
    androgens, a-fibrinolytics
  • - before operation is necessary C1-INH
    concentrate or a
  • fresh frozen plasma administration
  • - stomatology procedures are performed in
    hospital
  • Immediate - C1-INH concentrate or fresh frozen
    plasma administration
  • tracheotomy in severe larynx edema
  • treatment with ACE inhibitors is contraindicated

20
ACQUIRED IMMUNODEFICIENCIES
  • causes
  • mechanisms involved
  • AIDS

21
ACQUIRED IMMUNODEFICIENCIES
  • Acute and chronic viral infections EBV, CMV,
    herpetic virus, influenza, HIV
  • Metabolic disorders diabetes, renal failure,
    disorder of liver function
  • Autoimmune diseases autoantibodies against
    immunocompetent cells (neutrophils, lymphocytes)
  • Allergic diseases
  • Chronic GIT diseases, nephrotic syndrome
  • Malignant diseases (leukemia, lymphoma, myeloma)
  • Hypersplenism/asplenia, splenectomy deficiency
    in generation of antibodies against encapsulated
    microorganisms (Pneumococcus, Neisseria)
  • Burn, postoperative status, injuries
  • Severe nutritional disorders, chronic stress
  • Drug induced immunodeficiencies (chemotherapy),
    immunosupression
  • Chronic exposure to harmful chemical substances,
    ionizing radiation

22
AIDS
  • Acquired ImmunoDeficiency Syndrom
  • - caused by a retrovirus called human
    immunodeficiency virus
  • - current incidence 40 mil.people, predominantly
    in central Africa, CZ about 1000 infected
    people
  • viral transmission occurs through
  • - sexual intercourse
  • - contact with blood
  • - transplacentally, during the birth
    process or
  • through a breast milk

23
VIRUS HIV-1
  • virion is consisted of a capside with marrow
    protein - p24 and RNA
  • RNA is copied into double-stranded DNA using
    reverse transcriptase
  • virus integrates to the human cell genome and
    arise a provirus
  • an activation of provirus leads to the
    replication of viral nuclear acid and genesis of
    a virion that goes through the cell membrane and
    caused the lysis of cell

24
PRIMARY INFECTION
  • Infection - begins by HIV-1 with a tropism for
    macrofages
  • - the membrane molecules of dendritic cells
    bind
  • glycoproteins on HIV-1 surface and transport
    viruses to the lymphatic nodes (LN), where
    activated T cells are infected viruses
    are replicated in the lymphatic nodes and
    transfer to the blood
  • features malaise, fever, pain of muscles and
    joints, sweating, loss of appetite, vomiting,
    diarrhoea, rash, lymphadenopathy
  • Immunological findings elevated C-reactive
    protein, lymphopenia, decrease of CD4 cells
  • specific antibodies against HIV-1 dont generate
  • identification of viruses is performed by PCR or
    by the evidence of viral protein p24 presence

25
ASYMPTOMATIC PERIODE
  • asymptomatic period HIVs-1 with a tropism for
    macrophages are changed into viruses with a
    tropism for T cells and demage T cells (CD4)
  • viruses replicate in cell secondary lymphatic
    organs
  • - the period can last a several years
  • lasting depends on
  • - virus doses and virulence
  • - an individual condition of immune system
    an infected
  • person
  • - an acceleration occures by repeated
    infection of
  • different HIVs

26
AIDS
  • AIDS- Related Complex (ARC) presents with
    lymphadenopathy and comes before fully developed
    AIDS
  • Clinical features of AIDS
  • - candidiasis of mouth and esophagous
  • mucose, colpitis
  • - oral leucoplakia, opportunistic
    infections
  • - Kaposi sarcoma, non-Hodgkins lymfoma

27
VACCINE
  • development of a vaccine is unsuccessful
  • due to
  • - unsuccesful searching for a dominant
    viral antigen
  • - variability of the viruses HIV-1 in the
    course of time
  • - absence of an animal experimental model
    (even the
  • primates infection course isnt
    identical with human)

28
TREATMENT
  • Inhibitors of reverse transcriptase - 2 types
  • Inhibitor of viral protease
  • Therapy result to the inhibition of DNA
    synthesis, stop the progress of the disease and
    prolong the life of HIV infected persons

29
IMMUNOGLOBULIN REPLACEMENT THERAPY
  • Indication
  • Contra-indication
  • Adverse reaction

30
IVIG is approved for treating
  • X-linked Bruton agammaglobulinemia
  • Common Variable ImmunoDeficiency
  • others

31
CONTRA-INDICATIONS
  • Repeated severe side effects
  • Selective IgA deficiency with anaphylactic
    reaction to immunoglobuline
  • Severe acute infection

32
IG ADMINISTRATION
  • Intramuscullar maximum dose 1,5 g IgG/ week
  • Subcutaneous total dose/month 400mg/kg,
    administration every week
  • Intravenous - 400 mg/kg/month

33
AUTOIMMUNE DISORDERS
  • examples

34
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

35
EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES
  • examples
  • autoantibodies

36
SYSTEMIC AUTOIMMUNE DISEASES
  • Systemic lupus erythematosus
  • Rheumathoid arthritis
  • Sjögrens syndrome
  • Dermatopolymyositis
  • Systemic sclerosis
  • Mixed connective tissue disease
  • Antiphospholipid syndrome
  • Vasculitis
  • Sarcoidosis

37
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

38
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

39
AUTOANTIBODIES
  • Autoantibodies ANA, dsDNA (double-stranged), ENA
    (SS-A/Ro, SS-A/La), Sm, against histones,
    phospholipids

40
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

41
Antiphospholipid syndrome
  • autoimmune disease characterized by vein and
    arterial thrombosis, repeated abortions
  • accompanied by anti-phospholipid autoantibodies
    (APA) and antibodies against ß2-glykoprotein I

42
EXAMPLES OF ORGAN- SPECIFIC AUTOIMMUNE DISEASES
  • diseases
  • autoantibodies

43
ORGANOLEPTIC AUTOIMMUNE DISEASES
  • Ulcerative colitis
  • Crohns disease
  • Coeliac disease
  • Autoimmune hepatitis
  • Primary biliary cirhosis
  • Primary sclerotic cholangoitis
  • Pulmonary fibrosis

44
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

45
Crohns 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

46
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

47
ORGAN SPECIFIC AUTOIMMUNE DISEASES
  • Autoimmune endocrinopathy
  • Autoimmune neurological diseases
  • Autoimmune cytopenia
  • Autoimmune cutaneous diseases
  • Autoimmune eye diseases

48
AUTOIMMUNE ENDOCRINOPATHY
  • Hashimotos thyroiditis
  • Graves-Basedow disease
  • Postpartum thyroiditis
  • Diabetes mellitus I. type
  • Addisons disease
  • Autoimmune polyglandular syndrome
  • Pernicious anemia

49
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 thyroglobulin (a-TG)

50
Graves 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

51
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

52
AUTOIMMUNE NEUROPATHY
  • Guillain-Barré syndrome (acute idiopathic
    polyneuritis)
  • Myasthenia gravis
  • Multiple sclerosis

53
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

54
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-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

55
IMMUNOSUPRESSION
  • non-specific treatment
  • examples of drugs
  • indication
  • risks

56
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
  • Treat autoimmune diseases
  • Treat some other non-autoimmune inflammatory
    diseases (allergic asthma, atopic eczema)

57
Glucocorticoids
  • suppress the cell-mediated immunity
  • cytokine production
  • suppress the humoral immunity
  • side-effects hypertension, dyslipidemia,
    hyperglycemia, peptic ulcers, osteoporosis,
    disturbed growth in children

58
  • Drugs affecting the proliferation of both T cells
    and B cells - Cyclophosphamide, Methotrexate,
    Azathioprine, Mycophenolate mofetil
  • Drugs blocking the activation of lymphocytes
    Tacrolimus, Sirolimus, Cyclosporin A
  • Monoclonal antibodies - Daclizumab
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