igg and igm based immunopathological reaction (reaction of hypersensitivity type ii)
DESCRIPTION
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). - PowerPoint PPT PresentationTRANSCRIPT
IgG and IgM based immunopathological reaction (reaction of hypersensitivity type II).
antibodies produced by the immune response bind to antigens on the patient's own cell surfaces
•= antibody-dependent
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.
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
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
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
PRIMARY IMMUNODEFICIENCY
clinical manifestactions examples
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
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 (<1%)
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
HUMORAL DEFICIENCY DISORDERS
Bruton’s X-linked hypogamaglobulinemiaCVID - Common Variable
ImmunoDeficiencySelective immunoglobulin A deficiency
<0,07 g/l
Bruton’s 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: < 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.
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 symptom’s 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.
Selective deficiency of IgA
level of IgA up to 0,05 g/l, age > 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
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 symptom’s onset soon after the birth – hypocalcemic spasms and manifestations of congenital heart disease - treatment: symptomatic, transplantation of a thymus
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
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
HEREDITARY ANGIOEDEMA
pathophysiology clinical manifestations
treatment
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
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 !
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
ACQUIRED IMMUNODEFICIENCIES
causes mechanisms involved
AIDS
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
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
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
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 don‘t generate identification of viruses is performed by PCR or by the
evidence of viral protein p24 presence
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
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-Hodgkin‘s lymfoma
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
primate‘s infection course isn‘t identical with human)
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
IMMUNOGLOBULIN REPLACEMENT THERAPY
IndicationContra-indicationAdverse reaction
IVIG is approved for treating
X-linked Bruton agammaglobulinemia
Common Variable ImmunoDeficiency
others
CONTRA-INDICATIONS
Repeated severe side effects
Selective IgA deficiency with anaphylactic reaction to immunoglobuline
Severe acute infection
IG ADMINISTRATION
Intramuscullar – maximum dose 1,5 g IgG/ week
Subcutaneous – total dose/month 400mg/kg, administration every week
Intravenous - 400 mg/kg/month
AUTOIMMUNE DISORDERS
examples
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
EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES
examples autoantibodies
SYSTEMIC AUTOIMMUNE DISEASES
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
AUTOANTIBODIES
Autoantibodies: ANA, dsDNA (double-stranged), 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
Antiphospholipid syndrome
autoimmune disease characterized by vein and arterial thrombosis, repeated abortions
accompanied by anti-phospholipid autoantibodies (APA) and antibodies against β2-glykoprotein I
EXAMPLES OF ORGAN- SPECIFIC AUTOIMMUNE DISEASES
diseases autoantibodies
ORGANOLEPTIC AUTOIMMUNE DISEASES
Ulcerative colitisCrohn‘s diseaseCoeliac diseaseAutoimmune hepatitisPrimary biliary cirhosisPrimary sclerotic cholangoitisPulmonary 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
ORGAN SPECIFIC AUTOIMMUNE DISEASES
Autoimmune endocrinopathy Autoimmune neurological diseases Autoimmune cytopenia Autoimmune cutaneous diseases Autoimmune eye diseases
AUTOIMMUNE ENDOCRINOPATHY
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 (a-
TPO) and/or against thyroglobulin (a-TG)
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 (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 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
AUTOIMMUNE NEUROPATHY
Guillain-Barré syndrome (acute idiopathic polyneuritis)
Myasthenia gravis
Multiple sclerosis
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
IMMUNOSUPRESSION
non-specific treatmentexamples of drugs
indicationrisks
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)
Glucocorticoids
suppress the cell-mediated immunity
cytokine production
suppress the humoral immunityside-effects: hypertension, dyslipidemia,
hyperglycemia, peptic ulcers, osteoporosis, disturbed growth in children
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